Practical Considerations in Managing Relapsed Multiple Myeloma

Abstract

Considerable advances have been made in the treatment of relapsed and relapsed/refractory multiple myeloma, with numerous novel agents and combination strategies receiving regulatory approval worldwide during the past several years. An increasing body of phase III data has clearly demonstrated increased overall response rates, improved depths of response, and more durable responses when a third novel agent is incorporated into lenalidomide-dexamethasone and bortezomib-dexamethasone platforms, in most cases with acceptable toxicity. The carfilzomib-dexamethasone doublet has also demonstrated promising activity. With this rapid progress has come many new questions. We review the data supporting the use of these novel treatment paradigms for relapsed/refractory multiple myeloma, discuss the place of autologous and allogeneic hematopoietic stem cell transplantation in this rapidly evolving treatment space, and propose strategies to best use these regimens, considering the disease, host, and previous treatment factors.

Introduction

Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of a monoclonal plasma cell population in the bone marrow producing a monoclonal immunoglobulin and evidence of end organ damage, which usually includes renal failure, anemia, bone lesions, hypercalcemia, and immune dysfunction. The outcomes and management of MM in the United States have changed dramatically during the past 15 years, with tripling of the survival of the average MM patient.¹ Even in the era of novel therapies, the natural history of MM follows a relapsing–remitting course, such that with subsequent relapses, the remissions tend to be shallower and the duration of response shorter. Thus, most patients will MM will develop relapses,2, 3 requiring subsequent lines of therapy. We have recognized that MM is not 1 disease and that the transition of monoclonal gammopathy of undetermined significance to MM might be more indolent for some patients and very rapid for others. Recognizing the heterogeneity in the biology and clinical presentation of patients with newly diagnosed MM,⁴ current clinical investigations are moving away from a “one size fits all” treatment paradigm to both risk- and response-adaptive strategies.

The management of relapsed/refractory MM (RRMM) can be highly challenging, and the clinician must consider the disease biology (eg, cytogenetics, fluorescence in situ hybridization findings), previous therapy (eg, depth and duration of response to previous therapy, treatment tolerability), disease burden (eg, presence or absence of renal failure, symptomatic bone disease, plasma cell leukemia at relapse, presence of extramedullary disease), host factors (eg, age, comorbidities, performance status), access to clinical trials, and financial limitations (eg, cost of therapy, insurance). To date, 10 drugs have been approved by the Food and Drug Administration for use in MM (thalidomide, lenalidomide, bortezomib, doxorubicin liposome [DOXIL], carfilzomib, pomalidomide, panobinostat, daratumumab, elotuzumab, ixazomib), with the last 4 approved in 2015 alone. In addition, several new novel drug classes and immunotherapy approaches are making their way through clinical development. The present review highlights some of the novel agent combinations with recently approved anti-MM agents in clinical trials and how best to incorporate them in clinical practice. Specifically, data from recent phase III trials of RRMM with 1 to 3 previous lines of therapy are discussed in the context of the practical management of RRMM.