Clinical evidence for immune-based strategies in early-line multiple myeloma: current challenges in decision-making for subsequent therapy

Abstract

Almost all patients with multiple myeloma (MM) will eventually develop disease that has relapsed with or become refractory to available treatments and will require additional therapy. However, data are still lacking on how best to sequence regimens in the relapsed/refractory (RR) setting after the failure of early-line lenalidomide, bortezomib, and/or daratumumab, the most commonly used agents in clinical practice today. With the treatment landscape rapidly changing in response to emerging clinical trial data and approvals of several new drugs and additional combinations, it is critically important to focus on patients with RRMM. Variability in patient baseline characteristics, such as the number of prior lines of treatment, refractoriness to prior treatments, prior stem cell transplant, and timing and dosing of prior lenalidomide, makes it difficult to select the best options for patients with RRMM for whom first-line treatments have failed. The aim of this review is to provide both an overview of current therapies and future directions within the RRMM treatment landscape, and a framework for clinicians to choose the most promising next treatment option.

Mezigdomide—A Novel Cereblon E3 Ligase Modulator under Investigation in Relapsed/Refractory Multiple Myeloma

“…Over the past 40 years, multiple myeloma (MM) has evolved from an acute disease with a median overall survival (OS) of only ~3–4 years [ 1 ] to become a chronic disease in which the median OS is now 7–10 years [ 2 , 3 ], and patients can require multiple lines of therapy over their disease course [ 4 , 5 , 6 , 7 ]. In the context of a global annual incidence of approximately 180,000 new cases [ 8 ], including more than 35,000 in the United States alone [ 9 ], and the continuing increase in survival rates [ 10 ], there is a growing population of patients requiring additional treatment options.…”

“…However, given the median age at diagnosis in the United States of 69 years [ 10 ] and the potential cumulative effects of prior regimens, these new therapies need to be feasible and accessible in this patient population and require a tolerable safety profile to enable long-term treatment. Furthermore, as there is substantial heterogeneity at MM diagnosis and through the disease course associated with multiple disease-related and patient-related characteristics [ 4 , 11 , 12 ], novel therapies need to be efficacious across patient populations, including in those with high-risk features. Finally, with standards of care evolving to include quadruplet induction regimens and triplets as second-line therapies [ 7 , 13 , 14 ], there is an ongoing need for new treatment options that are active in patients who have relapsed following treatment with multiple standard classes of drugs or who may be multi-drug refractory [ 15 ].…”

“…Regimens incorporating novel targeted agents are also recommended as RRMM treatment, including the exportin-1 (XPO1) inhibitor selinexor plus bortezomib and dexamethasone (Vd) [ 17 ] and, in Europe, the cytotoxic drug–peptide conjugate melflufen plus dexamethasone [ 18 ]. More recently, novel immune-based therapies have been approved and are being investigated early in the RRMM treatment algorithm [ 4 , 16 , 19 , 20 , 21 ], including the chimeric antigen receptor (CAR) T-cell therapies idecabtagene vicleucel (ide-cel) [ 22 , 23 ] and ciltacabtagene autoleucel (cilta-cel) [ 24 , 25 ]; the bispecific antibodies/T-cell engagers teclistamab [ 26 ], talquetamab [ 27 ], and elranatamab [ 28 ]; and, in Europe, the antibody–drug conjugate belantamab mafodotin [ 29 ].…”

Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma

“…Multiple myeloma (MM) is a hematological cancer characterized by the accumulation of clonal plasma cells in the bone marrow. Despite therapeutic improvements to cure MM, most patients gain drug resistance and will require additional therapy [1][2][3][4][5][6][7]. Immunotherapy plays an important role in the treatment of MM, with agents such as elotuzumab (ELO), daratumumab, isatuximab, or bispecific antibodies for TC engagement being used to significantly improve survival rates.…”

Successful treatment of ultra-high-risk refractory multiple myeloma with anti-BCMA CAR-T therapy followed by allogeneic hematopoietic stem cell transplantation: a case report

“…Immunotherapeutic approaches are changing the current MM landscape [3]. Moreover, due to the impressive clinical efficacy and good tolerability, B cell maturation antigen (BCMA)-specific chimeric antigen receptor T cell (CAR-T) therapy has been approved by the Food and Drug Administration (FDA) for relapsed and/or refractory multiple myeloma (RRMM); however, most patients eventually relapse [4,5].…”