Adverse Effects and Other Pitfalls

Though the BCMA-directed CAR T-cell therapies have shown promise for treating heavily pretreated MM, they are associated with challenges, the review authors noted.1

Challenges include a lack of durable responses, the 2-week period required for CAR T-cell manufacturing, and the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity.


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Investigators are exploring potential solutions, including the use of tocilizumab to manage CRS and the development of allogeneic, universal, off-the-shelf CAR T-cell therapies, which might address the manufacturing delays.1

Physicians and patients should also be aware of common adverse effects associated with other novel therapies for MM, Dr Lee noted. With selinexor, for example, side effects may include nausea, vomiting, and weight loss, which are managed with aggressive antiemesis prophylaxis.

With belantamab mafodotin, ocular adverse events, including keratopathy, are common. These events are “managed in close collaboration with eye care specialists, with dose delays and dose reductions based on ocular exam findings and symptoms,” Dr Lee said.  

Emerging Therapies

The emerging immune-based therapies may hold the greatest potential for high response rates in RRMM, according to the review authors.1

Investigational BCMA-binding bispecific antibodies include AMG-701, teclistamab, REGN5458, and TNB-383B. Bispecific antibodies targeting other MM antigens include cevostamab, which targets FcRH5, and talquetamab, which targets GPRC5D.

Bispecific antibodies produce response rates greater than 60%, even in heavily pretreated MM patients.1 These antibodies are also associated with “generally manageable toxicities” and shorter infusion times compared with available therapies, according to the review authors.

However, both bispecific antibodies and CAR T-cell therapies are limited by “their reliance on functional immune effector cells and the presence of extracellular myeloma antigens,” the authors noted.

To address these issues, researchers are exploring numerous drugs that “modulate protein trafficking intracellularly…, ranging from drugs that target the ubiquitin-proteasome system to small ubiquitin-like modifier inhibitors that interfere with processes such as DNA repair,” the authors explained.

They noted that most of these agents are still in preclinical development. However, cereblon E3 ligase modulation drugs (CELMoDs) have demonstrated responses in 2 studies of heavily pretreated RRMM patients.

In one study, iberdomide (CC-220) was given in combination with dexamethasone and daratumumab or bortezomib.5 In the other study, CC-92480 was given in combination with dexamethasone.6

Remaining Needs

Among areas warranting further research in RRMM treatment, Dr Mikhael noted the need for “additional options for triple-class refractory disease as well as post-CAR T-cell therapy options.”

Other remaining needs include elucidating mechanisms of resistance to some of the novel MM therapies under development and assessing rational drug combination strategies for optimal efficacy as more of these agents become available, according to Dr Lee.

“Moreover, we still don’t have great biomarker-driven approaches to choosing therapy in myeloma aside from venetoclax in t(11;14) myeloma, so this remains an unmet area in the field, which will become all the more important with the growing number of therapeutic options in RRMM,” Dr Lee said.

Disclosures: Dr Lee disclosed affiliations with Amgen, Celgene, GlaxoSmithKline, Janssen, Sanofi, Takeda, Daiichi Sankyo, and Regeneron. Dr Mikhael disclosed affiliations with Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, and Sanofi. The review authors reported no conflicts of interest.

References

  1. Nathwani N, Bertamini L, Banerjee R, Gay F, Shah N, Krishnan A. When and how to treat relapsed multiple myeloma. Am Soc Clin Oncol Educ Book. 2021;41:358-375. doi:10.1200/EDBK_320129 
  2. Lee HC, Cerchione C. How I treat relapsed and/or refractory multiple myeloma. Hematol Rep. 2020;12(suppl 1):8955. doi:10.4081/hr.2020.8955
  3. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384:705-716. doi:10.1056/NEJMoa2024850
  4. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Published online June 24, 2021. Lancet. doi:10.1016/S0140-6736(21)00933-8
  5. van de Donk NWCJ, Popat R, Larsen J, et al. First results of iberdomide (IBER; CC-220) in combination with dexamethasone (DEX) and daratumumab (DARA) or bortezomib (BORT) in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(suppl 1):16-17. doi:10.1182/blood-2020-137743
  6. Paul G. Richardson, Annette J. Vangsted, Karthik Ramasamy, et al. First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2020;38(suppl 15):8500-8500. doi:10.1200/JCO.2020.38.15_suppl.8500