We have 5 regimens for induction that are good choices. My order of preference is CRd (or KRd), RVD, CyBorD, VDD (bortezomib, doxorubicin, dexamethasone) and VDT, which is not used in the United States but is commonly used in Europe. They all yield about a 95% to 100% response rate and elicit deep responses. We don’t have definite evidence that one of these regimens is preferable.

I would consider administering CRd for most patients. We have a better chance of achieving deeper responses with CRd, based on the published data. Also, the likelihood of developing peripheral neuropathy is lower with carfilzomib than with bortezomib. I often prefer to use the same regimen for induction also for post-transplant therapy. I can determine how well the CRd regimen is tolerated prior to transplant and continue the same regimen after transplant.

We have enrolled patients on a study investigating CRd prior to and after stem cell transplant in patients with newly diagnosed MM (NCT01816971). No unexpected toxicity occurs, and the results are outstanding. I believe that CRd is eventually going to be the preferred regimen.

When I use bortezomib as part of an induction regimen I generally administer it subcutaneously at 1.3 mg/m² using the twice-weekly schedule for both standard and high-risk disease. I monitor toxicities, and if I observe side effects I switch to a weekly schedule. I prefer to start with the twice-weekly regimen, as we have better evidence of efficacy with that schedule.

I recommend the subcutaneous route of administration for all patients. Patients tolerate this route of administration better, with less neuropathy. Treatment-emergent neuropathy occurs even with the subcutaneous route, but it is of a different quality.

We conducted a study in which we administered CRd for 45 patients with newly diagnosed MM. If this regimen were reimbursable, I believe it would become standard therapy. However, it is not covered by insurance, and that is the problem.

In terms of what schedule and route of bortezomib administration I use when I use this agent for induction therapy, I recommend bortezomib at 1.3 mg/m² subcutaneously on days 1,4, 8 and 11 throughout the course of treatment. Recently we had a 60-year-old otherwise healthy patient who was diagnosed with MM. She received IV bortezomib for 4 doses and developed Grade 3 neuropathy and had to walk with crutches. After such an experience it’s hard to recommend IV bortezomib.

We had a patient on bortezomib who developed severe cerebellar toxicity after treatment with IV bortezomib on the DETERMINATION trial. We may either consider the subcutaneous route or switching to carfilzomib for this patient. However, we generally reserve carfilzomib in combination with lenalidomide and dexamethasone for the relapsed/refractory setting.

The schedule and dose of bortezomib that I use during induction for an otherwise fit patient is bortezomib subcutaneously on days 1, 4, 8 and 11. I generalIy administer 1.3 mg/m² biweekly but may switch to 1.5 mg/m² every week. I prefer the subcutaneous route. If the patient doesn’t want to receive treatment because of toxicity, that would lead to a delay in treatment.

The study by Moreau and colleagues suggested that the efficacy of bortezomib administered subcutaneously or intravenously was equivalent. However, if a patient develops renal failure and a quick response is required, I might consider the IV route initially.

I do not routinely administer carfilzomib up front. I would only consider it if the patient presented with neuropathy or had severe intolerance to bortezomib. The Phase III ECOG study is comparing bortezomib to carfilzomib for patients with newly diagnosed MM and should shed some light on this issue (NCT01863550).

I rarely administer carfilzomib unless the patient has preexisting neuropathy. Not a lot of published data exist with carfilzomib for newly diagnosed MM. Until we have more data, I would reserve it for patients with neuropathy. These are patients for whom a neuropathy-sparing agent is preferable, such as those with diabetic neuropathy. I am surprised that the NCCN listed a carfilzomib-based regimen as a possibility, because it has not been approved by the FDA in the front-line setting. The regimens with carfilzomib that have been investigated in the front-line setting include CRd (carfilzomib/lenalidomide/dexamethasone) and CCD (carfilzomib/cyclophosphamide/dexamethasone). I believe that carfilzomib has a lot of potential in the future. The ongoing Phase III ENDURANCE study is investigating CRd versus RVD in patients with newly diagnosed multiple myeloma. As part of an induction regimen, I would typically recommend bortezomib to be administered subcutaneously and weekly at 1.5 mg/m². The efficacy of subcutaneous bortezomib weekly has been confirmed. We usually continue the subcutaneous route during the entire course. Rarely we may choose the IV route if a patient develops a skin reaction to subcutaneous administration. We observed a decline in the rates of neuropathy when we changed from the IV to the subcutaneous route and due to the decrease in frequency from twice weekly to once weekly. In both cases, the decline was an absolute difference of 10% in Grade 3 or higher neuropathy. The rates of Grade 3 or higher neuropathy have dropped to 2% to 3% compared to 12% to 15%. With the subcutaneous weekly administration, Grade 3 neuropathy is only rarely observed. Importantly, we’ve not seen a significant drop in efficacy when used as part of a combination regimen, especially with the slightly higher dose of 1.5 mg/m². There is not a big difference in the total dose of bortezomib administered at 1.3 mg/m² 4 times versus 1.5 mg/m² weekly for 3 weeks. One of the reasons why the efficacy has not dropped is that with the weekly administration, the dose does not have to be reduced as frequently. We have learned that neuropathy has more to do with frequency of dosing as opposed to the single dose delivered daily.

I would not consider carfilzomib because the drug is not approved in France. The CRd combination is attractive and has impressive results but has not yet received approval. I believe that it will take some time before the drug is approved in Europe in the front-line setting. I would like to see a comparison of carfilzomib versus bortezomib for newly diagnosed MM.

We use bortezomib as part of a triplet induction of VTD or in some cases CyBorD, and the schedule and route of administration that we use is bortezomib biweekly on days 1, 4, 8 and 11, subcutaneously. The goal is to reduce the tumor burden prior to stem cell transplantation. It’s not possible to recommend lenalidomide- or carfilzomib-containing regimens because they are not available in the front-line setting in France.

We have less toxicity, especially peripheral neuropathy, with the subcutaneous route. We recently published data showing that the rate of peripheral neuropathy was reduced with the VTD regimen front line compared to a historic control group treated with VTD, but with bortezomib administered intravenously (Lok 2014).

Carfilzomib is not available in Italy in the up-front setting. I’m fairly conservative, so I would wait for data from a Phase III study before considering this drug. I believe that in the future it will replace bortezomib, because it’s more active and less toxic.

When using bortezomib as part of an induction regimen I typically administer it subcutaneously at 1.3 mg/m² on a twice-weekly schedule. With subcutaneous administration, patients spend less time in the clinic. I switch to once weekly at the first sign of peripheral neuropathy. We prefer the twice-weekly regimen for patients younger than age 65 and once weekly for those older than age 65.

Currently I only administer carfilzomib in the context of a clinical trial. I am not convinced that switching from RVD to CRd would be preferable. The efficacy of carfilzomib needs to be demonstrated in a Phase III study.

If I plan on using a bortezomib-based induction, I recommend it on a weekly schedule subcutaneously in the majority of patients who don’t need to have their disease controlled overnight. In specific situations, such as with patients who have a high tumor burden with high protein levels that may be affecting their kidneys, I might consider a twice-weekly subcutaneous bortezomib schedule.

I have observed a lot less neuropathy with subcutaneous bortezomib. I believe there are 2 reasons. First, with the subcutaneous route, the AUC of the drug is modified and the patient is exposed to lower concentrations of the drug for a longer period. Second and more importantly, the drug is also being administered less frequently when administered subcutaneously.

I would use carfilzomib if there were any concern about neurotoxicity. I would recommend the classic CRd combination.

A bortezomib-based induction regimen that I would use in younger patients is the classic RVD regimen. I usually administer bortezomib subcutaneously, at 1.3 mg/m² on days 1, 4, 8 and 11. I use lenalidomide at 25 mg, 2 weeks on and 1 week off. Dexamethasone is administered at 20 mg on the day of bortezomib and on the day after.

We have had success with subcutaneous bortezomib in prospective studies. However, we do not have published data, so one has to be careful. In our experience the subcutaneous approach is both well tolerated and active.