I generally administer bone-targeted therapy every month for 2 years. After that I continue treatment but at a lower frequency of every 3 months. Extended treatment with zoledronic acid or clodronate has been associated with necrosis of the jaw or other toxicities. The ASCO recommendation initially was to administer zoledronic acid for 2 years and then stop. However, that was changed after the MRC Myeloma IX study showed that indefinite treatment prolonged survival. Based on this study my preferred choice is zoledronic acid. I consider switching to pamidronate if the patient is not tolerating zoledronic acid.

With extended treatment certain toxicities do emerge. Side effects appear to be less likely with dose or schedule modifications. That’s why I reduce the frequency to every 3 months after 2 years.

I believe that the whole field of bone disease is changing. I think with bad myeloma therapy the need for bone therapy is greater. During the active treatment phase bisphosphonates should be administered. After that they can be administered every 3 months for another year.

We recommend monthly treatment for at least 2 years for patients who have active bone disease. After that the course of treatment is more heterogeneous, but I like to administer therapy at least 4 times a year until disease progression if patients can tolerate it. I believe that continuing treatment until progression is supported by data from the MRC Myeloma IX trial. It is important to monitor the dental health of patients on zoledronic acid. Patients with renal insufficiency have to be watched closely, and therapy must be changed to pamidronate if zoledronic acid is impairing renal function.

There is general agreement that bone-targeted therapy should be administered monthly and continued for a minimum of 2 years. I follow the International Myeloma Working Group (IMWG) recommendations and recommend therapy for a minimum of 2 years. After 2 years, I reassess patients in terms of activity of their bone disease. I decide on one of 3 options: to continue therapy monthly if they’ve relapsed or have active bone disease, to continue it but at a reduced dose every 3 months or, for the occasional patients who didn’t have much bone disease to begin with and are now in complete remission, I would stop therapy and reinstitute it if they experience relapse.

I recommend bone-targeted therapy for patients with active bone disease for a duration of 1 to 2 years. I generally recommend zoledronic acid because the results of the MRC IX study showed a survival benefit with bisphosphonates.

I’m not in favor of a longer duration because the administration is intravenous. Additionally the European guidelines do not recommend treatment beyond 2 years, to avoid osteonecrosis of the jaw.

We continue bone-targeted therapy for a maximum of 2 years. We alter the duration according to the response. For a patient who achieves a stringent CR I would recommend a shorter course of therapy, say 12 months, because that patient is not at a high risk for new bone lesions or fractures.

I continue bone-targeted treatment indefinitely for patients with active bone disease. I alter the frequency of bisphosphonate administration to every 3 months. My choice of therapy is usually zoledronic acid. In certain situations, if there were concerns about zoledronic acid, as for patients with low creatinine clearance, I would consider pamidronate. But in general I believe that either one would be fine. The ASCO guidelines suggest 2 years of treatment. Beyond that the duration is at the physician’s discretion.

We’ve conducted a clinical trial called the Z-MARK study in which we’ve continued therapy on a 3-monthly schedule for up to 4 years after initiation. We demonstrated that bone-targeted agents continue to have a bone-protective effect well beyond 2 years. The risk of skeletal-related events still exists. Hence, keeping patients on a bisphosphonate, even if it’s less frequent, is justified in my opinion.

I recommend bone-targeted therapy for a minimum of 2 years. After that, I continue treatment but at a lower frequency of every 3 months to minimize side effects. I don’t believe there is a rationale for stopping bisphosphonate therapy. In the MRC IX trial, which showed a survival benefit with bisphosphonates, therapy was not discontinued. Patients received zoledronic acid monthly for up to 5 years to derive a survival benefit. The patients didn’t live long enough for us to determine what indefinite means because most of the patients had passed away by 5 years. But the median survival for the overall patient population was around 3 years. So in my view the level of evidence is that after 2 years the frequency of therapy can be reduced but not discontinued altogether.