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New Approaches in R/R MM
My Thoughts on New Approaches to Manage Relapsed/Refractory Myeloma

Released: October 29, 2018

Expiration: October 28, 2019

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Data presented at the 208 ASCO Annual Meeting highlighted continued progress in treatment options for multiple myeloma. Standard initial therapy of myeloma increasingly incudes a proteasome inhibitor and an immunomodulatory drug (IMiD), most commonly bortezomib or lenalidomide. However, patients at the time of first relapse have often become refractory to lenalidomide.

Managing Lenalidomide-Refractory Patients
Many recent phase III trials have shown that PFS and OS in patients with myeloma can be improved by the use of a triplet regimen that incorporates at least 2 active agents in addition to dexamethasone. However, given the fact that phase III data leading to the approval of carfilzomib, daratumumab, ixazomib, and elotuzumab relied heavily on combinations of these drugs with lenalidomide—and did not include patients refractory to lenalidomide—there has been significant interest in developing multidrug combinations that include the next-generation IMiD pomalidomide or that are devoid of an IMiD.

The phase III OPTIMISMM trial demonstrated significantly improved PFS in lenalidomide-exposed and lenalidomide-refractory patients by adding pomalidomide to bortezomib and dexamethasone. This is consistent with the benefit of combining an IMiD and a proteasome inhibitor demonstrated in newly diagnosed myeloma. A subgroup analysis of the phase Ib MMY1001 trial, which used the combination of carfilzomib and daratumumab plus dexamethasone in an IMiD-sparing strategy, demonstrated excellent activity including deep and reasonably durable responses in lenalidomide-refractory patients with relapsed myeloma (median PFS: 14.1 months; median OS: 21.1 months). These studies may help to expand treatment options for patients with lenalidomide-refractory/relapsed myeloma by combining pomalidomide with an alternate proteasome inhibitor such as carfilzomib or ixazomib or with a monoclonal antibody such as daratumumab.

Improving Carfilzomib Therapy
Two important trials focused on identifying the best dose and schedule for using carfilzomib in myeloma treatment. The phase III ARROW study compared a higher dose of carfilzomib given once weekly with dexamethasone in patients with relapsed/refractory myeloma to the standard dose given twice weekly. This is intended to increase the acceptance of regimens containing carfilzomib by alleviating the patient burden of twice-weekly clinic visits. Results demonstrated that a higher weekly dose of carfilzomib at 70 mg/m2 in combination with dexamethasone was associated with significantly longer PFS in patients with relapsed/refractory myeloma and 2-3 previous lines of therapy vs the traditional dosing strategy of 27 mg/m² given twice weekly. Median PFS was 11.2 months vs 7.6 months, respectively, with benefit seen across patient subgroups. However, the phase II SWOG S1304 study also examined 2 carfilzomib doses—27 mg/m² and 56 mg/m², both given twice weekly—but failed to demonstrate a significant survival advantage for the higher dose of carfilzomib in this scenario, contributing to continued uncertainty over the optimal dosing strategy for this drug.

The 2018 ASCO meeting also showcased interim phase II data from a study of carfilzomib in combination with dexamethasone and venetoclax, a BCL-2 inhibitor that has shown significant activity in t(11;14) myeloma. The combination was quite effective in patients with relapsed/refractory myeloma (N = 43), with very high response rates (~ 83% across patient subgroups). Of note, all 7 patients with t(11;14) responded.

bb2121: A Promising CAR T-Cell Therapy
Updated data from a phase I study of the anti-BCMA CAR T-cell therapy bb2121 strongly suggested efficacy with this therapeutic approach in relapsed/refractory myeloma, with long-term follow-up demonstrating excellent PFS, especially in patients achieving deep responses. In this study, median PFS in measurable residual disease–negative responders was 17.7 months.

Overall, the data from myeloma clinical trials presented at ASCO 2018 highlight ongoing efforts to improve treatment of patients with relapsed/refractory myeloma, especially novel combinations that allow incorporation of drugs that patients have not been exposed to as well as therapies with new mechanisms of action.

In your current clinical practice, which of these new and emerging regimens or agents are you most looking forward to using in the treatment of relapsed/refractory myeloma? Do these data change your plans? Answer the polling question to see what others are saying and share your thoughts in the comment box below.

For expert recommendations on current standards of treatment for multiple myeloma, use our Interactive Decision Support Tool to compare your choice of therapy with expert recommendations from me and my colleagues, Irene M. Ghobrial, MD; Carol Ann Huff, MD; Sagar Lonial, MD; and Noopur Raje, MD.

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Which of the following investigational agents or approaches do you think will have the greatest impact on your treatment of patients with relapsed/refractory myeloma?
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