Chimeric antigen receptor T‐cells, bispecific antibodies, and antibody‐drug conjugates for multiple myeloma: An update

Lakshman, Arjun; Kumar, Shaji

doi:10.1002/ajh.26379

Cited by 30 publications

(29 citation statements)

References 128 publications

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“…170 Several bispecific antibodies targeting various antigens on the myeloma cell surface have been tested in clinical trials, and have shown promising single-agent activity. 171 Bispecific antibodies have dual specificities to enable them to bind to both plasma cells and T cells. Most bispecifics (teclistamab, elranatamab, TNB-383B, AMG-701, REGN 5458) currently target the BCMA antigen on plasma cells and CD3 on T cells.…”

Section: Emerging Optionsmentioning

confidence: 99%

“…Of these, the most promising involves the use of bispecific antibodies 170 . Several bispecific antibodies targeting various antigens on the myeloma cell surface have been tested in clinical trials, and have shown promising single‐agent activity 171 . Bispecific antibodies have dual specificities to enable them to bind to both plasma cells and T cells.…”

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

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Multiple myeloma: 2022 update on diagnosis, risk stratification, and management

2022

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Disease Overview: Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis:The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsyproven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Risk Stratification:The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. The presence of any two high risk factors is considered double-hit myeloma, and three or more high risk factors is triple-hit myeloma.Risk-Adapted Initial Therapy: In patients who are candidates for autologous stem cell transplantation, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard-risk patients can collect stem cells, get additional cycles of induction therapy, and delay transplant until first relapse. Patients who are not candidates for transplant are treated with VRd for approximately 8-12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression.Maintenance Therapy: Standard-risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high-risk myeloma.Management of Relapsed Disease: A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse.

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Section: Emerging Optionsmentioning

confidence: 99%

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

Multiple myeloma: 2022 update on diagnosis, risk stratification, and management

2022

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“…These results support the use of PSGL-1-targeted liposomal BTZ-containing formulations to overcome drug resistance and improve patient outcomes in MM ( 319 ). Several recent review papers summarize the plethora of available immunotherapies and their mechanism of action in MM (checkpoint inhibitors, or T-cell engaging bispecific antibodies and/or adoptive T-cell/NK cell therapy) ( 320 – 322 ), therefore we will not cover this topic in the present review. Targeting the interaction of malignant PCs with the TME may weaken the TME-mediated drug resistance and/or decrease the immunosuppressive activity and environment induced by active MM.…”

Section: Overcoming Tme-mediated Pi Resistancementioning

confidence: 99%

Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors

Schwestermann

Bešše

2022

Front. Oncol.

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Virtually all patients with multiple myeloma become unresponsive to treatment with proteasome inhibitors over time. Relapsed/refractory multiple myeloma is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations, diverse proteomic and metabolic alterations, and profound changes of the bone marrow microenvironment. However, the molecular mechanisms that drive resistance to proteasome inhibitors within the context of the bone marrow microenvironment remain elusive. In this review article, we summarize the latest knowledge about the complex interaction of malignant plasma cells with its surrounding microenvironment. We discuss the pivotal role of metabolic reprograming of malignant plasma cells within the tumor microenvironment with a subsequent focus on metabolic rewiring in plasma cells upon treatment with proteasome inhibitors, driving multiple ways of adaptation to the treatment. At the same time, mutual interaction of plasma cells with the surrounding tumor microenvironment drives multiple metabolic alterations in the bone marrow. This provides a tumor-promoting environment, but at the same time may offer novel therapeutic options for the treatment of relapsed/refractory myeloma patients.

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“…The continued expression of BCMA in some patients relapsing on BCMA-based therapies provides the option of continuing to target this antigen. Agents include antibody-drug conjugates (ADCs), autologous chimeric antigen receptor engineered T cells (CAR-T), and bispecific T cell engagers [53,54].…”

Section: Promising Investigational Options Other Bcma-targeted Therapiesmentioning

confidence: 99%

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

et al. 2022

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A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.

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Chimeric antigen receptor T‐cells, bispecific antibodies, and antibody‐drug conjugates for multiple myeloma: An update

Cited by 30 publications

References 128 publications

Multiple myeloma: 2022 update on diagnosis, risk stratification, and management

Multiple myeloma: 2022 update on diagnosis, risk stratification, and management

Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

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