Toxicity Considerations for Multiple Myeloma Combination Therapies

Keith Stewart, MB, ChB:The four new drugs that were approved last year in the United States for relapsed multiple myeloma were all approved on the basis of phase III clinical trials. Each of those trials showed that using three drugs instead of two produced a faster, more common, and deeper response, with resulting improvement in the time the patients remained in remission and off therapy or progression-free survival. Thus, in general, the use of three drugs instead of two has become the gold standard for treatment of patients like this.

In this particular case, we have chosen to move from lenalidomide to pomalidomide based on the inactivity of lenalidomide, at least at low doses. We’ve also chosen to use the most effective proteasome inhibitor available to us in this situation, which is carfilzomib. Recently, Dr. Shah from MD Anderson Hospital reported the combination of carfilzomib and pomalidomide could be safely applied in this combination in patients like this. And those results were published in the journal Blood last year. They also demonstrate with this toxicity profile if that combination is acceptable, and really, they’re quite easy to combine together.

In that particular study published from MD Anderson on this combination of carfilzomib and pomalidomide, and dexamethasone, they were able to show acceptable toxicity and a decent progression-free survival in response rate, but it is only a phase II trial and we can’t really compare that with the phase III results that we have from other studies. But clearly, this is a combination that can be tolerated; is highly effective, with a high response rate in this population; and has really become one of our therapies of choice in this situation.

In lenalidomide-refractory patients who are beginning relapsed therapy and lenalidomide is not the drug of choice, we can switch to pomalidomide, which is a more potent immune modulator, or we can sometimes add other drugs, such as the alkylating agent cyclophosphamide or perhaps one of the new monoclonal antibodies. Our experience, however, is that the combination of carfilzomib with pomalidomide is very effective, very potent, very rapidly acting, and has really become a combination we’re very comfortable using. And that would be my own personal recommendation for this patient.

The toxicity profile of carfilzomib has been well publicized. This drug appears to have some influence in the vascular system. Patients feel somewhat short of breath. Sometimes they experience fluid retention. Hypertension is common. The things that we worry about most, however: a small percentage of patients, probably 3% to 5%, can develop what appears to be a congestive heart failure, or elevation of the creatinine. Both of those tend to be reversible. They occur in only 3% to 5% of patients, and in even perhaps less, tend to be severe. And so, overall, those are things that we worry about with carfilzomib.

With pomalidomide, this is a quiet a well-tolerated drug. Myelosuppression, particular low neutrophil count, is something we have to be cautious about. And generally speaking, I might use this drug at 2 mg instead of 4 mg when it’s used in combination with carfilzomib. As with all the immune modulators, we have to worry about deep venous thrombosis, and patients do need to be prophylaxed against that. And the more common side effects are familiar to most hematologists, which include fatigue, muscle cramping, and GI disturbance.

Case Scenario 1:

July 2011

• The patient is a 61-year-old Caucasian female who was diagnosed with stage II MM. Genetic testing showed her to have t(4:16). At the time she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation.
• She achieved a partial response with RVD and remained in remission. Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy.

August 2016

• Routine follow up shows that her M-protein levels have now risen to 1.4 g/dL and her light chain levels continue to rise.
• Although she has developed mild anemia and her creatinine level is slightly elevated to 1.3 mg/dL, she continues to work full-time, has no bone pain, and a has a normal calcium level.