Immunotherapy of Multiple Myeloma: Current Status as Prologue to the Future

Abstract

The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease’s five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of antimyeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), bi- and multitargeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for “off-the-shelf” (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured.

Hallmarks of tumor-experienced T cells are absent in multiple myeloma patients from diagnosis through maintenance therapy

“…Checkpoint blockade monotherapy has performed poorly in refractory and/or relapsed MM (RRMM). 21 In solid tumors, evidence of pre-existing, tumor-reactive T cells predicts response to checkpoint blockade, 22 , 23 while patients with cold tumors lacking tumor-reactive T cells tend to respond poorly. 24 While our study did not include samples from RRMM patients, our data suggest that combination immunotherapies that draw inspiration from strategies targeting cold solid tumors 25 may enhance T cell participation in the anti-myeloma response and increase therapeutic efficacy.…”

Establishing Monoclonal Gammopathy of Undetermined Significance as an Independent Pre-Disease State of Multiple Myeloma Using Raman Spectroscopy, Dynamical Network Biomarker Theory, and Energy Landscape Analysis

“…To diagnose MM, the ratio of plasma cells to bone marrow cells must be more than 10%. The primary treatment for MM is chemotherapy, with immunotherapy [1] and targeted therapy [2] also now being applied; however, achieving a cure remains challenging. In contrast, monoclonal gammopathy of undetermined significance (MGUS) is a condition that does not meet the diagnostic criteria for MM because there are fewer than 10% plasma cells in the bone marrow, even though it is clear that these cells are clonally proliferating from the appearance of the M protein [3].…”

Efficacy and Safety of Anti-CD38 Monoclonal Antibodies in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Randomized Clinical Trials

“…MGUS comprises patients with serum M-protein levels (<3 g/dL) and monoclonal PC in the BM (<10%), while patients with serum M-protein levels (≥3 g/dL) and/or PC in the BM (≥10%) are classified as MM [7,10,11]. In addition, the diagnosis should consider end-organ damage resulting from the serum M-spike and/or monoclonal PC in the BM [12,13].…”

“…MM remains incurable, and most patients undergo several lines of treatment, with the choice relying on exposure and previous response [20,[23][24][25]. Currently, clinical treatment options include proteasome inhibitors, immunomodulatory agents, steroids, alkylating agents, and monoclonal antibodies, often combined with autologous stem cell transplantation in eligible patients [12,[26][27][28]. The need for new therapeutic approaches for relapsed or refractory MM has generated monoclonal antibodies targeting CD38, including daratumumab and isatuximab [29][30][31][32][33].…”