Immunotherapy with Antibodies in Multiple Myeloma: Monoclonals, Bispecifics, and Immunoconjugates

Abstract

In the 2010s, immunotherapy revolutionized the treatment landscape of multiple myeloma. CD38-targeting antibodies were initially applied as monotherapy in end-stage patients, but are now also approved by EMA/FDA in combination with standards-of-care in newly diagnosed disease or in patients with early relapse. The approved SLAMF7-targeting antibody can also be successfully combined with lenalidomide or pomalidomide in relapsed/refractory myeloma. Although this has resulted in improved clinical outcomes, there remains a high unmet need in patients who become refractory to immunomodulatory drugs, proteasome inhibitors and CD38-targeting antibodies. Several new antibody formats, such as antibody–drug conjugates (e.g., belantamab mafodotin, which was approved in 2020 and targets BCMA) and T cell redirecting bispecific antibodies (e.g., teclistamab, talquetamab, cevostamab, AMG-420, and CC-93269) are active in these triple-class refractory patients. Based on their promising efficacy, it is expected that these new antibody formats will also be combined with other agents in earlier disease settings.

Emerging Role of Antibody-Drug Conjugates and Bispecific Antibodies for the Treatment of Multiple Myeloma

“…CC-93269, previously known as EM801, is a trivalent (2:1) T-cell engager IgG antibody which is a bispecific binder for the BCMA antigen on myeloma cells (bivalent binding) and CD3 epsilon receptors on T cells (monovalent binding) [ 91 ]. The trivalent structure of CC-93269 with simultaneous attachment to both BCMA and CD3+ epsilon receptors causes T-cell myeloma cell interaction, activating CD3 downstream signaling pathways and increasing the expression of CD25 and CD69, thereby releasing granzyme B and proinflammatory cytokines such as IFN-γ or TNF-α [ 92 ]. These cytokines from redirected T cells attack myeloma cells and induce apoptosis.…”

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

“… 1 , 2 Immunotherapy with monoclonal or bispecific antibodies offers a non-cross resistant mechanism of action. 3 , 4 Monoclonal antibodies (moAbs) specifically bind to antigens expressed on tumor cells triggering antibody dependent cell-mediated toxicity and complement-dependent cytotoxicity. Bispecific antibodies concomitantly bind a tumor-antigen and a target on immune cells (e.g.…”

“…Several MM surface antigens are used as targets. 4 Daratumumab or isatuximab (directed against CD38), elotuzumab (directed against CS1) and the antibody drug conjugate belantamab mafodotin (targeting BCMA) are approved for the treatment of MM. 3 , 5 T-cell bispecific antibodies in development include CC-93269 (BCMA-CD3 trivalent), teclistamab (BCMA-CD3) and talquetamab (GPCR5D-CD3).…”

Immunotherapy in Myeloma: A Theme Issue in Honor of Prof. Dr. Gösta Gahrton

“…The development of monoclonal, bispecific, and immune conjugated antibodies is described by Christie Verkleij, Wassilis Bruins, Sonja Zweegman, and Niels van de Donk from Amsterdam [5], while Benedetto Bruno together with Giuseppe Lia, Francesca Bonifazi, and Luisa Giaccone describe the development and progress in allogeneic stem cell transplantation for myeloma in the last decades [6]. This Special Issue closes with an article by Luis Gerardo Rodríguez-Lobato from Joan Bladé's group in Barcelona summarizing the current knowledge about the failure of immunotherapy in multiple myeloma [7].…”