Case: A 66-year-old man who received multiple lines of therapy for chronic lymphocytic leukemia (CLL) without undergoing mutational testing is ultimately determined to harbor a 17p deletion

MS GOODRICH: He was diagnosed in 2006 with his CLL. He got a lot of standard therapies. He got just about everything under the sun. He was 55 at the time, so he got FCR at that time.

He relapsed several years later. He got BR. He got idelalisib and rituximab and had colitis. And they did not rechallenge him. He had some GI bleeding as well at that point in time. Then he went on to get obinutuzumab. And when he came to us, he was really sick. He was having fevers. He had huge lymph nodes. His counts were not horrible, but he was just diaphoretic continuously. He was a guy who wasn’t going to brew long. He really needed something.

And as we went through his records, we realized he had never had mutational testing done. He had never had FISH studies done. So he certainly is someone who when you look at his history probably started out with normal or favorable cytogenetics and then over time became less and less responsive to therapy, including things that should work with 17p, like the idelalisib, like the ofatumumab.

So we at that time, because he had had this relatively recent history of GI bleeding, his local doctor gave him an ibrutinib script. And his wife, who is really very — she’s a great historian. She really is all over this. She looked at the side effects and said, “He’s not taking this. It’s time for us to really get another opinion,” and so they came to Hopkins.

And fortunately at that time, venetoclax was available.

DR LOVE: This was June of 2016.

MS GOODRICH: Correct.

DR LOVE: And was he working? What was his quality of life like?

MS GOODRICH: No. He was not working. He had retired by that time. He was a guy who really liked to be outdoors. He was an avid gardener and really had stopped doing everything, right? Literally had stopped doing everything. He was on the sofa all day long. His fatigue was really life altering. So again, he was somebody who needed treatment.

So it took us a little bit to sort him out in terms of getting all these studies done and figuring out that he had a 17p. And so his creatinine clearance was around 30. He had bulky adenopathy. He was sick. So he was someone who we really followed the package insert and admitted him for his 20-mg dose. Venetoclax is — you move the doses up because of the risk for tumor lysis syndrome.

So if you look at the package insert, everyone should be monitored for tumor lysis syndrome. But if folks meet certain criteria, you should consider admitting them. And since the drug was really relatively new and this guy was clearly sick and on the older side, we admitted him for his 20-mg dose and then his 50-mg escalation. He had no problems with tumor lysis syndrome. He was just in for a couple of nights and got out.

But has remained on the drug. His lymph nodes, within a couple of months, were gone. His symptoms really rapidly improved in terms of his fevers and his continuous state of being diaphoretic and his fatigue. And so for him, the most exciting thing, the last time I saw him, which was in the past month, he was planning his garden. He was planning his spring garden. His wife was so happy that he was really feeling well enough to get back to a lot of the things that had fallen off for him in his retirement years.

DR LOVE: That’s an amazing story.

MS GOODRICH: It’s a great story. Yes.

DR LOVE: So at this point, does he have any evidence of disease?

MS GOODRICH: So we have not marrowed him. In terms of his scans, which was really what prompted us to treat him, his nodes have almost normalized. So the last time we scanned him, he was in a really good PR.

DR LOVE: So I want to go back through this man’s history, because it seems like he’s gotten treated with almost everything you use for CLL. And we can go through it, but I’m curious. How long has it been since he felt this good?

MS GOODRICH: Oh. It was really between the ibrutinib and — or between the bendamustine and the idelalisib, so probably 2012.

DR LOVE: So maybe 5 years?

MS GOODRICH: Yes, maybe 5 years.

DR LOVE: Wow!

MS GOODRICH: Yes. So he’s thrilled. His wife is thrilled. They are very happy people.

DR LOVE: Wow! What’s it like to see him walk into clinic nowadays?

MS GOODRICH: Oh, it’s fantastic. He was somebody who we were really worried about. And we were really worried about just getting the oral drug, just obtaining it, which we all know can take some time. And I was really anxious about him during that period that we were going back and forth and just trying to get him the drug. So he was a sick guy who pretty quickly turned around.

Clinical experience with venetoclax in CLL

DR LOVE: So — all right. Let’s go back through the various things that he’s been treated with. Maybe we’ll start with the current one, which is venetoclax. So maybe you can talk a little bit about what you said to him in trying to explain what venetoclax was and what to expect.

One other thing I want to ask you, though: Do you feel like the venetoclax — or does he feel it’s in any way affecting his quality of life, like, causing any side effects?

MS GOODRICH: Not at all. He’s had no nausea. He’s had nothing. He’s had no bowel changes. He’s had no rashes. He really has had no issues. He’s had no cytopenias.

At one point in the past, he was on IV IgG for a hypogammaglobulinemia. And it’s not really clear to us why that ever stopped once it was started, because that’s usually something for patients with CLL, once they develop hypogammaglobulinemia, it doesn’t typically reverse to the point that you can get people off it for long periods of time.

So he’s had a couple of infections recently that are really along the patterns of what he had years ago, when he started IV IgG. So we have since sent him to our immunology folks. And they’re working him up. And he may get started again. I think the thing for him, he’s had so many therapies and he’s definitely somebody who’s been around the block.

Oh. And he’s also a smoker, so that doesn’t help his upper respiratory tract much either.

DR LOVE: Wow! He’s continued to smoke while he’s had CLL?

MS GOODRICH: Yes. And he’s really trying to cut down. He at times has smoked up to 2 packs a day. And he’s down to about 5 or 6 cigarettes a day, so he has really tapered down. But he still is a smoker.

DR LOVE: Wow! That's interesting. What kind of work did he do in the past?

MS GOODRICH: He lives in Pennsylvania. He did road work. Yes.

DR LOVE: Huh. So just to finish out, though, on the venetoclax, because I do want to ask you about tumor lysis, which is kind of what you all — that’s the first thing everybody says, but I’d also like to verify and go back, like, about the fact that once you get beyond the tumor lysis, how it’s tolerated. Because what I’ve heard is, once you solve that problem and they get their response like he does, it’s a pretty easy therapy.

MS GOODRICH: It is. It is. I’ve had one lady who several months into it developed a rash. She had not changed any meds. She had not done anything differently. And I did an exhaustive literature search, and I really didn’t think it was the venetoclax. But the fact that nothing else had changed for her — so we reduced it from 400 to 300. The rash improved. And maybe 3 months later, I went back up to 400, and the rash has not returned.

DR LOVE: Hmm. Interesting.

MS GOODRICH: So I’ve had to do a little finessing just once. That’s it. Otherwise, people have really tolerated this beautifully.

Monitoring for and preemptive measures to address the risk of tumor lysis syndrome in patients with CLL about to initiate therapy with venetoclax

DR LOVE: And then in terms of the tumor lysis syndrome, as you mentioned, like, in the package insert of the drug, there’s a very straightforward table, tells you whether they need to go into the hospital.

MS GOODRICH: Mm-hmm. Mm-hmm.

DR LOVE: But the bottom line is, that precaution, that’s mainly until they get their response, right?

MS GOODRICH: It’s at the 20- and 50-mg dose that the monitoring is the most intensive and includes, potentially, inpatient admission. And then as they escalate further, the monitoring tapers off. But we follow that package insert religiously.

DR LOVE: And I’m just kind of curious, have you seen tumor lysis? This man didn’t have it.

MS GOODRICH: No, this man didn’t have it. And honestly, I thought for sure he would, but he didn’t. And he was actually the first person at Hopkins that we had ever admitted for venetoclax, which was quite a learning experience for the inpatient team, because they’re really not used to admitting people to get oral drugs.

DR LOVE: Right.

MS GOODRICH: But this one is different. And everybody quickly wrapped their head around it, and it’s still a relatively new drug at that point. And you know —

DR LOVE: How high was his white count?

MS GOODRICH: His white count was in, like, the 80,000 range, so not sky high. He was slightly anemic, not transfusion dependent, though, nor platelet transfusion dependent. I think his platelets were around 75 or 80 as well.

DR LOVE: But, I mean, he had a lot of adenopathy. It just shrank right down.

MS GOODRICH: Yes.

DR LOVE: And so basically, what exactly were you doing other than monitoring his blood work? Hydrating him? What were doing about his uric acid?

MS GOODRICH: So allopurinol. And then the package insert talks about using rasburicase, the — and it is essentially the acute leukemia algorithm for rasburicase. It’s not anything different than folks would do for acute leukemics. So right, it’s the standard guidelines for using rasburicase. Yes.

DR LOVE: Again, in this situation where you’re really having this massive tumor drop, how aggressively do you hydrate? You mentioned his renal function was kind of compromised.

MS GOODRICH: Mm-hmm.

DR LOVE: How aggressively do you hydrate?

MS GOODRICH: So our inpatient service just used their regular algorithm. But even for people who get it as an outpatient and don’t need to be admitted, hydration is really critical for these folks. And we really push them to hydrate, hydrate, hydrate.

The other little pearl here is that people should not start these drugs late in the week. They should start them on Monday or Tuesday, because you’re going to need to do outpatient tumor lysis monitoring on them.

DR LOVE: That's interesting. So what are you looking for, specifically, in their blood work?

MS GOODRICH: So we’re doing comps. We’re looking at renal function but also looking at the calcium and the phos and the potassium and the magnesium, just making sure that they’re okay.

If I’m worried about people coming into the first dose dehydrated, I will give them hydration in clinic. And you shouldn’t be afraid to do that. Because some people just can’t drink that much. And if you’re going to have them in every day to be doing lab work, there’s no downside to giving them a liter of fluid and really making sure that they’re as wet as they can be, within reason, certainly, because this is an older population, so you’ve got to balance congestive heart failure and other things that you may not want to fluid overload folks.

Identification and management of idelalisib-related colitis

DR LOVE: So let’s talk about some of the other therapies that were either given or considered for him. Another regimen that this man got, I guess, in 2015 — because again, he relapsed 2011, gets some BR. Then he gets idelalisib-R.

And, first of all, did he respond to it? Did the disease respond?

MS GOODRICH: So it did. He did respond. He had lots of bulky adenopathy. And again, it was like the picture that we treated, that the counts were not terribly high, but lots of cytopenias — or lots of adenopathy, not cytopenias, but lots of adenopathy. And he did initially respond. But once he developed colitis and he was hospitalized, and it was colitis and he had this GI bleeding issue around that same time. So he was off drug for 2 or 3 months, and then the disease pretty quickly starts coming back again.

DR LOVE: Yes. I wanted to ask you about that colitis, because idelalisib, I mean, it is an effective drug. It’s approved in CLL, as well as follicular lymphoma.

MS GOODRICH: Yes.

DR LOVE: But it does have this thing that you don’t see — I don't know. It’s not that common that you see with drugs some kind of immune — I’ve heard about this colitis.

MS GOODRICH: Yes.

DR LOVE: What have you observed? What kinds of problems do you see with idelalisib?

MS GOODRICH: Right. So the idelalisib really — of course, there are count issues that you’re monitoring for. But there are really 2 phases to the diarrhea. The first phase is after initially starting the drug. And almost all of our drugs can do this. They can cause diarrhea or bowel changes. And that’s really garden-variety diarrhea. And you manage that the same way that you manage any diarrhea, chemotherapy diarrhea.

But then the colitis picture comes 6, 7, 8 months later. So this is really late, much later than just starting the drug and getting acclimated to the drug. And it can be severe. The drug needs to be held. Some patients will require steroids to get it under control. It’s something that nurses really need to be aware of. A lot of times patients will think, “Oh, I must have food poisoning, or something else is going on.” But no. This is pretty classic when that colitis happens. It’s 6, 7, 8 months after they’ve started.

DR LOVE: And I’m just trying to think. Is there anything else about idelalisib that you want to comment on? Are you utilizing the drug right now? And it kind of makes me think — reminds me a little bit — but Hopkins is so well known for all the research on checkpoint inhibitors. And with checkpoint inhibitors, you’re always worried about diarrhea.

MS GOODRICH: Yes.

DR LOVE: Somebody comes in, it’s not like anybody else with diarrhea. If they have — on a checkpoint inhibitor, you’re worried about an immune colitis, maybe.

MS GOODRICH: You’re worried — yep.

DR LOVE: And is that kind of the same approach you take to idelalisib?

MS GOODRICH: It is, because patients can also develop pneumonitis. And they can develop iritis. So they can really develop a lot of the same “itises” that checkpoint inhibitor patients develop. Yes.

DR LOVE: Interesting.

Evolving role of obinutuzumab based on the results of the Phase III GALLIUM study of obinutuzumab- versus rituximab-based induction and maintenance therapy for patients with previously untreated follicular lymphoma

DR LOVE: So he also, I see along the way, received the anti-CD20 antibody obinutuzumab.

MS GOODRICH: Yes.

DR LOVE: Similar to rituximab, but not exactly the same. I don't know whether he got it with — a lot of times it’s used with chlorambucil, but I don't know how he got it.

MS GOODRICH: You know what? I think he just got the obinutuzumab.

DR LOVE: And I’ve heard about people using obinutuzumab alone. I guess he didn’t really benefit, but, of course, he’d already gotten a bunch of treatments, and maybe he already was 17p at that point.

MS GOODRICH: Correct.

DR LOVE: But I am curious, because I know you have an interest in the whole issue of monitoring for toxicities. I am curious what your experience has been with obinutuzumab, because now not only is it used in CLL, but there’s a big paper out there — we’ll see how people respond to it — using it up front in follicular lymphoma.

MS GOODRICH: Correct. And then — right. And folding it in with bendamustine as well. So really trying to move obinutuzumab more into places that we have typically used rituximab. And so I think it’s a more toxic drug in terms of the cytopenias and the infusion reactions.

I think the hardest part about it is we’re so used to giving rituximab. And we are so used to the schedule and the monitoring, and so the obinutuzumab is a little different. The dosing is different. The schedule is different. And I think it’s going to take a while for people to get into a groove. I think it’s a little tough, because we’re all so comfortable with rituximab, and it works, right? And so displacing our favorite antibody for lymphoma patients is not something that people are just going to do just — just because 1 paper comes out. And I hate to say that, but we’re all used to it.

And we’re used to hearing about, in these low-grade lymphomas and CLL, that some of how you choose therapy is, yes, based on a lot of the biological markers that we can test. But if there are 3 or 4 things that are appropriate, you’re going to do what your practice is most comfortable. You have a go-to regimen. And for many years, rituximab has been included in our go-to regimen.

So I think that as more data comes out, yes, if more positive data comes out about obinutuzumab, we’ll see more of a shift. But this is not something that folks are just all of a sudden abandoning their rituximab.

DR LOVE: No. I mean, I think rituximab almost has an emotional place in a lot of people’s hearts, because you think about what happened when that drug came along and how it affected so many people.

MS GOODRICH: Yes.

DR LOVE: But I think also — and I kind of wonder. I’ve seen this in a lot of researchers, like, there’s almost a reluctance to believe that something could be better than rituximab. And yet obinutuzumab is a different antibody. I mean, it works — it’s the same target, but, I mean, it doesn’t do the same thing. And you look at the data. And, I mean, I don't know. You can debate whether it’s really worth it or not. But in any event, it might be up and coming, seems like it is, new trial.

But from a nursing point of view, again, the issue of toxicity.

MS GOODRICH: Right.

Frequency and severity of obinutuzumab-associated infusion-related reactions

DR LOVE: So I’m kind of curious, because I’ve heard different things about what you’ve observed. The big issue, as far as I know, with obinutuzumab is infusion reaction.

MS GOODRICH: More infusion reactions. Yep.

DR LOVE: And yet I hear that people end up getting through it, that not less people get —

MS GOODRICH: Absolutely.

DR LOVE: — treated. So what’s the mechanics of how this actually happens? I’ve also heard that it’s mainly just the first infusion, then it’s actually easier than rituximab. What’s your experience?

MS GOODRICH: Right. So I find it’s like rituximab in that the first infusion, and maybe the second one, are the tough ones. And we tend to, if we’re really worried about people having infusion reactions, we will aggressively load them with some oral steroids at home the day before and really making sure we use them sparingly.

But certainly with these folks with high white counts and lots of adenopathy, there’s really no upside to having them rigoring in your infusion chair. So we really try to pick the patients who could benefit from some up-front steroids to try to decrease those infusion reactions. But then once we do that, I find that it’s very similar to rituximab infusion reactions in terms of the severity. And certainly how you manage them are identical.

Subcutaneous versus intravenous administration of rituximab

DR LOVE: So as long as we’re talking about rituximab, there’s one other thing I want to ask you about kind of in my mind, if I can. Which is subQ rituximab. What’s the deal?

MS GOODRICH: So I am just starting to wrap my head around subQ rituximab. My point of reference to this is alemtuzumab. So when that was in vogue for patients with CLL, it was revolutionary, the difference in infusion reactions with giving it IV versus giving it subQ. And we’ve seen other drugs that route as well.

I think it’s an exciting alternative. But again, I think the jury is going to be out on this, because we’re all so used to giving our IV rituximab. We all have a system for doing it. But I think it’s an exciting alternative because for the majority of patients, whatever regimen they’re getting, their rituximab time is their longest time in the chair.

So if they can reduce that — and even when you get to rapid rituximab infusions and giving it over 90 minutes, when you’re talking about giving bendamustine and rituximab, it’s still a longer chair-time drug.

I think it would really help patients, their quality of life, both from an infusion reaction perspective and a time in the chair perspective.

DR LOVE: So it’s administered in clinic, correct, not by the patient?

MS GOODRICH: Correct. It’s administered in clinic.

DR LOVE: And what are the mechanics? How much volume? Where do you inject it? Is there a downside?

MS GOODRICH: So it’s your typical subcutaneous sites. And like many, the abdomen is the preferred site. And really, it’s just subcutaneous form. And the infusion reaction rate appears to be much lower. Because it’s not an infusion. It’s very slowly absorbing subcutaneously.

DR LOVE: So this is being debated at your center, whether to do this?

MS GOODRICH: So we’re not, at this point, giving subcutaneous rituximab.

DR LOVE: Is your team motivated to do this, or not really?

MS GOODRICH: Oh, we would totally be motivated to do this, because like every other place who treats oncology patients, we are all so busy. Our chairs are so full all the time that if we can reduce the time that patients are in the chair — not only for the patient, but for our operations perspective. I mean, no one is hurting because of empty chairs by any means. So if we can get people in and out of them quicker — the first revolution with rituximab was the 90 minute.

DR LOVE: Right.

MS GOODRICH: If we could get that down to a subcutaneous across the board, that would be spectacular.

DR LOVE: Hmm. Interesting.

Case: A 67-year-old man with relapsed mantle cell lymphoma (MCL) who received the “R-squared” regimen of lenalidomide/rituximab

DR LOVE: Okay. Let’s talk about your 67-year-old man with mantle cell who presented in 2004.

MS GOODRICH: All right. So he is a guy who is now 67, who was diagnosed with Stage IV mantle cell in 2004. And he got pretty typical therapy. He got CHOP/rituximab. And he at that point was 55. So instead of an auto, he got an allo. So when you get treated at a transplant center, you’d be antsy a little bit.

So he achieved a CR, a complete remission. He remained in a complete remission for about five years.

DR LOVE: Hold on. Hold on. Let’s go back a little bit here.

MS GOODRICH: Okay.

DR LOVE: So he presents at the age of 55 with mantle cell.

MS GOODRICH: Mm-hmm.

DR LOVE: Gets chemo/R, and then an allo transplant.

MS GOODRICH: Yes.

DR LOVE: So was that at your place?

MS GOODRICH: Yes. At that point, he was very high risk. And we do consider allos for our high-risk mantle cells, that blastoid variants or people who — I have a lady now who had CNS involvement. So if folks are high risk, it is still on the table.

DR LOVE: I don't know. Maybe he would have had the same thing, if he got an auto.

Actually, he has the allo in 2005, and then he recurs in 2009. So he gets 4 years.

MS GOODRICH: Right. He got 4 years. Yep.

DR LOVE: Which, I guess you might see that with an auto or even without —

MS GOODRICH: Absolutely.

DR LOVE: — either one, right?

MS GOODRICH: Right. Right. And so today, I’m not sure we would have done that same thing. But back in 2005, we didn’t have some of these novel therapies that we have today. And as you see these people who have been diagnosed for a number of years, that’s a very common story, that we would have potentially have managed him differently today. But at least he’s here, right? He’s here that we can talk about this, which is great.

Evolving treatment landscape for older and younger patients with MCL

DR LOVE: And then he kind of then enters a common round of relapsed disease.

MS GOODRICH: Correct.

DR LOVE: And he’s gotten several therapies, including lenalidomide/rituximab.

Let’s kind of lay out the infrastructure of how you approach mantle cell, and then we’ll talk about how he fit into that.

MS GOODRICH: Sure.

DR LOVE: Right now, when people with mantle cell, I guess, present, it seems like one of the things people think a lot about in mantle cell is, is the patient younger, in a good condition and maybe up for a transplant versus older? How do you make that determination, and what usually happens?

Another thing I’ve seen in the up-front setting that’s happened — I’ve seen a lot in the last few years — is the increasing use of rituximab maintenance. And I think at one point, he had that.

MS GOODRICH: Yes.

DR LOVE: But how do you approach up front now in the older and younger patient?

MS GOODRICH: So CHOP with rituximab is still a mainstay in mantle cell for initial therapy. To me it used to be, really, there were no decisions, right? So if an average-risk mantle cell patient got CHOP and rituximab, we would let them then observe. And at the point they relapsed, you would be doing salvage and taking them to some sort of transplant.

The issue now, which is a great issue to have, is, we’ve got ibrutinib that we are really using for a lot of patients. I have many patients now who are relapsing after their auto, right? So they got their CHOP/rituximab. They relapsed. They got something else. They got an auto, right, which, at that point, was standard management for these patients.

And so 5 or 10 years ago, we would have been talking about reinducing them and getting them to allo, right, as their long-term plan. And so now the whole landscape has changed. And we are putting those people on ibrutinib and saying, “You know what? We’ve got this great pill. If it works, this could keep you in remission for a short time. It could keep you in remission for a long time. If you get several years out of this, then maybe we’ll have another pill to give you or something else that is less risky, less toxic than taking people to an allotransplant.”

So these oral drugs have really changed the landscape for us. The thing that is uncomfortable is that historically when drugs hit the market, we would have at least 10 to 15 years of follow-up data on patients to understand long-term toxicity and really know the whole story about a drug. So for these newer drugs that have gotten breakthrough status from the FDA, where they have an expedited approval process and some of them have been approved on Phase II data, not even Phase III randomized data, we don’t have those years of follow-up.

So even though we’ve got these great, exciting new drugs, we always have very frank conversations with patients about the fact that we don’t know what the long-term toxicities of these drugs are doing to be, but as we learn them, we’ll share them. But most patients are really very happy to go on them and not have to receive systemic chemotherapy.

Counseling patients who are about to begin treatment with lenalidomide

DR LOVE: So certainly 2 of the most commonly used drugs are oral, which is, as you mentioned, ibrutinib, as well as lenalidomide. And he actually got lenalidomide. Can you talk about the side-effect issues that come up with lenalidomide and lenalidomide/rituximab, the R² regimen that he got and he actually responded to?

MS GOODRICH: Yes.

DR LOVE: What are the tolerability issues with lenalidomide in lymphoma patients?

MS GOODRICH: Right. So there are a couple of things that I always prep patients for, so the first thing is cytopenias. And then the second thing, when patients initially start they can have a tumor flare, where their nodes — and this guy definitely did. He had cervical lymphadenopathy. And I had warned him, “This is how this drug works. You can have this flare.” His cervical adenopathy essentially doubled and then really quickly shrank down.

So we’ve got to understand these little nuances to these drugs to be able to have our patients be ready for that so they’re not just completely losing their minds over these things.

Our typical chemotherapies all worked essentially the same way. Nothing got bigger, nothing got worse before it got better. Yes, they could have a little tumor pain with the rituximab, but not doubling of lymph nodes. But he was ready for that. He was completely ready. And he messaged me through our medical records system. And I remember this, him saying, “Hey, it happened. Thanks for letting me know this was going to happen. I’m not worried about this. I’ll keep you posted.” And the next time I saw him, it was significantly smaller, his cervical adenopathy, so it pretty quickly flared and then reduced in size.

DR LOVE: And so did he have any quality-of-life issues with len? Did he feel bad or anything happen?

MS GOODRICH: With the lenalidomide? His counts didn’t tolerate the lenalidomide. We had to abandon it because of his counts, even with several dose reductions. Now, he’s somebody who came into it very heavily pretreated. So his marrow just did not like the lenalidomide despite several dose reductions, but we did mission accomplished, right? So his adenopathy improved significantly. And we’ve been monitoring him since that time.

So just because you start people on these drugs that are hypothetically being done until toxicity or progression it doesn’t mean that if they stop for toxicity that they’re not going to get really a decent remission out of that.

DR LOVE: So that’s really interesting. How long has he been off therapy now?

MS GOODRICH: So he’s been off therapy for probably 6 months now, 6, 8 months now.

DR LOVE: So that’s really interesting. So you kind of threw him into a remission. You had to stop because the counts were low.

MS GOODRICH: Mm-hmm. Yep.

DR LOVE: Then he’s staying in remission off therapy.

MS GOODRICH: And he’s staying in remission off therapy. Yes.

DR LOVE: That must be awesome for him.

MS GOODRICH: It is awesome for him. Yes. He’s a nice guy. He’s got a bunch of grandchildren, and he’s recently retired. And he’s all over the country visiting his grandchildren. And he’s another one, it’s all good. He feels well. When he has issues it’s cardiac, because he’s also got congestive heart failure. So when his cardiac regimen is not right, that’s what his symptoms are from, not the lymphoma.

DR LOVE: Huh. Fascinating. So he’s got, hopefully, maybe, ibrutinib sitting out there in the future potentially.

MS GOODRICH: Correct. Yep.

DR LOVE: Also bortezomib. And I don’t know how often you actually use bortezomib for mantle cell. Do you use it? And what do you tell patients about it?

MS GOODRICH: So we actually use it pretty rarely at this point, because of the toxicity and the neuropathy and the cytopenias. I just feel like we have drugs that are less toxic. But it’s certainly something that we keep in our back pocket.

Case: A 74-year-old man with Stage IV peripheral T-cell lymphoma (PTCL) with widespread adenopathy and bone involvement

DR LOVE: Interesting. So let’s talk a little bit about T-cell lymphoma. Let’s hear about your 74-year-old man.

MS GOODRICH: Yep. So he is a now 74-year-old. He was diagnosed in 2014 with peripheral T-cell lymphoma not otherwise specified, which is the most common T-cell lymphoma in this country.

DR LOVE: How did he present?

MS GOODRICH: So he was sick. And this is very typical for these patients, so rapidly progressing abdominal pain. He had a 60-pound weight loss. He had massive splenomegaly when he was finally diagnosed. And he got his initial workup done because he was hypercalcemic.

DR LOVE: Wow!

MS GOODRICH: So he was really a sick guy. So his workup showed that he had Stage IV disease. And he had bone involvement, which is certainly something that happens with these more aggressive lymphomas.

DR LOVE: Now, that 60-pound weight loss is really impressive. How much did he weigh? And he lost his appetite, or what was going on? Was he obstructed? What was going on?

MS GOODRICH: He just completely lost his appetite. And that’s very common with T-cell lymphomas, to see really significant B symptoms. He did not have fevers, but the weight loss was very impressive. And I’m sure it was from the splenomegaly and the disease itself.

DR LOVE: What was his general condition before that time? What was he doing?

MS GOODRICH: So he was a retired police officer, so somebody who was really used to being in control. And it’s hard for folks like that when they are reduced to something that they never thought they would be reduced to, losing 60 pounds and not being able to get out of bed.

DR LOVE: So he had been previously healthy?

MS GOODRICH: Yes. Mm-hmm. Yep.

DR LOVE: So healthy 74-year-old man, all of a sudden, just cataclysmically losing weight —

MS GOODRICH: Correct.

DR LOVE: — a lot of tumor, big spleen. Could you feel his spleen on the physical exam?

MS GOODRICH: Oh, absolutely. Absolutely. It was probably halfway to his pelvis.

MS GOODRICH: Wow!

MS GOODRICH: Yes. It was one of those spleens you could see across the room when someone got on the exam table and lifted up their gown. Yes.

DR LOVE: So it sounds like things have been pretty rough since that point. What’s been going on?

MS GOODRICH: So they have been rough. So he started CHOP, which, again, is not great therapy for T-cell lymphoma, but it’s still where we start. And he progressed through therapy, which is never good. It’s never good when patients progress while on therapy.

So he got switched to gem/ox, which is a gemcitabine-based regimen. And he had a phenomenal response to that.

DR LOVE: That’s really interesting. So he had a complete response, although he walked right through CHOP.

MS GOODRICH: Yes. We were not expecting that.

DR LOVE: Wow! Interesting. Did he start feeling better?

MS GOODRICH: He did. He actually felt better initially on the CHOP. And patients rarely feel as bad as they do when they’re diagnosed, because they know what’s happening and we’re watching them. So even when they start to feel bad again, it’s hardly ever like it was in the beginning.

But he got gem/ox. He got into a complete remission. Now, he was somebody who — when you’re primary refractory, you’re going the aggressive route. So he earned that, unfortunately. So he underwent a nonmyeloablative or reduced-intensity transplant from a child, a haploidentical child, in late 2014. And he really did well for essentially 3 years, which is — it’s strange that he was so refractory initially and then got 3 years of remission from the transplant.

But he very recently has relapsed. And the second he walked in the exam room, I knew. I knew. He had ascites and he was talking about not being able — he was in bed, like, 22 hours a day. And it was really — yes, we worked him up and scanned him and biopsied him and all of those things just to make sure, because anybody who treats lymphomas, you know that these things — they can switch up. Different things can happen. You never make assumptions about what’s going on.

Choosing among available treatment options for relapsed PTCL: pralatrexate, romidepsin and belinostat

MS GOODRICH: So then we talked about treatment options for him. And so for folks who relapse with peripheral T-cell lymphoma, on the plate of options are certainly pralatrexate and then romidepsin and belinostat, which is the newest drug.

And so when we really talked to him about the pros and the cons and clearly talked to him about the fact that we were palliating, right, that our curative options were exhausted at this point, short of doing something radical, like retransplanting or — and he’s really not interested. He’s not interested in that. But when you think about pralatrexate, which is a good drug for T-cell lymphomas, but has a lot of toxicity in terms of mucositis and count issues.

We talked about that. We talked about romidepsin. And then we also talked about belinostat, which is given daily for 5 days. That’s a cycle. It’s a 5-day cycle with also a decent toxicity profile. And so he really made an informed decision that romidepsin was what he wanted to do, because they live about 2 hours away from us. And so to come every day was going to be a hardship. And the response rates are about the same, 25% to 30%. And so he really was a very active participant in choosing that therapy.

So he’s now in his second cycle of romidepsin. He’s really tolerating it well. His counts are holding. It’s really helpful that he went 3 years after transplant without needing therapy. So although he is relatively heavily pretreated, he had a little hiatus from chemotherapy. So I’m hoping that we can get enough cycles in him that he can get some sort of remission and, hopefully, get some more time.

He’s a very avid country music fan and goes to Nashville several times a year to the Grand Ole Opry. So I’m telling him, “Make your plans. Make your plans. We’re going to do our best to keep you as healthy as we can and as functional as we can, but no promises.” But it’s not that there’s no hope. It’s just that now we’re working for time and not cure. So he’s planning his next Grand Ole Opry trip, and hopefully he gets there.

DR LOVE: What kind of toxicity/tolerability issues do you see with romidepsin? I hear people often talking about starting it first, because they think it’s better tolerated. But when you do see problems, or how often do you see problems, what kinds of problems and any problems this man had?

MS GOODRICH: So it’s usually count issues, which he’s not gotten enough to have. And then patients can have little bits of nausea. And what he was doing was he just decided to take an ondansetron every day, just 1 in the morning. And he’s had no nausea. I’ve talked to him about seeing if he could play with that a little bit, if he wants. If he just wants to take 1 a day I have no issue that that, either.  So he certainly has been around the block in terms of chemotherapy and side effects and managing those side effects. And so really he’s had nothing. He’s had no issues.

Significance of establishing short-term personal goals in patients living with incurable cancer

DR LOVE: So wow! This has really been a rollercoaster ride for him. Wow!

MS GOODRICH: Mm-hmm.

DR LOVE: He starts out in this desperate situation, doesn’t respond to treatment. Then he responds to gem/ox, and he gets the allo. He does really well. Maybe he was thinking he was cured at that point.

MS GOODRICH: You know what? We were hoping he was cured at that point, because usually with T-cell lymphomas they relapse pretty quickly if they’re going to, after transplant. But he and his wife are very practical people. And they’re very thankful that they got those 3 years of remission and he felt well and really was business as usual.

DR LOVE: But I guess at this point it’s kind of more of a palliative mode?

MS GOODRICH: Yes. We’re definitely in palliative mode at this point.

DR LOVE: When you look back at him, what do you think it is that’s helped him deal with all these things of going up and down like this?

MS GOODRICH: I think that for him, he understood how ominous it was when he did not respond to the CHOP. And so when he responded to gem/ox, he just felt like he was getting a second chance. And really, these were really incredible people, in that they really made the most of every day between that — like, he got it, that this was really serious.

And they have enjoyed every day. They do a lot of traveling. They have family in Florida. They’re always going somewhere. They really have made the most of the time that he’s gotten, even though it has been a rollercoaster.

Finding meaning and satisfaction as an oncology nurse

DR LOVE: So final question. You know we can’t go through an interview without me asking about being in oncology in general and an oncology nurse.

MS GOODRICH: Mm-hmm.

DR LOVE: And this man, really, I think, hearing this story, I’ve got to think that it must affect you and the way you look at your life. You have this patient and his wife getting a new lease on life. Does that make you look at your life differently?

MS GOODRICH: Oh, absolutely. It absolutely does. Anybody who works in oncology, you don’t sweat the small stuff. You can’t get upset about every little thing that happens all day long. You’ve got to focus on the big picture. It does make you think about life completely differently. And you appreciate the little things. And then you don’t worry about the little things, either. Yes. It is an emotional rollercoaster.

And then to have people like this, who you’ve followed for many years and they’re doing great and then they’re not doing great — and, honestly, when he relapsed, I was seeing him all the time. And they both said — like, when they left the last time I saw them, they said, “We’re so glad it was you who told us all this.”

And I think as a nurse practitioner, you figure out what makes people tick in a way that is not necessarily how physicians are trained. I don't know. I don't know if that’s stereotypical or what it is, but I just feel like coming from a nursing background, you can really connect with people in a way that comes very naturally to you. You don’t even know you’re doing it.

Counseling patients with lymphoma about disease classification and goals of treatment

DR LEONARD: Lymphomas are tumors of the lymph cells. And I tell patients all the time the lymph cells are like the Army or the Navy or the Air Force, the Marines. They fight infections. And so there are many different types of lymph cells and, therefore, there are over 100 different types of lymphoma, depending on where the switches get broken.

So lymphoma is complicated. And those of us who work in oncology know that we’re typically dealing with a relatively small number of types of breast cancer or lung cancer or colon cancer. In lymphoma the type is very, very important. And the classifications keep changing. When I was a medical student in the late ‘80s, there were, in some ways, maybe 10 or 15 types of lymphoma. Now there are over 100 types of lymphoma.

That, in some ways, typifies the precision oncology approach coming to cancer treatment, in that we have been in lymphoma, subdividing groups of patients into smaller groups with different prognosis and treatment for a long time within the lymphoma field. And we’re moving toward the cell type and what it looks like, to the molecular testing and genetic testing, to even more sophisticated subclassification. So, for instance, I think we’re going to have 300 types of lymphoma before too long, because within each of these groups, we’ll learn even further different subclassifications and define our treatments on that basis.

So the different types have different treatment. So we need to make the diagnosis accurately. And I think it’s very important for the patient to understand the goals of therapy. And for certain lymphomas, particularly aggressive lymphomas, we’re aiming to cure the disease, meaning that there’s a good chance, or a meaningful chance, that we go through a course of treatment, the disease goes away and doesn’t come back.

On the other hand, for some lymphomas it’s a chronic disease state. They’re really strategizing to provide long-term management for the patient, much as we treat patients with diabetes or hypertension, where we’re hoping to manage the patient and the disease over a long period of time with a good quality of life and that hopefully the patient dies with the disease and has a normal lifespan and has a good quality of life during that time despite the fact that they have a lymphoma during that time period.

We are clearly recognizing that there are new ways to understand the disease and its biology and treatment. And I think this is one area where clinical trials can continue to make a big impact.

Factors influencing the development of lymphoma and effect of lymphoma subtype on long-term prognosis

DR LEONARD: One interesting aspect of lymphoma is that, like most cancers, it is more common in older patients. But even more interestingly and, in some ways, disturbingly, the incidence of lymphoma over recent decades has gone up. And in the 1970s versus the early 2000s, the incidence of lymphoma, particularly in the older patient population, increased at least by 2-fold. So the question would be, why did this happen? Why does it happen? Is this all the aging of the population, or are there other factors at play even over just a few decades?

And so patients often ask all of us, “Why did I get this? Why did this happen?” They’re used to lung cancer and asking about smoking, although clearly there are many other factors outside of smoking for lung cancer. There’s less of a direct causal relationship or risk factor that we know of in lymphoma.

Clearly, the tumor cell genetic abnormalities are driving what’s happening in the disease. And as we look at the biology of lymphoma, the microenvironment of the patient, meaning the seed or the soil, meaning where the tumor is growing, something about that patient in one person versus another that allows the immune system of that individual to tolerate or to be predisposed to a lymphoma. There are issues in genetic polymorphisms, meaning genetic differences between all of us that may make us more or less prone to getting a lymphoma and maybe genetic risk factors that are not so easy to identify in an individual patient.

When I speak with patients, I really tell them that the main risk factor for lymphoma is a funny immune system, meaning if you have an immune system that is overactive or you’re prone to autoimmune disease, like thyroid disease, lupus, rheumatoid arthritis, another autoimmune disease, that’s a marker that your immune system is not regulating itself in an ideal fashion. And that may predispose one to have mistakes of the regulation of the cell growth that would lead to a lymphoma or at least be connected with a lymphoma.

The other side, immune suppression and patients that are taking immunosuppressive drugs. Those, again, with the lupus and rheumatoid arthritis may be on immunosuppressive drugs, as an example. Patients who have had organ transplants are on immunosuppressive drugs. Those may be factors that predispose one to getting a lymphoma. So to some degree it’s the chicken-or-the-egg phenomenon. If you have an overactive or an underactive immune system, that may be a scenario that sets one up to be more likely to get lymphoma.

So what does a patient want to know? Typically their big question is, “What’s my prognosis? Am I going to live a long time? Am I going to be cured? And what’s the plan for me?” And I think that I emphasize to patients that the crucial thing — there’s not any one thing that tells one the prognosis and treatment. It’s a mixture of features.

Predominantly, the type of lymphoma is the key factor that defines the prognosis and treatment, but there are other components that are going to change what that patient’s outlook is and how we’re going to approach them, the age of the patient, the fitness of the patient, the stage of the disease. Do they have extranodal disease from their lymphoma? What are their blood tests? Are they anemic or do they have an LDH abnormality, for example? That could be something that is associated with an unfavorable lymphoma. And then certainly some of the special tests, such as pathology tests or other areas, may impact how we approach an individual patient.

Case: A 77-year-old man is observed for several years before receiving multiple lines of treatment for CLL

DR LOVE: I want to go through your case of the 77-year-old man with CLL who presented 12 years ago. Maybe you can kind of take this case all the way through, explaining CLL as you go along.

DR LEONARD: Sure. So this is a 77-year-old man who, when I first met him, was in his midsixties. And basically he works in business, in finance. He’s got a family business. And had an incidentally detected lymphocytosis. And over time, we watched him. He had some small adenopathy. He was really more or less asymptomatic. He seemed to be coping with kind of the watch and wait state very well.

His disease got to a point that he needed some treatment. He was getting more anemic. He had some small adenopathy and was getting thrombocytopenic.

DR LOVE: So before you go on, can you kind of go back to his initial presentation and go through the way you evaluated him, what his white count was, what kind of diagnostic workup and how you thought through the initial options that got you to observe him?

DR LEONARD: Sure. So when I first saw him, he was feeling well, which is obviously the most important thing. And he came to me with a CBC, so I knew he had a lymphocytosis, some anemia, some thrombocytopenia.

DR LOVE: How high was his white count?

DR LEONARD: His white count at that point was in the 20,000 to 30,000 range. And his hemoglobin was about 13, and his platelets were in the low 100s, so nothing that urgently needed any treatment but certainly outside of the normal range of all that part.
And at that point, we confirmed on his peripheral blood immunophenotype that he did, in fact, have CLL, because he had an elevated lymphocyte count.

We sent FISH testing to look at his cytogenetics and cytogenetic abnormalities based on the FISH, because we knew at that point — and this has evolved over the last 12 years, but we know that a patient who’s likely to do better or worse, depending on different cytogenetic abnormalities, might have a better or worse prognosis, may be more likely to watch and wait for a while and may benefit from one treatment or another, which we’ll get to in a minute.

So at the time, he did not have any particularly — he had normal risk by his FISH testing. He was asymptomatic. We talked about it. He said, “I feel fine. This is not bothering me. I understand that I have CLL. I’m working. I’m traveling,” and we basically, for several years, watched him, saw him every 3 to 4 months, checked his blood counts, did a physical exam, asked him about his symptoms.

And then several years into this, really, we noted that he was getting a little more anemic. And in conjunction with that, his white count was going up and his platelets were going down, to the point that his white count was about 50,000 or so. His hemoglobin was down in the 10 range. He was a little more fatigued. And his platelet count was going down into, like, the 70,000 range, so not a dangerous range but in a range that we were starting to think about treatment.

DR LOVE: What about lymph nodes? Were they growing?

DR LEONARD: He had some growth of his lymph nodes. Lymphadenopathy in this patient was not a major issue. He’s had 2- to 3-cm lymph nodes. That’s the biggest his lymph nodes have really ever gotten. And he knew they were there, and all along, he’s had them on and off. But they’ve never been a big problem. This is somebody who tracks his counts and knows what’s going on with that.

Selection of an up-front treatment regimen for patients requiring active therapy for CLL

DR LOVE: So this patient did well on observation for a while. And then it sounds like it, as things were progressing, that there was a need for treatment, particularly, it sounds like, related to his counts going down. How did you think through what treatment to give him at that point?

DR LEONARD: So at that point which we’re talking about, that would have been about 7 years ago, give or take — the main treatments that we had — this was kind of just before we were starting to use a lot of bendamustine, I would say. We didn’t have obinutuzumab, the new anti-CD20, available at that time.

And so the typical questions would be, is this an elderly person who we would have given chlorambucil or CVP? Is this somebody that we would give FCR, fludarabine/cyclophosphamide/rituximab? Or would we give FR, fludarabine/rituximab, recognizing that adding the C, the cyclophosphamide, would worsen his infection risk, worsen his cytopenias but also would provide a greater depth of response and a more durable response?

So in talking with him, he was comfortable and we were kind of on the fence at FR versus FCR. At that point in time, he was more or less around 70 or so. And we erred on the side of giving him FR. And he had a good 5-year response. His counts improved. His lymph nodes got smaller. He continued to work and travel and was pretty asymptomatic. And that lasted about 5 years until essentially the same pattern happened again.

DR LOVE: So we’re going to talk a little bit about the choices that are available today, but just maybe a word about FR and FCR. One of the issues with those regimens is, although they’re very effective, they’re not that easy to get through. What are some of the typical problems that you see? And what happened with this man?

DR LEONARD: So the typical problems that you see with FR and FCR are infectious problems, meaning that patients are at risk for — fludarabine affects your T cells. So T cells provide some of the protection against various infections, such as pneumocystis. It can predispose, fludarabine, to shingles and zoster infections and then other viral infections and then cytopenias in general, having low blood counts. So with FR and FCR, the biggest issues one deals with are infections and low blood counts.

He managed this well. I think the tradeoff of FR and FCR and what led us to the FR is that he wanted to minimize his infection risk and his cytopenias. And he did well with it. He tolerated it very well.

DR LOVE: So one of the things that’s been observed with some of the chemo/rituximab regimens, including FCR, and one of the things people like about it is the possibility that you could launch somebody into a period where they won’t need any treatment. So what happened with him?

DR LEONARD: So he had a good response. He was in remission about 5 years or so. And then towards the end of that time period, basically the same pattern happened. And he noticed his lymph nodes getting a little bigger. We were tracking his counts. His white count was creeping up. And he’s got mild anemia, although he really hasn’t had transfusions. But his platelet count was also an issue, and again, falling from the mid to lower 100s down to the 70, 60 to 70 range. And we pretty much knew as his white count was going up that this was his pattern again and we needed to treat his disease again.

Later-line options for the treatment of CLL; prognostic and therapeutic significance of 17p deletion

DR LOVE: So he now is in relapse. What were the options you were thinking through at that point?

DR LEONARD: So at that point in time — again, at that point bendamustine had come onto the scene. And we gave him bendamustine. I think we did dose reduce it a little bit based on his age. We gave him 70 mg/m², which is more commonly used in CLL anyway, as opposed to the little higher doses in lymphoma, follicular lymphoma particularly.

He again tolerated that well. He was traveling and working. And that was really, I think, the main option at that time that we were excited about outside of clinical trials.

DR LOVE: And so what happened at that point?

DR LEONARD: So in that time frame, he responded about 2 years to that treatment. And then again, the exact same pattern again with the blood counts, et cetera. And at various points along the way, we had checked his FISH testing, because it’s important to keep in mind that as CLL patients relapse, their FISH testing profile can evolve over time.

And he’s an example of that, in that by repeating his FISH testing after the BR kind of relapse, he had a deletion of 17p. Chromosome 17p in CLL has been associated with a less favorable outcome. And it’s been associated with better responses to ibrutinib or venetoclax, which we’ll talk about, because he’s received both of those. And so in some ways, those are the treatments of choice, or at least very high on the list for patients with a 17p deletion, which is an area that is associated. This chromosomal deletion on chromosome 17 is associated with a less favorable survival and a lower chance of responding well to most of the chemotherapies we have.

Tolerability profile of the Bruton tyrosine kinase inhibitor ibrutinib

DR LOVE: So what happened at that point?

DR LEONARD: So we gave him ibrutinib. And ibrutinib is the Bruton’s tyrosine kinase inhibitor. He responded well to that. He had a partial response that lasted about 2 years. He still has some lymphocytosis and some mild adenopathy. And then he progressed and —

DR LOVE: Could I just ask, so — and when you started the ibrutinib, after you started the ibrutinib, did you observe any tolerability issues? Did he have any side effects or complications?

DR LEONARD: Yes. So ibrutinib, he tolerated it pretty well. The things to keep in mind with ibrutinib are that the white count can go up temporarily. Patients can have myalgias or joint pain sometimes, some fatigue. They can have some diarrhea symptoms. He had a little bit of that, but he didn’t mind it. Many older people are happy to have something help their bowels move.

And then the other thing to keep in mind is that there’s some bleeding risk, and so we’re always careful with these patients and if they’re having any procedures or dental work or other things. And the atrial fibrillation is also a possibility in these patients.

So he tolerated it well. He had a little fatigue, a little GI upset, but beyond that, no other major problems.

DR LOVE: Just out of curiosity — I mean, it is an oral agent. How do you think he would compare his experience with the 2 years of ibrutinib to the 2 chemotherapy regimens he had previously?

DR LEONARD: I think in general he would compare it — and I think your question really typifies what we’re doing in oncology. Do you take a 6-month course of treatment, or do you take a chronic 2-plus-year, depending on where you’re going with it, course of treatment?

So I would say that he would find that the first 6 months was much easier on ibrutinib. I mean, we were watching him, but he kind of pretty much knew what to expect. Most of those side effects or symptoms are not life-threatening sorts of things. They’re not the infection, the bad infection risk category that we worry more about with chemotherapy, or the neutropenic fever.

So I would say that he probably would say that the first 6 months were easier for him but that over time he had to be watched a little more closely while he was chronically on ibrutinib than he would have been kind of set free a little bit after FR or BR.

Explaining the mechanism of action of ibrutinib to patients with CLL and other lymphomas

DR LOVE: Can you talk a little bit about the way ibrutinib works and what you typically see in terms of its effect on the disease?

DR LEONARD: So ibrutinib is an inhibitor of Bruton’s tyrosine kinase. So how I would explain this to patients is that the B cells, which are the malignant cells in CLL, have a variety — normally, B cells go around the blood and they bind to antigens or targets that they go after when they are doing their job of fighting infections. And they have, on their surface, something called the B-cell receptor.

That B-cell receptor is abnormally turned on in CLL. And that’s one of the reasons why the cells stay alive and they proliferate. One of the switches that keeps those cells alive and proliferating is Bruton’s tyrosine kinase. So ibrutinib — and you see the link in the name — essentially is a pill. It’s a chemical pill that goes into the cell, binds that switch and keeps it from firing, from being turned on.

And so the net effect of that is, the cell is unhappy. The cell is less likely to proliferate or grow. And the cell is more prone to die off, either on its own or in conjunction with other therapies. And so the effect is pretty profound in patients with CLL and certain other lymphomas. The main things that you observe on patients with ibrutinib is that the lymph counts in the blood can temporarily go higher, so that’s something to keep in mind. If you give a patient ibrutinib and they start at a white count of 20,000, it may go to 40,000, for example. And that’s okay. The lymph nodes may be shrinking at the same time.

But it’s important to keep in mind that that doesn’t mean that that rise — the patients get nervous. We all get nervous. “Oh. Is the drug not working?” When, in fact, that’s just the normal course, that sometimes it goes up like a rollercoaster and then it comes down over time.

Mechanism of action and side-effect profile of venetoclax in CLL

DR LOVE: So this patient then, as you mentioned, received ibrutinib for a couple of years, did well, same pattern, relapse again. So how did you think through treatment at that point?

DR LEONARD: We knew he had been through a lot of chemotherapy. He’s now 77. And we knew he had a 17p deletion, and so we were fortunate in that venetoclax, which is an inhibitor of Bcl-2, became approved in this recent time frame. And Bcl-2 is a protein in the cells that helps keep the cells alive, what we call antiapoptotic protein. That keeps the cells alive and, to some degree, also makes them resistant to chemotherapy and other things.

And so it turns out that venetoclax, this pill, is very effective in CLL. In particular, it does work in patients where chemotherapy is not working, including the 17p deletion group of patients. And so we decided to try that. And he’s done well with that at this point.

DR LOVE: So I guess one of the things that’s interesting about venetoclax, from what I’ve heard, first, it is oral, again. And do you see any quality-of-life side effects?

DR LEONARD: The biggest thing with venetoclax is that you can have tumor lysis syndrome. And I know the audience is familiar with that. When you have a patient, typically with Burkitt lymphoma or an aggressive lymphoma, the cells die off quickly and you get release of chemicals from inside the cell. The phosphorus goes up. The uric acid goes up. The kidney function gets abnormal. The electrolytes, like potassium, get out of whack. And it can be a very serious and, in fact, life-threatening issue.

That can occasionally happen with venetoclax, particularly when the patient has high-tumor-burden disease, meaning they have a very high white count or they have bulky lymph nodes. And so there are very clear guidelines based on the white count and based on the kidney function and the size of the lymph nodes. Can you monitor these patients as an outpatient, or do you have to admit them to the hospital? And there’s a very clear dose escalation, where you start with 20 mg, go to 50 and, over the course of about 5 weeks or so go up to the full dose.

And so quality-of-life-wise I would say, depending on the situation of the patient and their risk, it’s a busy time in the beginning of things because you’re really keeping a close eye on these labs and seeing them often. But most patients can be treated as an outpatient. And once they’re kind of settled and been through this tumor lysis risk period, the quality of life is pretty good. You have to watch the blood counts. There can be a little GI upset. But generally, once the dust has settled and the patient’s on it, a month or two into it, it can be a pretty manageable treatment.

Monitoring and treatment strategies for tumor lysis syndrome in patients receiving venetoclax

DR LOVE: Yes. This tumor lysis thing is interesting, because if you think about it, it’s kind of a consequence of the drug’s activity.

DR LEONARD: That’s right.

DR LOVE: It’s coming about because so many cells are getting killed. So it’s kind of — it’s like a good thing, but maybe, I guess, it just happens too quickly. Can you talk practically, though, about what are some of the specific consequences of tumor lysis syndrome and how you prevent or treat that?

DR LEONARD: So what happens in tumor lysis is that the cells die off. They die off rapidly. And so that releases phosphorus, which can cause a variety of different problems. It can release potassium, which causes a variety of different problems, including arrhythmias. It can release uric acid, which can affect the kidneys and cause renal failure and start a cycle of then the electrolytes are more out of whack, because the kidneys are not working well, et cetera. And so that can lead to complications of renal failure, really, and electrolyte abnormalities that can be risky with regard to arrhythmias and other problems.

So the most important thing is to kind of be able to predict it and to watch for it, not to give the patient the drug and then say, “Come back in a month” but actually see them again the next day or whenever it’s appropriate. And so the management of tumor lysis typically is monitoring and dealing with these lab abnormalities as they come up, dealing with things to lower the potassium or the phosphorus, if those go elevated, and largely treating with hydration, with fluids, either orally or intravenously.

And giving allopurinol to help prevent the aspects of the uric acid damage or, in the higher-risk patients, giving them rasburicase, which is a recombinant urate oxidase inhibitor that basically affects uric acid levels and is given in very high-risk patients.

And so in the outpatient setting, patients with a white count of less than about 25,000 and small tumor burden, in the range of a couple of centimeters, you might give them their first dose — and again, there are very clear guidelines on exactly how to do this. There’s a blister pack that gives you the first week’s pill, the second-week pill, et cetera.

But in that low-risk patient, you might check their labs, make sure everything’s in good shape, give them their first pill. Maybe have them come back that afternoon, check their labs again. Have them come the next day, check it again. And then at several time points, when you go through the first week, the next week you’re going to go up. You kind of repeat the first day process again to make sure that that first day, which is the higher-risk day, everything goes smoothly.

In the intermediate group, where the nodes are bigger and the white count is higher, you might watch that patient a little more closely, check the labs, still do it as an outpatient, maybe give them some IV fluids in the clinic.

And then the highest-risk patients, those that have high white counts and bulky disease — let’s say, 10-cm nodes — those are people that you would probably admit to the hospital each time you raise the dose the first day of that week’s cycle to keep them out of trouble and to watch them more closely.

DR LOVE: So as you said — and I don't know if I’ve ever seen a package insert that has a table like that. It tells you kind of exactly what to do. So it’s really helpful, as long as you know that it’s there.

Role of maintenance therapy in CLL

DR LOVE: There have been a couple of studies that just came out at the last American Society of Hematology meeting, looking at lenalidomide as maintenance. What is lenalidomide? And does it have a role in CLL?

DR LEONARD: Right. So the issue of maintenance treatments or the idea that the patient has gotten an initial, they get put largely into remission. And then you’re doing to give additional therapy while the patient’s in remission, usually over a longer period of time, maybe a year, maybe 2 years, maybe longer, to try to prolong that remission.

So the issues, as one thinks about using a maintenance — so if you’re in remission and you’re sitting there meeting with a patient and saying, “Gee, should we do maintenance,” in most maintenance strategies there are tradeoffs, right? You’re saying, “We give you this drug. There’s, whatever, time involved, expense involved, side effects involved in staying on this drug for a year or two” or whatever it is. And so that’s the downside versus just taking a break and dealing with the disease when it pops up.

The upside is, if you’re in remission longer, then you may do better. And people tend to like being in remission. The question also is, do you live any longer? And most of the maintenance studies, at least in CLL and in lymphoma, keep people in remission longer but don’t live longer. So that, at the end of the day, if you live the same amount of time, do you stay on the drug longer now, or do you just take a break and pick up with a drug when you need it, when the disease is getting worse?

And so that’s the practical question that we have with patients. And patients, in my experience, have different preferences. Some are like, “I loved getting to know you the last 6 months. I want to stay away.” And others like coming in. They like the security blanket. And they say, “Yes, anything you can give me to stay in remission, why not,” as long as they tolerate it well.

So the drugs that have been used for that the most, at least so far, have been rituximab, the CD20 antibody, obinutuzumab, which is a new anti-CD20 antibody that has different immune system activation and different properties that in some situations may work better than rituximab, albeit it’s given at different doses than rituximab. And then we’re now seeing some studies using lenalidomide or some of the other pill medicines, because it’s obviously relatively easier, if you tolerate it well, to take a pill every day rather than get an infusion as maintenance.

So those studies, I think, one has to keep the eye of the ball of are you living longer? Are you just staying in remission longer? And is the tradeoff for the patient’s quality of life worth being in a longer remission versus taking a break?

Now, lenalidomide is getting a lot of interest in lymphoma. It’s approved. I think the audience probably knows that lenalidomide is an IMiD, an immunomodulatory drug that is in the same family as thalidomide. And it has been approved in multiple myeloma. It’s approved in certain types of lymphoma, including mantle cell lymphoma. And it’s been studied in aggressive lymphomas, follicular lymphomas. And across the board in various types of lymphoma, it shrinks the disease about 30% to 40% of the time, maybe a little higher or lower.

Its main side effects are blood count changes, occasional rashes, some GI side effects. And you have to watch for blood clotting risks and thrombosis. But lenalidomide, for some people, is very well tolerated and can get a durable remission. And in others, you might say it’s not worth the tradeoff. So we’re doing those trials right now, and we’ll see the longer-term impact of that.

Rationale for combining lenalidomide with rituximab and ongoing evaluation of this regimen in different lymphoma subtypes

DR LOVE: One regimen that you’ve been very involved with that I think is really interesting and bring up the question of chemotherapy-free treatment is the so-called R² regimen, which is lenalidomide and rituximab. Can you talk about the rationale for that and what we know about the activity of this combination in different lymphomas?

DR LEONARD: Sure. So rituximab has been used, everyone knows — it was approved in 1997, so it’s been around 20 years for various types of lymphoma. And we give it by itself or we give it with chemotherapy, typically, or some of these newer agents.

Lenalidomide shrinks the disease in follicular lymphoma, again, about 30% of the time, 40% of the time, depending on which patient subset that it’s looked at. So the effects of lenalidomide are very numerous, meaning that it can directly affect lymphoma cells. It can activate the immune system to make various immune parameters work better. It can interfere with blood vessel formation. It can do a lot of different things.

And so the concept is that if rituximab works for the immune system and lenalidomide can activate or enhance the immune system, giving them together may work even better. And so there are a variety of trials looking at lenalidomide/rituximab. We’ve looked at it in relapsed follicular lymphoma patients. There are studies looking at it as initial treatment for follicular lymphoma patients. It’s also been looked at in mantle cell lymphoma, other lymphoma subtypes.

And the idea there is that the patient who might want to avoid chemotherapy could potentially take this pill with rituximab and have a long remission and that it’s an alternative to chemotherapy. So the patient may be able to avoid or delay chemotherapy.

Obviously this term, chemotherapy, is a semantic argument, because some people have side effects with nonchemotherapy drugs. And some people tolerate chemotherapy just fine. But I think this offers another opportunity that perhaps is a little more targeted, a little more elegant than just kind of the typical chemotherapy wipe things out.

DR LOVE: Where are things now with this so-called R2 regimen? I know there’s some big trials out there, like, comparing it to more conventional treatments.

DR LEONARD: So there are trials of R2 as initial treatment for follicular lymphoma. There’s a large trial that’s in follow-up right now that is — patients were randomized to lenalidomide/rituximab or chemotherapy/rituximab. So that’ll be interesting to see, either is the lenalidomide better than chemotherapy/rituximab? Is it just as good? Or, even, maybe it’s a little bit worse, but it’s better tolerated. So is that a good tradeoff for the patients? So those data are going to be very interesting. I’m hopeful we’ll have them before too long.

And then we also have studies in follicular lymphoma that have looked at rituximab versus rituximab/lenalidomide. And again, that’s a randomized trial to see, does lenalidomide add to the efficacy of rituximab? And that’s, again, a study that’s ongoing. And those results hopefully will be available before too long.

Case: A 75-year-old man with relapsed multiple myeloma (MM) who initially presented with severe back pain is found on evaluation to have renal insufficiency and compression fractures

DR KAUFMAN: When we first met him, going on 7 years ago now, he actually presented with severe back pain. He was found to have multiple compression fractures and ultimately was diagnosed with light-chain myeloma. He was so debilitated that he actually had to be hospitalized. And I remember him very well. And I’ve worked with him now for 7 years. And he’s become a good friend of mine.

At the time, he couldn’t get out of bed. And he was so depressed and debilitated by this fact that he just said, “I’m never going to get out of bed again. I’m in so much pain. I’m never going to get out of my bed again.” And I told him, I said, “Our treatments are so effective today for myeloma that you’re going to be out of pain and you’re going to get out of bed. And you’re going to get through this.”

And we actually had to treat him in the hospital for several weeks. And through effective therapy and good supportive care and physical therapy and occupational therapy, he walked out of the hospital.

DR LOVE: Was he generally healthy before this? Did he have comorbidities? How was he spending his time?

DR KAUFMAN: Yes. He was a very healthy person at the time. I mean, he had retired, but he was doing a normal life. He was married. He had kids. He was generally very active and started to have — and again, but became debilitated because he had such severe back pain.

DR LOVE: And he had a spouse?

DR KAUFMAN: He had a spouse at the time.

DR LOVE: At the time.

DR KAUFMAN: Yes. She has subsequently herself deceased from another type of cancer —

DR LOVE: Wow!

DR KAUFMAN: — since then. Yes.

DR LOVE: Hmm. So how long after that, his diagnosis, did that occur?

DR KAUFMAN: She probably died 3 or 4 years ago now.

DR LOVE: Wow!

DR KAUFMAN: He’s a very unique guy. He was one of these guys who would fill his entire first floor of his house with a toy train —

DR LOVE: Wow!

DR KAUFMAN: — setup. And he was the guy in town who would invite everybody over to come see his Christmas trains. And it would take him 2 weeks to set up every November. And then he’d have it open all through the holidays. And then it’d take him 2 weeks to break down in January.

DR LOVE: Wow! What kind of work did he do?

DR KAUFMAN: You know what? I only knew him as retired. And I don’t — he was in some type of sales, but I don't know specifically.

DR LOVE: Interesting.

DR KAUFMAN: Yes.

DR LOVE: I’m also interested by what sounds like his sense of despondency.

DR KAUFMAN: Right.

DR LOVE: How did you see that evolve not just during that hospitalization, but over time? How did he — I don't know — recover or heal from that?

DR KAUFMAN: As soon as — like I said, I sat and I told him — he said, “I’m never going to walk again.” And I told him — I was — I’m usually — the way I manage patients is I’m not always directive. In this case, I was very directive with him. I told him. I said, “You are going to get better, and you are going to walk out of here.”

And finally, he started to embrace that and started working with physical therapy. And as soon as that happened, as soon as he was able to walk again and control the pain, his spirits have been amazing. He believed himself that he could conquer anything. And even though now — he was in a remission for probably 6 years after transplant.

And even though he relapsed, his relapsed disease in no way ever impacted him negatively. Once he knew he could overcome that first challenge, he’s never had any problems with overcoming any challenges. And nothing bothers him anymore. Having relapsed myeloma doesn’t bother him. Not feeling good all the time doesn’t bother him anymore. And a lot of times, it became from that overcoming that initial challenge.

Pathophysiology of renal dysfunction in patients with MM

DR LOVE: So let’s talk a little bit about the renal dysfunction that he had. First of all, in general, what’s the pathophysiology of renal dysfunction in myeloma? Why do you see this?

DR KAUFMAN: Yes. So we can see renal dysfunction for many reasons. This patient had renal dysfunction for the most classic reason, which is the deposition of the light chain within the kidney itself. And this would really be true myeloma kidney. And in these cases, by treating the patient, getting rid of the light chain, you could have rapid resolution of the underlying renal dysfunction. And this is really the classic myeloma kidney disease.

Now, that’s the classic and the most common one, but there are other common causes for renal dysfunction. As I mentioned before, it’s very common for these patients to go months and months with back pain before they find out they have myeloma. And it is very common that these patients are on NSAIDs for months, very high doses of NSAIDs. And we often see that as a cause of renal dysfunction.

And then there are other types of light chain deposition in the kidney that are different than the classic myeloma kidney, things like light chain deposition disease or amyloidosis, where the misshapen light chain actually gets incorporated into parts of the kidney, which cause kidney dysfunction.

Approach to induction therapy for patients with MM with and without renal insufficiency

DR LOVE: Right now, when you see a patient like this who does have compromised renal function, how does it affect the way you select therapy, at least up front? What’s the — now, this man, I want to clarify. Was he 75 at diagnosis, or he’s 75 now?

DR KAUFMAN: He’s 75 now.

DR LOVE: Okay.

DR KAUFMAN: So this was — he was in his late sixties, yes.

DR LOVE: So he was actually in his late sixties. Did you have a previous creatinine on him from before he had myeloma, to know what it was?

DR KAUFMAN: I don’t remember. But he didn’t have a known history of renal dysfunction before this happened. So this was really an acute episode.

DR LOVE: Right. So what’s the normal induction — so he was a younger man. I guess in the late sixties, you would have been thinking about transplant.

DR KAUFMAN: Right. Exactly.

DR LOVE: And so now you’re thinking about an induction regimen. What’s the typical induction regimen that’s being used or was being used in 2010? And how does that change in a patient like this who has renal dysfunction?

DR KAUFMAN: Right. So our standard induction then, and it remains one of our most common standard induction now, is the combination of lenalidomide/bortezomib and dexamethasone. And for the standard patient who doesn’t have acute kidney dysfunction, that’s the regimen that we would choose.

In those patients who present like this, with acute kidney injury, for whatever reason, whether it’s from myeloma or for the myeloma kidney, like it was in his case, or other reasons, we often initially leave off the lenalidomide. And we leave off the lenalidomide because the toxicities associated with lenalidomide in patients with significant renal dysfunction is higher — we find that we have to make dose modifications to safely deliver lenalidomide. And so we have a long history of being able to give bortezomib and dexamethasone.

And then we often try to give a third agent. Our approach is to give thalidomide, which is not commonly used anymore. But thalidomide is not impacted by kidney function. And we know that the 3-drug regimen of bortezomib/thalidomide and dexamethasone is superior to the doublet regimen.

The other regimen that is commonly used is the addition of cyclophosphamide, because we know we can also give cyclophosphamide safely in patients with renal dysfunction. But our approach is — and usually, these patients with renal dysfunction are actually in the hospital. So you’re trying to do things very quickly. And we know that as soon as you make the diagnosis of myeloma in the hospital, the next day you can initiate the combination of bortezomib and dexamethasone and very rapidly try to turn things around.

You get your thalidomide written, get that into the patient as soon as possible. And then what we do, as soon as the patient’s kidney function turns around and they’re no longer on dialysis and they’re having a remission, then we switch them from thalidomide to the standard IMiD/lenalidomide.

DR LOVE: So it looks like this man, though, just got the bortezomib/dex, though, right?

DR KAUFMAN: At the time, he just received bortezomib and dexamethasone.

DR LOVE: Right. And how did he respond to the therapy? And what was the next step?

DR KAUFMAN: So he responded very well to therapy. He was able to rehab, get out of the hospital. He achieved, actually, a PR to his initial therapy. And then his performance status was so good that we moved him to a transplant. We collected stem cells. And he had high-dose therapy and autologous stem cell transplant and achieved a VGPR from there.

DR LOVE: And how did he tolerate the transplant?

DR KAUFMAN: He did great. He really had minimal complications.

Carfilzomib as a component of front-line therapy for patients with MM

DR LOVE: So before we go on to the next step, just to backtrack a little bit, you were talking about the standard approach being bortezomib/lenalidomide and dexamethasone. But there is another regimen that actually is being studied in a big trial right now where the proteasome inhibitor being used is carfilzomib.

DR KAUFMAN: Right. Right.

DR LOVE: What about that approach? And what do we know about the comparative approach? And do people ever use carfilzomib up front?

DR KAUFMAN: Yes. That’s a great question. So I think to just give a little historical background about why we had the combination bortezomib/lenalidomide/dexamethasone, it was about 10 years ago now that we studied this combination. And there was a lot of debate about what the optimal induction therapy was. And we were using the doublet, lenalidomide and dexamethasone, for induction.

Sometimes we were using bortezomib and dexamethasone for induction. I think a very common induction therapy at that time was thalidomide and dexamethasone. Some people were using, again, like we do in our renal failure patients, the bortezomib/thal/dex combination that — that’s a very good regimen, but with both bortezomib and thalidomide causing neuropathy, it could never be a long-term induction therapy.

And Dr Paul Richardson from Dana-Farber Cancer Institute led a multicenter Phase I/Phase II study of the combination of bortezomib/lenalidomide and dexamethasone. And in a relatively small study, 66 patients, the overall response rate was 100%. And even though it was a small study, it was groundbreaking in its efficacy. And it changed, overnight, the standard of care for us. We participated in the study. And as soon as the study ended, it became our standard of care. And then it swept across the country, and many people, that became their standard of care.

And this idea of this triplet versus doublets was finally tested in a randomized study. And that was the SWOG study that compared lenalidomide/bortezomib/dexamethasone to lenalidomide and dexamethasone alone. And the triplet versus the doublet was associated with higher response rates, higher improved progression-free survival and, most importantly, an actual improvement in survival. And if you look out 5 years, the absolute survival benefit was 10%.

And so now everybody accepted that triplet’s important. And so then the question now becomes, okay. We now know that the triplet’s the best way to go. It’s using lenalidomide/bortezomib/dexamethasone as shown to be the right triplet. How can we improve upon that? I think the greatest challenge with giving bortezomib for a long time is underlying peripheral neuropathy. And the other issue is that while that initial study had a response rate of 100%, now, when we’ve had many more years of experience and many more patients treated with that regimen, the overall response rate’s probably on the order of somewhere between — some studies show as low as 80% but probably closer to about 90%.

And the other thing is that not everybody goes into complete remission. So we still need things like high-dose therapy and autologous transplant. And so people have tried to say, “Can we do better than that?” And when you look, at least in the relapsed setting, the use of carfilzomib is superior to the use of bortezomib — when looked at the ENDEAVOR study in terms of response rates and progression-free survival and so forth.

And so I think a very natural step was to look at, can we move that to the induction therapy? And so carfilzomib/lenalidomide/dexamethasone has been studied in multiple small studies that have shown that in a large part it is very effective, very high response rates, very high VGPR rates, near-CR rates, MRD negativity rates. So every measure of disease control has shown really positive results.

And a very important study was done by the French, which looked at a comprehensive carfilzomib/len/dex induction therapy followed by transplant followed by consolidation followed by maintenance. And it modeled a previous experience they had in this same exact design, taking out bortezomib and putting in carfilzomib. And what they showed is — what we’ve seen previously was that very impressive response rates and so forth.

The challenge that they showed was a significant percentage of patients had serious adverse events, whether they be cardiac or hypertension or renal dysfunction. And about 18% of patients had a serious adverse event on that study, which is higher than what we saw with bortezomib. And so now, in contrast to when bortezomib/len/dex became the standard, it was transformative overnight.

Now we’re on somewhat finer margins of improving on outcome. And when we’re on the finer margins, we really have to balance the benefits — that is, higher response rate, higher CR rates, higher NRD negativity rates with the toxicity. And so in order for an approach like that to take over as standard of care, I have advocated that we really need a Phase III study to answer the question. And, fortunately, we have a Phase III study now that is answering that question. This is the ECOG study looking at carfilzomib/len/dex versus bortezomib/len/dex.

Clinical experience with carfilzomib-associated dyspnea and cardiac dysfunction

DR LOVE: And maybe you can talk a little bit more about your own clinical experience with carfilzomib. You referred to the adverse events. And one thing we’ve been hearing ever since it came out is this question of dyspnea that sometimes people have. It seems like it’s around the time of the infusion, may be related to the volume in the infusion, a question about whether it affects the heart. What’s your take on this, both clinically and research wise at this point?

DR KAUFMAN: Yes. I think when we first were giving carfilzomib, we clearly were giving too much IV fluids. And I think we’ve backed a little bit off from that. Our experience, and what’s published experience, there is a small percentage of patients, probably around 5%, who will have some sort of real cardiac dysfunction, including a decline in their EF and really a requirement to stop the carfilzomib.

But more commonly is the side effect that you mentioned of dyspnea on exertion and the feeling of dyspnea. And that is more common. It’s usually not dangerous. When a patient has it, it’s our obligation to make sure it’s not something from a significant cardiac dysfunction. But it’s common. And the classic story is, the 1 to 2 days around the carfilzomib the patient will feel short of breath, and then as you get further away, the shortness of breath will dissipate.

I don’t think we understand the exact pathophysiology of it. I think the most reasonable explanation is that it’s some sort of vascular dysfunction within the cardiopulmonary system. But I don’t know if we know for sure. But it’s not transient heart failure and so forth. And if patients have it and they know it’s not serious, in a large part you can coach them through this. And they know to expect it, modify their life for the 1 to 2 days and then move on.

Minimal residual disease detection in MM

DR LOVE: You’ve referred to the term “MRD.”

DR KAUFMAN: Right.

DR LOVE: Can you explain what that is and at this point what it means in clinical practice?

DR KAUFMAN: Right. So MRD stands for minimal residual disease. And now that we’re getting therapies that are more effective, we’re seeing more complete remissions. And complete remission, the standard dose that — I’m sorry — the standard definition of complete remission is that we can’t detect any evidence of myeloma by our standard means. And the standard means means bone marrow biopsies, serum protein electrophoresis and immunofixation and urine protein electrophoresis and immunofixation.

The reality is that even though we can’t detect it, we know there’s myeloma underneath. And that’s where MRD comes into play, is that MRD detects myeloma that we can’t otherwise see in those patients who are in complete remission. And whereas a complete remission, the concept of complete remission would be that we could detect in a bone marrow biopsy 1 in 1,000 cells, MRD negativity is that we’re getting to the level that we could detect 1 myeloma cell in 10,000 or in 100,000 or even 1 myeloma cell in a million other cells.

Trials investigating the role of transplant in the era of effective up-front treatment strategies for MM

DR LOVE: So one other question related to this initial phase is the issue of the transplant that he had.

DR KAUFMAN: Right.

DR LOVE: And I think the original idea behind transplant — you can explain that — came out before all the new drugs came out.

DR KAUFMAN: Right.

DR LOVE: And there’s been questions out there of do we still need to be doing transplant in these people who are getting much more effective drugs. Can you talk about the idea behind transplant?

DR KAUFMAN: Right.

DR LOVE: What it is attempting to do and whether or not we know today that it’s still relevant?

DR KAUFMAN: So what we do with a transplant is that we give a very high dose of conventional chemotherapy after the original induction therapy. We call induction therapy, because we’re trying to induce a remission. And then the transplant, the very high dose of chemotherapy’s goal is to try to drive that remission level, whatever it is, to its lowest possible level. And then the subsequent positive outcome from the driving that remission level low is to be associated with an improvement in both progression-free survival and overall survival from the patient.

So I haven’t mentioned transplant at all. All I’ve mentioned was the very high dose of chemotherapy. And so the positives is the disease control and subsequent improvement in time-related outcomes, like PFS and overall survival. The side effect of the very high dose of chemotherapy is the elimination of the body’s ability to make blood and the damage to the body’s immune system. And so before we give that high dose of chemotherapy, we collect the patient’s own stem cells.

And we collect those stem cells several weeks before transplant. We then freeze them then give the very high dose of chemotherapy. And then 1 to 2 days later reinfuse those stem cells with the idea that the body will recover in terms of making blood again, restoring the normal immune system and the myeloma will stay away.

And so when transplant was compared to no transplant, which now it’s been more than 2 decades since that initial study was published, there was clearly a survival advantage to the transplant versus the no transplant. And ever since that study was initially published and then subsequent studies then confirmed, there have been multiple studies asking the question, say, “Hey, look. We have more effective therapies now. Maybe we don’t need transplant.”

And studies that were published all showed the same finding, which is, doing the transplant no matter what other therapy is done is associated with an improvement in disease control, as measured by complete response rate, MRD negativity rate and improvement in progression-free survival.

Now, in those patients who don’t get initial transplant up front, we still collect the stem cells. And so then if we subsequently transplant those patients later, the ultimate overall survival doesn’t change. And so when I talk about transplant to my patients and I say, “If you take a population of patients and you compare doing transplant versus never doing transplant, there is a clear survival advantage. You live longer.” And the survival advantage is on the order of several years. And several years, while it’s not the difference between cured and not cured, it’s still a long time. It’s still a lot of time that people can spend with their families.

DR LOVE: And that’s a median, too, because some people might have greater benefit.

DR KAUFMAN: That’s exactly right. That’s a median. That’s exactly right.

Now, and so then if you compare transplant now versus collecting stem cells and saving them for a rainy day in a population of patients, the percentage of patients who are alive is the same. The overall survival is the same between those 2 groups.

And so that’s what the new study that was published by the French group showed, that when everybody had RVd as induction therapy and you compared early transplant versus ongoing RVd and 1 year of maintenance therapy, that response rates were higher, CR rates were higher, MRD was higher and progression-free survival was higher with early transplant. Overall survival was the same.

And so with that data, you could look at that data and interpret it in many different ways. But I think what that tells us about where transplants fit in populations. It doesn’t tell us individual patients. And so we, for a very long time, have recognized that there are some patients who might be able to go without a transplant. And I think the goal of our initial therapy now is to induce MRD negativity, the best possible response.

And I think probably one of the smartest thinkers in all myeloma, our colleague Antonio Palumbo from Italy, probably said the thing that has stuck with me the most when I think about what the right thing to do is. And he said in myeloma, “It’s very simple. If what you’re doing is working, continue it. If what you’re doing has stopped working, then change.”

DR LOVE: When you’re kind of trying to make this complicated decision, I would imagine another issue might be kind of the patient’s lifestyle. This man was retried.

DR KAUFMAN: Right.

DR LOVE: I can imagine you have people who are working, supporting a family. I don't know how, for example, how long you have to be out of work in order to get a transplant.

DR KAUFMAN: Yes. I mean, I think — we tell people in terms of staying out of work — and, on some levels, it depends on their job. A patient who is outside and doing heavy lifting and being exposed to who knows what in the environment, I’m going to want that patient to stay away from work for at least 3 to 6 months. A patient who works in an office, if they feel up for it, I let them go back to work 4 to 6 weeks later.

But 4 to 6 weeks is really an outlier of going back to work. Most people can do most of their activities sometime between 3 and 6 months after the transplant.

Benefit of indefinite lenalidomide maintenance after autologous stem cell transplant (ASCT)

DR LOVE: And that really kind of leads into the next thing I was going to ask you about, which is post-transplant and the issue of maintenance. And you were talking about Dr Palumbo’s concept of long-term or continuous therapy. Where are we today in terms of the use of so-called maintenance therapy after transplant?

DR KAUFMAN: Right. So the most commonly used maintenance therapy after transplant is lenalidomide as a single agent.

And it was approved at 10 mg a day, continuously, and can go up to 15 mg after several months of tolerance, or it can go down to 5 mg a day, if there’s less tolerance. And the data is very strong.

There is a dramatic improvement when lenalidomide as maintenance therapy is used until progression or in terms — intolerance of therapy as opposed to a fixed period of time. And so when used to progression, the CALGB study demonstrated a more than 3-year improvement in progression-free survival. And that ultimately translated into an improvement in overall survival.

I think there are several challenges or risks that we need to be aware of when using long-term lenalidomide maintenance therapy. One is the increase in second primary malignancies. The baseline rate after a transplant is somewhere around 2%, 2% to 3% and primarily looking at hematologic malignancies.

And that rate probably doubles with the long-term use of lenalidomide as maintenance therapy. Even with that doubling, we still see the profound impact on improvement in progression-free survival and overall survival. And so the biggest risk in a myeloma patient’s life is their myeloma. And so in a large part, we counsel the patients on the risks of second primary malignancies and try to put it in perspective.

Management of toxicities such as diarrhea and rash associated with maintenance lenalidomide

DR KAUFMAN: The second challenge we face with lenalidomide as maintenance is the ongoing toxicities. The most common toxicities are fatigue, cramps and diarrhea. And I think the one that we’ve learned the most about that we can manage that I think probably our nurses can help the most is in diarrhea. We know that lenalidomide, when used as maintenance therapy over a prolonged period of time, can be associated with bile acid malabsorption.

And we get a classic story of diarrhea, which is, the patient’s doing fine, then all of a sudden, they have an extreme urge and then have diarrhea that happens very quickly. And it happens because of bile acid malabsorption. And so we’ve been using, for several years now, bile acid sequestrants, like cholestyramine or colestipol. These old cholesterol medications are profoundly impactful in terms of improving the quality of life in patients on maintenance lenalidomide in controlling the diarrhea. And using things like loperamide just is, quite frankly, not helpful.

And so very important. Recognize the diarrhea is from bile acid malabsorption, and get the patient on a bile acid sequestrant.

DR LOVE: When you see problems from lenalidomide, is it usually early on? Or sometimes people do well for a long time and then have problems?

DR KAUFMAN: Yes. So the early-on toxicities that happen are things like rash. That happens early. When the patient develops a rash, it’s usually not severe. You can hold the drug, dose reduce, the rash goes away. The belief is that rash is a direct immunologic effect and not an allergy. If a patient has a severe rash with blistering or lips blistering, that’s the type of rash that you would never want to reintroduce the medication.

But for the standard maculopapular rash, the redness on the chest or back, you can hold therapy, let the rash resolve and restart, sometimes give a methylprednisolone dose pack to help overcome that. The toxicities like fatigue, diarrhea and cramps are more of the long-term complications.

Use of bortezomib maintenance in a patient who did not receive lenalidomide as part of induction therapy for MM

DR LOVE: So one other question about maintenance. You mentioned lenalidomide, but also other maintenance strategies have been looked at, particularly including proteasome inhibitors, even RVd that your group’s looked at. I see this man got bortezomib maintenance.

DR KAUFMAN: Right.

DR LOVE: Now, were his kidneys back to normal by then?

DR KAUFMAN: His kidneys were. And so if you look at the CALGB study, the patients who did the best with lenalidomide in their maintenance are those patients who had lenalidomide up front. And this told me 2 things. One is that the patient tolerated the lenalidomide, and (2), that lenalidomide worked.

And so you selected a patient population where you know the drug’s already going to work. And because he had never had lenalidomide previously and he had had bortezomib previously — and there is data from the HOVON study that showed lenalidomide as maintenance — I’m sorry, bortezomib as maintenance therapy is associated with an improvement in outcomes, progression-free survival and overall survival. And again, going back to that principle, if the treatment works, continue to do it.

And so he was bortezomib responsive up front. And so our rationale was to use bortezomib in this patient as a maintenance therapy, because he had never had lenalidomide previously, knowing that we could always use lenalidomide in the relapse setting.

DR LOVE: And I see that he got bortezomib for 2 years as maintenance.

DR KAUFMAN: Yes.

DR LOVE: Any neuropathy or problems?

DR KAUFMAN: No, so if the patient didn’t have neuropathy in the first 4 or 6, 8 cycles, then he is, again, self selected for somebody who’s not going to have neuropathy later. The neuropathy of bortezomib, it’s going to happen in the first 4 cycles or so. And if it doesn’t happen, it shouldn’t happen.

DR LOVE: So he ended up finally, after going through all these things in 2013, 4 years ago, finished the maintenance. And so he then was just observed off treatment?

DR KAUFMAN: Right. And so the bortezomib, in contrast to lenalidomide, was studied for a fixed period of time. And so we went with what we knew, which was to treat for a fixed period of time. Again, I think that that’s actually unknown, how we should manage bortezomib. But we try to follow the data. And so the data suggested to stop. So he was observed, had an excellent performance status, back to his normal activities for 3 years.

DR LOVE: I’ve got to ask what it’s like to see somebody like this who you start out with thinking they’re never going to feel good again, they’re never going to have pain. And now he’s off therapy for 3 years, feeling great.

DR KAUFMAN: It’s a joy. It’s just an extreme joy, seeing him. This patient knows my family. My family knows him. We’ve been to his house. He hosts a charity — he is one of these guys who hosts the — and I don't know if you’re familiar with the St Baldrick’s events, which is when you shave your hair for childhood cancer research funding. He hosts one of those every year. We’ve been to his event. He gives me a card every year. So like I said, he — this has become a real friend.

DR LOVE: Fascinating.

Combination strategies for the treatment of MM in first relapse: elotuzumab/lenalidomide/dexamethasone, carfilzomib/lenalidomide/dexamethasone and ixazomib/lenalidomide/dexamethasone

DR LOVE: I want to ask you about the next step that occurred — I guess it was last — October of 2016. So he’s kind of cruising along, feeling good.

DR KAUFMAN: Right.

DR LOVE: Then what happened?

DR KAUFMAN: So we’re monitoring him. And we had noted, probably about 6 months previous, that without any symptoms, he had started to have a rise in his light chain. And so we observed him for about 6 months with what’s called asymptomatic or biochemical relapse. And so this patient — he was completely in a complete remission, and then we started to see his light chain rise.

We would follow him. He had no evidence of new bone disease. He had no symptoms. He wasn’t anemic, didn’t have kidney dysfunction. And over that time, probably about 6 months into this observation period, he started to become anemic. And that’s the key that — and we don’t necessarily need to treat the patient when they have a reappearance of a small light chain. But certainly if the patient has high-risk disease or if there’s a very rapid rise, or symptoms develop, we initiate a therapy.

And this initiation of therapy is really one of these moments today, which is such a hard decision to make. It really is a tough decision, because there are so many effective therapies out there for that first relapse.

DR LOVE: So maybe you can just provide an overview of what those potential therapies are and kind of what people are looking at in terms of the next couple of therapies.

DR KAUFMAN: Right. In no particular order, I think we now have probably — what, 5 or 6 randomized trials in this exact space. We have len/dex versus elotuzumab/len/dex. And again, elotuzumab was better than len/dex.

DR LOVE: And if you could just briefly comment on what elotuzumab is?

DR KAUFMAN: Right. So elotuzumab is a monoclonal antibody against a cell-surface glycoprotein called SLAMF7. It’s on myeloma cells and NK cells, and so when used in combination with len/dex was associated with very good outcomes. And then when the randomized trial came out, it was associated with higher response rates and improvement in progression-free survival.

We also saw the use of carfilzomib/len/dex versus len/dex. And again, the carfilzomib is the second-generation proteasome inhibitor. And again, that 3-drug therapy was superior to the 2-drug therapy.

Ixazomib/len/dex was studied. Ixazomib is an oral proteasome inhibitor. It is similar to bortezomib in that it is a boronic acid and reversible proteasome inhibitor, but it’s not oral bortezomib. And ixazomib has a different side-effect profile than bortezomib, whereas the main thing we worry about with bortezomib is peripheral neuropathy, especially that painful peripheral neuropathy. And ixazomib, there is peripheral neuropathy, but it’s much less frequent and it’s much, much less likely to be associated with painful peripheral neuropathy. The more common side effects with ixazomib are GI toxicities like nausea or diarrhea. And then there also can be rash associated with this.

Clinical experience with ixazomib and potential advantages to the use of an oral agent in the maintenance setting

DR LOVE: Could I just ask what your experience is with ixazomib, particularly related to the GI side effects? I’ve heard different things. Do you preemptively use antiemetics? How often do you see a problem?

DR KAUFMAN: I have actually been very impressed with using ixazomib. And GI toxicity, since it’s been approved, has never been a reason that I’ve had to discontinue therapy. And we don’t typically premedicate patients. We provide patients with antiemetics. We counsel them. But most patients don’t require premedications.

DR LOVE: Have you had to dose reduce patients because of that?

DR KAUFMAN: We have. I would say that the most common reason that we actually have dose reduction with ixazomib isn’t the GI toxicity. It’s more of the fatigue/asthenia that people get that is really inexplicable and can’t be managed with medications but can be managed with dose modifications, dropping the 3 mg or 2 mg once a week.

DR LOVE: So you mentioned that this oral proteasome inhibitor is being used in relapsed disease. But I’ve got to say, when I heard about this drug — and I think there’s another one that’s kind of like carfilzomib, oprozomib, the first thing I thought about was people taking long-term treatment, because it’s one thing to take oral versus IV if it’s going to be a few treatments. But now here’s a man who got subQ parenteral therapy for 2 years.

DR KAUFMAN: Right.

DR LOVE: I would imagine it would have been a lot easier for him to have taken a pill.

DR KAUFMAN: Yes. And I think in a large part, where historically when we used bortezomib for a long period of time, like in the maintenance setting or using RVd in the maintenance setting, we have switched over to the use of ixazomib in that setting for that exact reason.

DR LOVE: So could I just — that’s interesting, though, because there’s always the question of when can you switch something or when can you move something up. So, for example, if this man were to present today, would you have given him bortezomib maintenance, or would you have given him ixazomib?

DR KAUFMAN: I probably would have given him ixazomib maintenance.

DR LOVE: Huh. Interesting.

DR KAUFMAN: Yes.

DR LOVE: Okay. So you mentioned a bunch of possibilities. But keep going, because we haven’t even gotten to daratumumab yet.

DR KAUFMAN: Yes. So right. And then the next one is ixazomib/len/dex versus len/dex. And again, the 3-drug therapy was superior. Three of those studies led to approvals. It led to additional approvals of carfilzomib, and it led to initial approvals of elotuzumab and ixazomib, again in combination, again in the relapsed setting.

Activity and tolerability of daratumumab-based regimens for relapsed/refractory (R/R) MM

DR KAUFMAN: And then the other 2 studies that are very important are the daratumumab studies. So daratumumab is a monoclonal antibody against CD38. In the 3-plus-line therapy, in the relapsed/refractory setting, it is effective as a single agent with about a 30% response rate. And toxicities are very manageable. The primary toxicities are infusion-related reactions, which occur in about 50% of patients in the first cycle, 10% of the patients in the second cycle and then rarely after that.

And there are other things that we have to look at to manage daratumumab over a prolonged period of time. But when you look in the early relapsed setting, there were 2 studies, daratumumab/bortezomib/dex versus bortezomib/dex and daratumumab/len/dex versus len/dex. And both of those studies showed much higher response rates and a higher progression-free survival.

And the types of progression-free survival that we just haven’t seen before in this patient population, with the caveat that we’re still very early in the follow-up. We’re still looking at median follow-ups of 18 months. And so I think it’s still early in its evaluation to really understand the very long-term impact.

Rationale for the investigation of pomalidomide in combination with other agents for patients with R/R MM

DR LOVE: So even though you put together a long list, actually there’s one other thing that I don’t think you mentioned yet, which is pomalidomide. And there’s the combination of — I’ve seen a lot of carfilzomib/pomalidomide and dex.

DR KAUFMAN: Right.

DR LOVE: What is pomalidomide? And where does that fit into the relapsed setting?

DR KAUFMAN: Yes. So pomalidomide is also an IMiD in the same family as thalidomide and lenalidomide. And now we have pomalidomide. Pomalidomide is a very potent drug in this class known as the IMiDs, or the immunomodulatory agents. Pomalidomide, when studied in the greater than 2 lines of therapy setting, is effective in patients where lenalidomide no longer works, so same class but becomes effective.

So if you look at pomalidomide and dexamethasone in this patient population, those patients where lenalidomide doesn’t work anymore, the response rate is right around 30%. And when I introduce using pomalidomide, it’s good news/bad news. Good news is, we have an option that’s going to work in about 30% of the patients and is going to work whether you have high-risk cytogenetics, it’s going to work whether lenalidomide worked or not.

The downside is, about 2 out of 3 patients, it doesn’t work. And so that’s really where we started thinking about combinations. We’ve looked at combinations like carfilzomib and pomalidomide when — there’s been several studies which have shown response rates around 2 out of 3 patients. There have been presentations using daratumumab and pomalidomide. And again, we’re right at that number of 2 out of 3 patients respond, maybe a little bit lower, maybe a little bit higher, whichever series you look at.

DR LOVE: And maybe we can finish out just following up on what happened with this patient and what his current situation is.

DR KAUFMAN: Yes. So we decided to use the all-oral regimen for him, using ixazomib/lenalidomide and dexamethasone. He has tolerated it very well. He’s currently in the midst of cycle 6. He’s in a VGPR. And his quality of life is excellent. And when we see him in clinic, it continues to be an absolute joy.

DR LOVE: And again, no issues with the ixazomib?

DR KAUFMAN: He has not had toxicity with his treatment so far.

Safety and efficacy of venetoclax monotherapy in R/R MM 

DR LOVE: And one final question about relapsed disease, which is, we’ve heard a lot about the agent venetoclax in, particularly, chronic lymphocytic leukemia, but we’re starting to hear about it in other diseases. Can you talk about what venetoclax is and how it’s starting to look like it might be relevant for myeloma?

DR KAUFMAN: Right. I will tell you that we at Emory, at Winship, are very excited about venetoclax. We’re lucky enough to have a scientist at our institution who is really one of the world’s experts in understanding apoptosis in myeloma and years ago made the observation that some myeloma cells are dependent, or at least codependent, on the antiapoptotic protein Bcl-2. Most myeloma cells are protected from dying from apoptosis by the antiapoptotic protein MCL1. And some myeloma cells are dependent both on MCL1 and Bcl-2 to survive.

And the patients with myeloma who are most likely to be dependent on, or at least codependent on, Bcl-2 to help the myeloma cell from dying are the patients who have translocation of 11;14. And translocation 11;14 myeloma is a unique type of myeloma.

And so if you looked at the Phase I study, we looked at venetoclax as a single agent. And if you look at the non-11;14 patients, the response rate is very low. It’s probably around 6%. But if you look at the translocation 11;14 patients, the response rate in the relapsed/refractory setting as a single agent was 40%. And that’s higher than as a single agent.

And again, when I say “single agent,” this is no dexamethasone, no other medication, just single-agent venetoclax. Forty percent response rate is higher than what we see with daratumumab, higher than bortezomib, higher than lenalidomide, higher than pomalidomide, higher than carfilzomib. And so it’s possible, for the first time, that we’re going to be able to see really predictive medicine in myeloma. That is, if you have 11;14, then that doesn’t guarantee a response, but that enriches the chance of response. And now we have a 40% response rate. And in the laboratory, we’re doing a lot of work to try to figure out which of those 11;14 patients is most likely to respond.

DR LOVE: One final thing about venetoclax, which is what we’ve heard from the lymphoma/CLL people is, very well tolerated, quality-of-life wise, essentially no quality-of-life side effects, but a lot of concerns in CLL about the potential for tumor lysis syndrome.

DR KAUFMAN: Right.

DR LOVE: Again, in myeloma you also see no quality-of-life side-effect things?

DR KAUFMAN: Yes, in general the drug is very well tolerated. I think the most common side effect that people have are GI-type side effects, whether it’s diarrhea or nausea. Our patient who’s been on the longest, though, is now approaching 3 years.

DR LOVE: Wow!

DR KAUFMAN: In a continuous stringent complete remission.

But, getting back to the other very important point, the one of tumor lysis, in CLL the management of venetoclax is very well outlined in CLL patients with starting it at very low doses, monitor carefully and increasing. In myeloma, we have not seen tumor lysis, symptomatic tumor lysis syndrome.

There are a handful of cases where we see tumor lysis laboratory abnormalities without symptoms, things like a rise in LDH, but we haven’t seen, even in patients exquisitely sensitive to the drug, haven’t seen clinical tumor lysis. We haven’t seen renal dysfunction. We haven’t seen electrolyte abnormalities. We haven’t seen people get sick.

And in myeloma, we don’t do a step-up dosing. We start at 400 mg, which is an effective dose. And, I mean, in the studies, we’re even starting at 800 mg.

DR LOVE: That’s fascinating.

DR KAUFMAN: Just straight off. We are cognizant of the tumor lysis potential. And so if we use venetoclax, we always hydrate, start allopurinol for several days beforehand and monitor for tumor lysis carefully in that first 24 hours.

Case: A 47-year-old woman with newly diagnosed MM receives lenalidomide/bortezomib/dexamethasone (RVD) induction followed by transplant and lenalidomide maintenance

MR BRIGLE: When we first saw her, she actually wasn’t expecting a diagnosis of multiple myeloma. She had a history of degenerative joint disease and already had a right hip replacement. And so her left hip pain she thought was actually just related to that. And so when they did x-rays and found a lesion in there and biopsied it and found that that was full of plasma cells, and so that was her diagnosis then of multiple myeloma. So she was very active for the most part, exercised every day. And so I think she just thought it was more of the same.

DR LOVE: What was her family situation? What kind of work did she do?

MR BRIGLE: Yes. So she kind of works in her husband’s business. He is actually a representative. He does orthopedic surgery implant-type things, sales for that. And she has 2 young children. One’s about 12 years old and the other’s around 9 years old, 2 young girls.

DR LOVE: And what were some of the key things about the workup of this patient that were important in determining how you were going to proceed?

MR BRIGLE: I think probably the first thing you think of was that she was very young to begin with and had lytic lesions. So her pathway was definitely going to be induction chemotherapy and then on to transplant. So that was kind of given from the start. And the fact, of course, that she had lytic lesions led us to look for other lytic lesions. That was an important thing then as well.

DR LOVE: Any other evidence of disease outside the bone?

MR BRIGLE: Just in the bone marrow she had disease, yes, but nothing else.

DR LOVE: So I see that she got lenalidomide/bortezomib and dexamethasone, the so-called RVd regimen.

MR BRIGLE: Correct.

DR LOVE: What did — I’m curious when you sat down with her to explain to her what multiple myeloma is — as you mentioned, she’s much younger than the average patient — and the therapy, the therapeutic course that you were recommending, what are some of the things that you went through with her?

MR BRIGLE: Of course with anyone, especially a woman who is of childbearing age, which she was, anyone under 50 has to go through a pregnancy test, so discussing lenalidomide and the potential of harm to unborn fetuses, that was probably the most important thing. People don’t like to hear that to begin with, and so I think that was where we really focused on that part of it.

And then we moved into other potential side effects with lenalidomide, of course, which are the blood clots. And she was a very active woman, but she still needed to be anticoagulated.

DR LOVE: Now, one other thing about the initial workup is the issue of cytogenetics and trying to figure out what the risk situation is. What do you typically do, and what did you see in this patient?

MR BRIGLE: Yes. So in this patient, of course, we do the FISH and the standard G-banding off of the bone marrow biopsy. And she had a number of cytogenetic abnormalities, nothing that was high risk. She had a number of, basically, duplications of chromosomes, which are not bad risk factors. And so she really staged as more or less a Stage I. She was actually, from that standpoint, a low risk.

DR LOVE: So you mentioned about the lenalidomide, but she also would be receiving bortezomib.

MR BRIGLE: Right.

DR LOVE: How is that generally administered in the RVd regimen? And what are some of the things that you discussed with her about receiving bortezomib?

MR BRIGLE: Right. And so in the RVd regimen, the bortezomib is administered, always, subQ. I know there are some individuals that still do it IV, but we also do it subQ, as it has fewer side effects. So the main factor with her that we discussed was the neuropathy, which is the dose-limiting side effect of the bortezomib. And so especially as a young woman, we didn’t want to impair her. She’s got a long life ahead of her if all this works really well.

So it was an important thing and not something you can see by labs. And so we always tell people that, “I can’t look at you and tell if you have neuropathy, but can we talk about it every single time? And talk to the nurses about it, as well.”

DR LOVE: What do you typically see when neuropathy does develop? What are usually the first signs of it?

MR BRIGLE: I think the first signs are really what the patient tells us, is that the numbness and tingling, typically in the fingertips and the toes. I think if anything, it happens more in the feet than it does in the hands. But still, that’s the red flag to think about dose reducing and/or holding it, if absolutely necessary.

DR LOVE: What about the dexamethasone in this situation? Again, anything that you mentioned to her about that?

MR BRIGLE: Yes. And I think the dexamethasone is always the bad guy in pretty much all the heme malignancies, and multiple myeloma is no different. And so we do talk about how to take the dexamethasone as well. And we kind of leave that up to the patient. We try to pick a start day and a good dexamethasone day for them. We talk to them all about the myriad of side effects with the dexamethasone, especially the labile mood and the lack of sleep that can associated with that.

And with a lot of patients, we tell them one of the better things to do is perhaps take it in the evening. And that way, it doesn’t really ramp up until later, maybe late in the morning or early morning the next day. And so it makes it a little more palatable. But I think also that discussion is really important to have with the caretaker or other family member there as well, to let them know that some of these emotional changes are going to happen that are really out of their control.

DR LOVE: How did she actually do when she got the RVd? Did she have any kind of tolerability issues?

MR BRIGLE: No, she didn’t. And, in fact, I think her most significant issue at the time of diagnosis was pain. And I think convincing her that really within the first couple of weeks of getting therapy with the steroids and the lenalidomide and the bortezomib that the pain would come under pretty good control as we treated the disease. And it really did. And so from that point on, I think when she saw how successful it was right from the start, it — she did really well with it and didn’t mind it.

DR LOVE: Was she taking pain medicines before therapy? And was she able to stop them?

MR BRIGLE: Yes. She took a little pain medicine. She is one of those people who didn’t like to take pain medicine. So she kind of grinned and beared it a little bit more than anything. And yes, shortly after, probably within the first month, discontinued all pain medication altogether and started actually doing some more low-impact type of exercises again.

Educating patients about the goals of treatment and expectations surrounding ASCT

DR LOVE: What kinds of discussions, if any, did you have with her about the goals of therapy? Did she bring up curability, survival, et cetera?

MR BRIGLE: Yes. And I think that’s always an up-front discussion as well, so pointing out that it is not a curable disease but certainly a treatable disease and that whole pathway again, induction to stem cell transplant, looking for long-term survival and with the idea that once you start therapy, you’re probably never going to be off of therapy. So we keep people on a maintenance regimen. And the hardest part, hopefully, is going to be the induction and, certainly, the stem cell transplant. But to make the maintenance part of the treatment as palatable as possible so she can continue a normal life.

DR LOVE: How did you assess her — I mean, this is not easy for a 47-year-old to hear, even though it’s treatable, that, really, not likely to be cured. How did you asses her coping strategies? Had she ever encountered a serious medical problem before?

MR BRIGLE: No, she hadn’t, short of the degenerative joint disease, which is probably pretty significant for a person her age. She really did not have any significant stressors like that. And so we actually referred her to one of our counselors. And we got her kids involved as well, so they talked to her. So I think involving the kids with the whole thing was pretty good.

DR LOVE: So getting back to this lady. So she gets the RVd. Sounds like she’s responding. Again, how did you explain to her what the rationale is to go through an autologous transplant, what an autologous transplant is and what should she expect from it?

MR BRIGLE: Yes. And so obviously, the rationale is that at least the current data suggests that going through an autologous stem cell transplant increases not just progression-free survival but overall survival. And so long-term survival is what we’re looking at here. And so we can get her through and again, not have to intensify her treatment later. That would be a good thing, if we can just keep her on maintenance.

And so it was that whole idea that the induction chemotherapy gets everything down to its lowest possible degree, maybe even what we call a complete response, but that we still know it’s there. And so the high-dose chemotherapy that she was going to receive would hopefully take care of the majority of what was left.

DR LOVE: And what do you tell them to expect in terms of side effects and toxicity and being out of work, et cetera?

MR BRIGLE: Yes. And so I think the transplant team does it really good. So in our typical organization, or in the way our organization is set up, we have a transplant floor and a transplant team. They don’t actually follow the patient all the way through. So we refer them up to transplant. They do a pretty good job, giving them all the side effects.

But, obviously, we prep them ahead of time and talk to them about potentially spending the 2 weeks in the hospital, losing their hair, potential mucositis, things like that, and that usually the magic number is day 100 when they can expect to be back, but some people a lot sooner than that. Especially younger people can be back and much more active sooner.

DR LOVE: Now, you admit people to the hospital?

MR BRIGLE: Yes. We do admit the people. I know there are some outpatient ones. We don’t yet have that.

DR LOVE: And how long are they typically in the hospital?

MR BRIGLE: Typically, I always tell them 2 weeks. And that’s about where it runs.

DR LOVE: So what happened with this lady when she went for a transplant?

MR BRIGLE: Oh, she did great, exactly like you might expect, good young bone marrow, went in and responded very nicely. And she was out within 2 weeks. And recovery, I think she was kicked back to us probably by about day 70, long before that day 100.

Dosing and tolerability considerations in patients with MM receiving indefinite lenalidomide maintenance therapy

DR LOVE: So when you see a patient after they’ve had transplant, what are some of the things that you look at as you start to think about what’s going to happen next?

MR BRIGLE: Yes. I suppose that one thing is how well they do with the transplant and what’s their performance status from that standpoint. Obviously, hers was really good. And then what do their counts look like in terms of the bone marrow reserve, because the next step is then putting them on maintenance therapy, at least by day 100. And so you may not be able to use the same dose of lenalidomide, if we’re doing the lenalidomide maintenance therapy as we used up front, as their marrow reserve might be a little bit less.

And so it’s a lot of, again, looking at the whole picture of the patient, not just the counts, performance status and sometimes it’s how active or how much they want to get back in the saddle and get going as well.

DR LOVE: And what was her disease status going into the transplant? What was it coming out of the transplant? And how do you assess disease status in patients?

MR BRIGLE: Yes. So obviously, going into the transplant, obviously, we do all the lab studies, the bone marrow biopsy. Again, we do the cytogenetics and the FISH as well, and then look at the molecular markers, the serum protein electrophoresis, the light chains and things like that. So she had a complete response going in. She still had a little disease left by IFE.

But coming out of the transplant, she had a good stringent complete response with no evidence of disease even by our best markers. We didn’t assay for minimal residual disease but by the best standard markers.

DR LOVE: So at that point, what did you recommend? What happened to her after having had the transplant and she’s had this really good response to treatment?

MR BRIGLE: Mm-hmm. Yes. And so she had actually started back exercising. And we had her get a repeat bone marrow biopsy. Again, everything looked good. And so then the discussion was where to go from here. And we talked about the standard 21 days on and 7 days off, very much like she was used to with the RVd regimen then as well. And again, we had to use a slightly lower dose, as her counts weren’t quite back up to snuff. So we started with a lower dose then, also.

DR LOVE: What do you typically see in — now, these people who get maintenance after transplant, a lot — do you generally use it indefinitely, as long as they’re tolerating it well?

MR BRIGLE: Yes. And then I think that’s the philosophy of our group, is to continue to use it indefinitely as long as the counts hold up, no problems with infections or any other significant side effects, is just to continue the maintenance therapy.

DR LOVE: Do you generally find that patients can tolerate it indefinitely, or do they often run into problems?

DR LOVE: Yes. I think the majority of patients do tolerate it. I think just finding the dose that’s proper for them. And so that’s probably the big thing, not starting out too high but starting out at a good dose and whatever the counts will tolerate.

DR LOVE: Other than blood count alterations, do you see anything else long term? I have heard about dermatologic issues. Do you see that?

MR BRIGLE: I haven’t really seen any significant dermatologic issues. I typically will see that when patients start the lenalidomide. They get this little rash. But it seems to be self limiting. And patients who might have had that rash when they had induction therapy might experience it again. But typically, that tends to go away as the cycles go forward.

Practical considerations with the use of carfilzomib

DR LOVE: So I’m kind of curious. Have you ever used carfilzomib up front now, the so-called KRd regimen, which is similar except instead of bortezomib you use carfilzomib? It’s being looked at in trials.

MR BRIGLE: Yes. We currently have a clinical trial open using carfilzomib up front in combination with lenalidomide and dexamethasone. So we have used it up front — I guess, kind of up front — in patients who do not respond to the typical RVd regimen right away. So we’re quick to switch over should we go 3, 4 cycles and don’t see much of a response. We’ll jump over that way. But I think the clinical trials have given us the best experience.

I think it’s one of the situations we have even when convincing patients to come onto the clinical trials. They do not currently like the idea and the way the clinical trial’s set up, that you have to come in twice a week for the carfilzomib. So it’s given 2 days in a row. And typically they’ll get steroids 2 days in a row as well, so that becomes the hard sell, I think, for the carfilzomib up front.

Patients tend to do well with that, also in combination with the lenalidomide. The dose doesn’t get quite as high. We do see, I think, more fatigue with the carfilzomib than we do with the bortezomib.

DR LOVE: I’ve heard people talk about dyspnea with carfilzomib, patients — I’m not sure if it’s related to fluid or whatever. Have you seen anything like that?

MR BRIGLE: Yes. I’ve seen that, but typically not in the up-front setting. But we’ve seen that more in patients who’ve relapsed. And so you’re right, I don't know if it’s fluid overload. We tend not to give the patients as much fluid as we did when the drug first came out. I think we saw a lot of it more frequently when we first started using the drug, a little less frequently now.

Case: An 88-year-old woman presents with worsening neuropathy and is found to have elevated M protein in the serum and a bone marrow biopsy showing 20% plasma cells

DR LOVE: So I think that was a great case to kind of get into the younger patient who’s going through transplant. But, of course, a much more typical situation is an older patient.

MR BRIGLE: Right.

DR LOVE: And I see you have an 88-year-old woman, so that sounds like it’s on the elderly side. Can you talk about how she presented?

MR BRIGLE: Yes. So she presented essentially with neuropathy and had gone to a neurologist or a number of neurologists to be worked up for the neuropathy, really couldn’t find a good source. And at some point, one of the outside providers apparently had done a hepatic panel, noted that there was elevated serum proteins and so also then ran the SPEP and noted that was the case as well, so referred them to us.

And she had elevated serum proteins and elevated light chains as well. And so a potential cause then, to the neuropathy, which was worsening with her over the time. And she was a very functional 88-year-old and her 90-year-old husband. They traveled around still. So this was becoming bothersome for her.

DR LOVE: And did she have any other disease? Particularly, did she have bone disease?

MR BRIGLE: No. She really didn’t. She has a long history of osteoporosis, which is a family problem, and so that, unrelated to the multiple myeloma, but, of course, we ended up giving her some bisphosphonates as well, for the myeloma. And it may have helped that osteoporosis as well.

DR LOVE: Now, had this lady had any serious medical problems in the past?

MR BRIGLE: No. Actually, she was amazingly healthy. She was perhaps on a high blood pressure medication and maybe a statin, but really nothing significant. So she and her husband were both, I’d say, very active for their age.

DR LOVE: And as you looked at her, what were some of the options that you sorted through? The other patient — and a lot of patients nowadays get triple therapy with a proteasome inhibitor, usually bortezomib with lenalidomide. What about older patients?

MR BRIGLE: Yes. I think the problem with triple therapy in her would have been the potential neuropathy with the bortezomib. So she was already suffering from a neuropathy, so that became a challenge. We could have gone, perhaps, to the carfilzomib, but as an older woman, we could always add that in.

So the decision was maybe just go with a doublet and keep the dexamethasone dose low as well and see how she did with that and if she was responding. And if just the doublet would help her neuropathy, that was probably the most important thing. Maybe we didn’t need to go to a triplet.

DR LOVE: So you were thinking that maybe the neuropathy might be reversible?

MR BRIGLE: Yes, absolutely.

DR LOVE: What’s the thinking about why people get neuropathy from myeloma? And how often do you see it?

MR BRIGLE: Yes. I don't know the national statistics or the disease statistics on that, but we do see some patients coming into their diagnosis with neuropathy. A lot of times that’s related to diabetes and things like that. But the thought is, of course, that those serum proteins actually adhere to those peripheral nerves then as well. And so potentially, if you can get any — I don't know if it’s a permanent thing, because we actually do see some of that neuropathy improve.

Choice of an induction regimen in older patients with MM

DR LOVE: What’s your typical approach to a patient who doesn’t have neuropathy but yet is older? One of the things I’ve heard is the so-called, quote, RVd-light, which is, you use RVd, but not as high a dose.

MR BRIGLE: Yes.

DR LOVE: Is that something you might have considered for her if she didn’t have the neuropathy?

MR BRIGLE: Oh, absolutely. Yes. We’re big fans of triple therapy. I think the data bears that out, that triple therapy is the way to go, either up front or in relapse then also. So yes.

DR LOVE: So this lady then got treated with lenalidomide and dexamethasone. How did she do?

MR BRIGLE: She did very well. I think it was a matter with her, also, adjusting the dexamethasone dose to something that she could tolerate. We started low but went a little bit lower for her. I think with her, as with a lot of patients, it was more her husband who complained about the steroid dose than she did.

DR LOVE: So she was getting, like, hyperactive?

MR BRIGLE: I think it was just this labile mood, not so much hyperactive but just that labile mood that patients can get with that and all. And then kind of the come down the day after the steroid.

DR LOVE: That's interesting. And so the patient’s husband was kind of providing that perspective?

MR BRIGLE: Oh. And that’s very common with patients with multiple myeloma, that we get a lot more comments concerning the steroid from the family members than we do the actual patients themselves.

DR LOVE: What was your assessment of her family situation, her husband? I don't know if there are other family members involved.

MR BRIGLE: Mm-hmm. Yes. And she has one son. And he lived way out of state, so there really wasn’t any family support from that situation. But they both drove, and so they were both active that way. And so I think also that was an important part about the regimen. While they lived about 30 miles away, this regimen means they don’t have to come to the clinic on a weekly basis and they could make it up the road.

And they usually had the late-afternoon appointments when the traffic was better. And so to work out for them really well by not having them have to come to the clinic.

DR LOVE: Huh. Interesting, because she was on an all-oral regimen.

MR BRIGLE: Mm-hmm.

DR LOVE: What happened with the disease? And what happened with the neuropathy as she was treated?

MR BRIGLE: Yes. So the disease responded very nicely. So serum proteins went down. And the neuropathy got perhaps a little bit better from her standpoint. Unfortunately, she was expecting it to go away. As she saw the markers go down in her blood, she was expecting the neuropathy to equal that. And it didn’t quite do that, so some of her neuropathy was certainly going to be permanent.

DR LOVE: So she still continues now on the lenalidomide?

MR BRIGLE: Right. Yep.

DR LOVE: So you would expect, unless she develops some other kind of medical problem, which, at the age of 88, may be not that unlikely, but if she doesn’t, you would expect at some point the disease is going to start to get worse.

MR BRIGLE: Yes. I would imagine that. Some people, though, can go for a very, very long time on this. And so that’s kind of what we’re hoping for, that that’ll happen. If it does progress, then I suppose we could go to an agent that’ll unfortunately have her come to the clinic. But, of course, we have other options, too, with other immunomodulatory agents.

Risk of second primary cancer in patients receiving lenalidomide maintenance therapy

DR LOVE: One other thing I was going to ask you about before related to lenalidomide. We were talking before about this idea of using indefinite lenalidomide maintenance.

MR BRIGLE: Right.

DR LOVE: And I’m curious — I don't know. You mentioned that this patient was very well informed — whether you got into the issue of second cancers with lenalidomide, and if so, what you told her about.

MR BRIGLE: Yes, we always talk about that. I think that’s one of the informed consent parts of that and talk about that increased potential. Patients with multiple myeloma always seem to have an increased risk of second primary cancers, and this almost doubles that. It’s still a pretty low number. And it’s always talking about that risk-benefit, potentially keeping the myeloma at bay for longer versus a second primary cancer. And so it’s a similar concept there. It’s a risk-benefit type of discussion.

DR LOVE: And was that a major concern for her, or she was okay with that?

MR BRIGLE: She — for her and obviously for her age, she wasn’t all that concerned about it, because she figured she may not develop a secondary cancer at any point in time. And again, she had not had any cancers, not even a skin cancer up to that point.

DR LOVE: Interesting.

Case: A 65-year-old man receives multiple lines of therapy for R/R MM, including most recently daratumumab with pomalidomide

DR LOVE: So let’s go on now and talk about your 65-year-old man. I know it’s kind of a complex case, and I really wanted to focus more on the later, more recent stages when he got some of the newer agents. So maybe you can kind of just briefly talk about how he started out. And then maybe we can focus more when he had the later stage of the disease.

MR BRIGLE: Yes. So he actually started out as a fairly young guy at 65 years old and had some kidney failure associated with hypercalcemia related to lytic lesions. And so the lesions were treated with radiation for pain control. And then he was once again started on the standard at the time, which was the lenalidomide/dexamethasone/bortezomib regimen.

Unfortunately, he’s one of these gentlemen who had a very severe reaction to the lenalidomide, and so we had to discontinue that at 10 — we went forward then with just a doublet. He did not have much response to that, so we moved forward then with just carfilzomib/dexamethasone. Did not get the greatest response out of that, but we did send him in Transplant. And Transplant was willing to take him.

And, unfortunately, very much like the first 2 parts of the treatment, he didn’t get the greatest response out of transplant either. So when he came out of Transplant, then we just really didn’t do much, because we didn’t really have any maintenance regimen for him. Because, obviously, we’re not going to rechallenge him with the lenalidomide because of that severe skin rash.

His counts started to rise and we went back with what worked a little bit, which was the carfilzomib/dexamethasone regimen then as well. So that continued for a little over a year until he started to progress then on that as well. And then I think the decision at that point was, do we challenge him with the pomalidomide, because that, of course, is very similar to lenalidomide, and would it cause the rash that we saw with the lenalidomide? And so that was where we started low and moved upward. And he had a very mild rash but responded nicely to that.

DR LOVE: Can you explain what pomalidomide is and what your clinical experience is with it?

MR BRIGLE: Yes. So pomalidomide is another thalidomide analog, again, I think, developed exactly at the same times as the lenalidomide, but then they went ahead with the lenalidomide first in terms of developing that. So pomalidomide then is, again, still a second-generation immunomodulatory agent. It does work in cases where either the thalidomide or lenalidomide have failed.

DR LOVE: Any tolerability problems or unique tolerability issues with pomalidomide?

MR BRIGLE: Yes. It might be a slightly more myelosuppressive than the other ones. And I’ve seen a little bit more fatigue with that than I have with the lenalidomide. But overall, patients seem to tolerate that fairly well. Again, finding the right dose for anybody is probably key there.

Efficacy and tolerability of daratumumab and elotuzumab for R/R disease

DR LOVE: I also see that the patient then received daratumumab, the monoclonal antibody.

MR BRIGLE: Right. Right.

DR LOVE: Can you talk a little bit about kind of what you explained to him about what daratumumab is and what your own vision is of how it works and what your experience is with it?

MR BRIGLE: Yes. So again, just prior to receiving daratumumab, we gave him ixazomib as well, which he did not respond to at all. And so we were essentially out of, quote-unquote, chemotherapy agents, if you will.

So the way to explain that to him was, we really weren’t relying on the chemotherapeutic approach but rather allowing his immune system to take care of the myeloma cells and explaining the marker on the myeloma cells that this antibody binds to and then recruits his immune system in to take care of them. And so it was the idea that it doesn’t make any difference if you’re chemo resistant, because now your immune system is taking over the rest of the process.

DR LOVE: I know there’s been an issue with the length of infusion that is sometimes necessary with daratumumab. How long, typically, does it take, particularly for the first infusion?

MR BRIGLE: Yes. That first infusion is 8 and a half hours. That’s what we tell patients. And we get them very — they’re the first patients in the clinic that morning. They get premedicated, which has to happen. And then following that, the infusions get much shorter. So a second infusion generally runs between 4 and 6, and most of them after that we tell them 4 hours.

DR LOVE: And I know there also was a report of the use of daratumumab subcutaneously. Do you know anything about that? Have you, your group, have to talk about the possibility of giving it subcutaneously?

MR BRIGLE: No, we haven’t done that. There was a good study where that was done. And people seemed to tolerate it very well. So I know that’s moving forward to see if it still has the same efficacy as the IV version. But that would be a very nice step forward.

DR LOVE: So this man, after having multiple therapies, now gets started on daratumumab, which really has not been around that long, a couple of years.

MR BRIGLE: No. It hasn’t. Yes.

DR LOVE: What happened when he got the daratumumab?

MR BRIGLE: Yes. So he responded like we’ve never seen him respond to any chemotherapy agent. And so for the first time ever, he actually went into a complete response.

DR LOVE: Wow!

MR BRIGLE: And so after all the years of chemotherapy agents, immunomodulatory agents, he experienced a complete response probably within that first 8 weeks when you’re getting it weekly. And now he’s on the every other-week dosing for another couple of weeks.

DR LOVE: And what has been your experience with the drug in terms of efficacy? Have you seen other patients like this with good responses?

MR BRIGLE: Yes. We’ve seen patients with really good responses. And then, of course, we’ve seen patients who haven’t responded as well or even at all. So as a single agent, which is where we started using it originally, it only had around a 30% response rate. And I suppose that’s probably where we saw it to get these kinds of complete responses. We’ve seen a couple of patients with really nice complete responses. A lot of people get partial responses, but again, I think we’re doing better now that we combine it with either the lenalidomide or pomalidomide as well.

DR LOVE: Can you talk a little bit about the issues in terms of transfusions for patients with daratumumab? I know there’s an issue in terms of blood typing.

MR BRIGLE: Yes. So yes. Before patients get their first daratumumab infusion, we have to send several samples to the blood bank as well, because it does confound the typing. And so if those patients do need transfusions later, we always alert the blood bank. And the blood bank knows ahead of time. They’re flagged in the system then as well. So there’re never going to be perfect cross-matches, and so the blood bank always tells us that, even though we know why they’re not. There’s some confounding issues in there.

DR LOVE: Any other issues with daratumumab in your clinical experience that you think are important to know about?

MR BRIGLE: I think it’s a very well-tolerated drug. And I don’t have a lot of bad experiences with it. I think the patients dislike coming in for that first one and maybe weekly for the first 8 weeks, in terms of if they’ve been just on an oral agent. That visit to the clinic becomes a challenge for 8 straight weeks. But after that, it’s okay.

DR LOVE: So there is another monoclonal antibody that’s been approved, elotuzumab.

MR BRIGLE: Right.

DR LOVE: It’s used with lenalidomide. Can you talk about your experience there, again in terms of efficacy and tolerability?

MR BRIGLE: Yes. So we’ve used less elotuzumab. It is slightly less effective in the clinical trials, needs to be used in combination with lenalidomide. And some of these patients have been quite resistant to lenalidomide as well, and so we’ve moved past that. And a lot of patients who may be early on in their relapse, already on lenalidomide, we can add that in there. But we tend to use less of the elotuzumab in our facility than we do the daratumumab.

DR LOVE: Any tolerability issues with elo?

MR BRIGLE: No. Again, I think the not significant tolerability issues, a few maybe minor infusion reactions. But infusion times are less as well, which I think patients appreciate.

Case: A 66-year-old woman with MM experiences disease progression while receiving lenalidomide maintenance and is switched to the all-oral regimen of ixazomib/lenalidomide/dexamethasone

DR LOVE: So let’s talk a little bit about your 66-year-old lady.

MR BRIGLE: Oh. Okay. My 66-year-old lady, yes. Yes. So she was a lady who was followed in the outside community for many years with monoclonal gammopathy of undetermined significance and eventually had progressed to multiple myeloma. She was initially treated in the community with lenalidomide/dexamethasone/bortezomib, had a pretty good response. And while she was young enough, she opted not to go to transplant, so she was just started on maintenance lenalidomide and continued on that for quite a long while.

And at some point, she started to progress. And that’s when she came to us for a second opinion and options of what to do. And that was actually at the point right when ixazomib was just being approved. And as she came from a distance — she drives about an hour and a half to get to our facility. And so it seemed like a really good option for her then as well, just to combine that, just add that into the mix with the lenalidomide and the dexamethasone.

DR LOVE: And what happened when you did that?

MR BRIGLE: Oh. Great response. So she responded very nicely to that, very quickly to it. And so when she really did not — achieve a complete response but a near complete response. And so we’ve just kept her on that. And she tolerates it very well. Again, we found the dose of those agents that seem to work out well for her.

DR LOVE: So what did you discuss with her when she started the ixazomib in terms of how often she would take it and what kinds of side effects it might have?

MR BRIGLE: Yes. And so I think the challenge with the ixazomib regimen is getting the sequencing right on the drugs, because the ixazomib has to be taken on an empty stomach. And so it’s that challenge of when do you take the ixazomib and when do you take the steroid? And the steroid is taken, preferably, with food to help with tolerability. The lenalidomide can be taken pretty much anytime.

And so she’s very used, of course, to that lenalidomide, 21 days on, 7 days off. And so actually just taking an additional tablet on day 1, or day 1, 8 and 15, wasn’t such a challenge. But the real challenge was finding out is there, I guess, discussing exactly how to take those medications during that day.

DR LOVE: So it does seem a little strange, though, to take a pill once a week. Do you have —

MR BRIGLE: Right.

DR LOVE: Is that a practical difficulty?

MR BRIGLE: Is it a practical difficulty? Not really, no.

DR LOVE: I mean, do you check on patients to make sure they take it, or they just take it?

MR BRIGLE: Yes. You have to — like all of our medications, and the lenalidomide as well, are they taking all 21 tablets and are they taking their ixazomib? And I think if they’ve taken the lenalidomide for 21 days, they’re more likely to join into that. I think it might be more of a challenge for patients who’ve not been on that type of a regimen ahead of time.

DR LOVE: What have you observed in terms of GI tolerability issues with ixazomib? Have you seen any problems?

MR BRIGLE: Yes. I think I’ve seen my combination of both constipation and diarrhea. Nausea has been extraordinarily minimal, so not nearly as high as I have seen in the clinical trials. But we do see, again, the constipation/diarrhea. And I tell patients I can’t really predict what they’re going to have if they take their first couple of tablets, and then we can work on it from there.

Factors affecting a patient’s ability to cope with the diagnosis and treatment of cancer

DR LOVE: I’m curious what this lady’s quality of life is like now. She’s been treated now for a few years. How does she spend her time?

MR BRIGLE: She travels, she and her husband. They tend to do a lot of things that they — I guess the most important part is they didn’t really miss a beat in terms of what they were doing, and so they didn’t really have to change their lifestyle any. Probably the biggest part is, she comes in to see us on a monthly basis. So it makes that travel into Richmond, but that’s really about the only significant problem.

DR LOVE: Do you think you can tell after you’ve met a patient for the first time how they’re going to cope with the disease? What are some of the things that you look for as clues?

MR BRIGLE: Yes. I wish I had a magic crystal ball there to look at those things. I think patients who come in with family support are going to obviously tend to do better, from that standpoint. There are obviously patients with poor financial means and some other comorbidities that we worry about the most. And again, with those patients, probably finding the right dose of the medications, that’ll help out.

In some patients, it’s — and I’ll just say that some patients come in not doing so well. And it’s due to their disease. But once we get the disease under control, they are very different people than when they presented. And so sometimes it’s a challenge, looking at the person right up front and guessing how they’re going to be in 6 months.