Management of Relapsed and Refractory Multiple Myeloma

From the Division of Hematology and Oncology, University of North Carolina – Chapel Hill, Chapel Hill, NC (Dr. Reeves), and the Division of Cellular Therapy and Hematological Malignancies, Duke Cancer Institute, Durham, NC (Dr. Tuchman).

Abstract

• Objective: To review the management considerations in patients with relapsed and refractory multiple myeloma (RRMM).
• Methods: Review of the literature.
• Results: RRMM is a heterogeneous disease and numerous treatment regimens have been studied. Despite improvement in progression-free and overall survival in newly diagnosed multiple myeloma with current therapies, myeloma remains incurable and repeated relapses are inevitable. Relapses are often characterized by diminished response to chemotherapy (refractoriness) and duration of response.
• Conclusion: Management of RRMM should be individualized using both patient- and disease-related factors, given substantial heterogeneity in both. Further research regarding the optimal timing, regimen, and duration of treatment is warranted.

Although advancements in treating multiple myeloma (MM) have resulted in improved median survival from approximately 2 years in the 1990s to more recent estimates of over 6 years, the disease remains incurable [1–3]. Its overall course is generally defined by a series of increasingly short remissions and treatment-refractory relapses until eventual death due to MM occurs. Objective criteria for defining both relapsed and refractory MM have been published [4]. Briefly, relapsed myeloma is that which has been previously treated with some form of systemic therapy and which has recurred. That recurrence can be clinical (ie, the development of new or worsening signs or symptoms of active MM) and/or biochemical (ie, rising monoclonal MM proteins in the serum or urine). Refractory MM on the other hand refers to MM that is resistant to particular drugs, defined as MM that is nonresponsive to primary or salvage therapy, or MM that progresses within 60 days of the last therapy [4]. At any juncture during the course of relapsed MM, patients will have disease that is either sensitive or refractory to specific myeloma drugs. In this article, we discuss management of these often concurrent entities together as relapsed and refractory multiple myeloma (RRMM).

There are numerous treatment options for patients with RRMM—3 new drugs were approved in November 2015 alone. The abundance of available drugs leaves treating clinicians with a daunting task of sequencing therapies among several choices. The durability of response to treatment typically lessens with each disease relapse, such that the clinician needs to think of sequencing not just second-line therapy, but third- and fourth-line as well, further complicating the decision. In this review, we aim to help clinicians individualize treatment plans for patients with RRMM.