- There is a continuing need for new multiple myeloma (MM) treatments, because all patients eventually develop resistance to existing agents, even after extended periods of remission.
- Idecabtagene vicleucel (ide-cel) is the first B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy approved for MM. Compared with current treatment protocols, ide-cel yields improved overall response rates and survival rates.
- Patients must be thoroughly assessed before receiving CAR-T therapy. Some degree of disease control is best for CAR-T therapy candidates, because treatment wait times can be significant. Bridging therapy may be necessary to prevent disease progression in selected patients.
- Using γ-secretase inhibitors to increase BCMA surface density on malignant plasma cells may improve treatment outcomes, and monoclonal antibodies and glucocorticoids can be used to manage associated toxicities.
- Preclinical and clinical trials are now investigating new antigens and strategies to improve target density, with the goal of improving CAR-T therapy outcomes in MM. Researchers are also studying new protein targets for immunotherapy, with the G-protein-coupled receptor class currently under investigation as a target for bispecific antibodies.
Andrew J. Cowan, MD, is a hematologist-oncologist and an associate professor in the clinical research division in the Seattle Cancer Care Alliance at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Dr Cowan specializes in the treatment of patients with MM and other blood disorders. He also leads clinical investigations into new treatments for these diseases, with approaches including engineered immune cells, combination strategies, and application of genomics data.
What are some limitations of current therapies for MM? Is drug resistance in MM inevitable?
Upfront treatment with proteasome inhibitors, immunomodulatory agents, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation has resulted in durable remission for many patients with MM, particularly those at standard risk. In the current era, many patients may experience survival of more than 10 years from the time of diagnosis. Development of toxicities — such as peripheral neuropathy from bortezomib, cardiomyopathy from carfilzomib, and myelosuppression from the immunomodulatory agents — limits the use of these agents in some patients.
In addition, all patients will inevitably develop resistance to these agents, which is why continued development of new drugs and identification of new targets are necessary.
How has the introduction of CAR-T therapy improved outcomes for patients with relapsed MM?
The introduction of CAR-T therapy has dramatically changed the outlook for patients with relapsed MM. Previously, if a patient had experienced disease progression on proteasome inhibitors, immunomodulatory imide drugs (IMiDs), CD38 antibodies, and transplant, then prognosis was poor, with most studies reporting survival of less than 12 months. With the introduction of the first BCMA-targeted CAR-T therapy, the vast majority of patients who receive this treatment will respond, and their responses will be durable.
Although not a randomized trial, an analysis presented at the 2020 American Society of Hematology (ASH) annual meeting1 compared outcomes with ide-cel vs standard-of-care regimens from a large retrospective cohort of heavily pretreated patients with relapsed MM. Compared with real-world patients with relapsed MM who received standard therapies, treatment with ide-cel resulted in improved overall response rates and survival. These data support the conclusion that CAR-T therapy has improved outcomes for patients with relapsed MM.
What studies should be undertaken before treating MM with CAR-T therapy?
Patients with MM undergoing CAR-T therapy are evaluated at an approved treatment center. Standard of care would usually involve assessment of vital organ capacity and comorbidities, evaluation for any active or ongoing infections, and then leukapheresis if the patient is deemed to be an acceptable candidate for CAR-T therapy. It is ideal for patients to have some degree of disease control, because there is a substantial waiting period for CAR-T manufacturing, during which time some form of bridging therapy is often necessary to prevent rapid progression of MM-related organ damage.
What strategies can enhance CAR-T therapy outcomes for patients with MM? How can providers limit and treat systemic toxicity and neurotoxicity associated with CAR-T therapy?
Studies are underway to evaluate strategies to enhance outcomes for patients receiving BCMA CAR-T therapy for MM. One example is the use of γ-secretase inhibitors to increase BCMA surface density on malignant plasma cells, potentially augmenting antitumor efficacy. These data were presented at the ASH conference in 2019.2
Early recognition and timely management of toxicity related to BCMA CAR-T therapy, including cytokine release syndrome and immune effector cell-associated neurologic toxicity, is important to the successful management of these side effects. Monoclonal antibodies against the interleukin-6 receptor, such as tocilizumab, and glucocorticoids may be used to manage more severe cytokine release syndrome and immune effector cell-associated neurologic toxicity.
What modifications to CAR-T synthesis, antigen selection, and production are currently being studied? Which MM cell antigens other than BCMA seem most responsive to CAR-T treatment? What are the benefits and risks of using third- and fourth-generation CAR-T cells?
Modifications to CAR-T manufacturing, the use of different antigens besides BCMA, and strategies to improve target density are all aspects of CAR-T therapy that are being explored in preclinical and clinical trials to augment the benefits of CAR-T therapy for MM. Another promising target for immunotherapy in MM is G protein-coupled receptor class C group 5 member D (GPRC5D). This has been studied as a target for bispecific antibodies (talquetamab)3 and is being investigated at Memorial Sloan Kettering Cancer Center in New York as a target for CAR-T cells (ClinicalTrials.gov Identifier: NCT04555551).
This Q&A was edited for clarity and length.
Andrew J. Cowan, MD, reported receiving research funding from Janssen, Nektar, AbbVie, Bristol Myers Squibb, Harpoon, and Sanofi. He is on the advisory board for AbbVie, Cellectar, Sanofi, EUSA, GSK, and Secura Bio. He is a consultant for Janssen and Celgene.
- Shah N, Ayers D, Davies FE, et al. A matching-adjusted indirect comparison of efficacy outcomes for idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy versus conventional care in triple-class-exposed relapsed and refractory multiple myeloma. Abstract 1653. Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020.
- Cowan AJ, Pont M, Sather BD, et al. Efficacy and safety of fully human BCMA CAR T cells in combination with a gamma secretase inhibitor to increase BCMA surface expression in patients with relapsed or refractory multiple myeloma. Blood. 2019;134(suppl 1):204.
- Berdeja JG, Krishnan AY, Oriol A, et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8008.
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Reviewed Aug 2021