Management of Adverse Reactions for BCMA-Directed Therapy in Relapsed Multiple Myeloma: A Focused Review

Journal of Clinical Medicine · 12 authors, 10 centres

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TL;DR

This review summarizes common adverse reactions (cytokine release syndrome, neurotoxicity, cytopenias, infections, hemophagocytic lymphohistiocytosis, and keratopathy) associated with FDA-approved BCMA-directed therapies (idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, belantamab mafodotin) in relapsed/refractory multiple myeloma. It provides stepwise management strategies based on FDA access data packages and clinical trials. The clinical significance lies in guiding clinicians to mitigate life-threatening complications and improve patient outcomes.

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**Background:** Multiple myeloma (MM) remains incurable despite advances in therapy, with a death rate of 3.1 per 100,000 population per year. B-cell maturation antigen (BCMA) is overexpressed on malignant plasma cells and can be targeted via chimeric antigen receptor T cells (CAR-T), bispecific antibodies (BsAbs), or antibody-drug conjugates (ADCs). Four BCMA-directed agents have received FDA approval for relapsed/refractory MM (RRMM): idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), teclistamab, and belantamab mafodotin (blenrep). Despite high response rates (70–100%), these therapies are associated with unique and potentially life-threatening adverse reactions.

**Methods:** This focused review included four original phase I/II clinical trials that led to FDA approval of the four agents. The authors also reviewed FDA access data packages for each agent to outline stepwise management of complications. The trials included KarMMa (ide-cel), CARTITUDE-1 (cilta-cel), MajesTEC-1 (teclistamab), and DREAMM-2 (blenrep).

**Key Results:** - **Cytopenias:** Incidence varied by agent. In KarMMa-2, neutropenia occurred in 80.6%, leukopenia in 29%, anemia in 22.6%. In CARTITUDE-1, neutropenia 95.9%, anemia 81.4%, thrombocytopenia 79.4%. In MajesTEC-1, neutropenia 72%, anemia 54%, thrombocytopenia 42%. In DREAMM-2 (2.5 mg/kg), anemia 21%, thrombocytopenia 19%. - **Infections:** Overall infection rate 78% in MajesTEC-1 (respiratory 56%, COVID-19 27%). Real-world infection rates: ide-cel 31%, cilta-cel 28.6%, teclistamab 35%, blenrep 1.9%. - **Cytokine Release Syndrome (CRS):** Incidence: ide-cel 58.1%, cilta-cel 94.8%, teclistamab 72%, blenrep 0%. CRS typically occurs 1–14 days post-CAR-T and 1–6 days post-teclistamab. - **Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS):** Incidence: ide-cel 6.5%, cilta-cel 21.6%, teclistamab 3%, blenrep 0%. Onset typically within 5 days of CAR-T and 2–8 days of teclistamab. - **Hemophagocytic lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS):** Incidence 1% post-CAR-T. Diagnosis requires ferritin >10,000 ng/mL plus two organ toxicities. - **Keratopathy:** Most common with blenrep (71% in DREAMM-2). Management based on grade (1–4) using keratopathy and visual acuity scale.

**Clinical Implications:** The review emphasizes the need for constant monitoring, early identification, and prompt management of these adverse reactions. Prophylactic measures include antiviral, antibacterial, antifungal, and pneumocystis prophylaxis; use of IVIG for hypogammaglobulinemia; and levetiracetam for seizure prophylaxis. Management strategies include supportive care (transfusions, G-CSF), tocilizumab and corticosteroids for CRS, anakinra for ICANS, and etoposide or ruxolitinib for HLH/MAS. For keratopathy, dose modifications or discontinuation of blenrep are recommended. The authors highlight that further phase III trials with longer follow-up are needed to establish safety.

STUDY TYPE

narrative_review

SPECIALTY

oncology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10487885

Management of Adverse Reactions for BCMA-Directed Therapy in Relapsed Multiple Myeloma: A Focused Review

Journal of Clinical Medicine

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ABSTRACT

Anti-B-cell maturation antigen therapies consisting of bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T cells have shown promising results in relapsed refractory multiple myeloma (RRMM). However, the severe side effects include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cytopenia(s), infections, hemophagocytic lymphohistiocytosis, and organ toxicity, which could sometimes be life-threatening. This review focuses on these most common complications post-BCMA therapy. We discussed the risk factors, pathogenesis, clinical features associated with these complications, and how to prevent and treat them. We included four original studies for this focused review. All four agents (idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, belantamab mafodotin) have received FDA approval for adult RRMM patients. We went through the FDA access data packages of the approved agents to outline stepwise management of the complications for better patient outcomes.

CITATION EXPORT

Razwana Khanam, Beth Faiman, Saba Batool et al.. Management of Adverse Reactions for BCMA-Directed Therapy in Relapsed Multiple Myeloma: A Focused Review. Journal of Clinical Medicine. (2023). https://doi.org/10.3390/jcm12175539

AUTHORS

12 · 10 CENTRES

Razwana Khanam, Beth Faiman, Saba Batool, Mohammed Musa Najmuddin, Rana Usman, Kiran Kuriakose, Arooj Ahmed, Mohammad Ebad Ur Rehman, Zinath Roksana, Zain Syed, Faiz Anwer, Shahzad Raza

1Department of Hospital Medicine, Baystate Medical Center, Springfield, MA 01199, USA
2Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44106, USA; [email protected] (B.F.); [email protected] (F.A.); [email protected] (S.R.)
3Department of Hospital Medicine, Carle Health Methodist Hospital, Peoria, IL 61636, USA; [email protected]
4The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA; [email protected]
5University of Tennessee Health Science Center, Memphis, TN 38163, USA; [email protected]
6Department of Hospital Medicine, UPMC Mercy Hospital, Pittsburgh, PA 15219, USA; [email protected]
7Department of Translational Hematology and Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, OH 44195, USA; [email protected]
8Department of Medicine, Rawalpindi Medical University, Rawalpindi 46000, Pakistan; [email protected]
9Sheikh Hasina National Institute of Burn and Plastic Surgery, Dhaka 1217, Bangladesh; [email protected]
10Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; [email protected]

EDITOR / REVIEWER

Eirini Katodritou, Thomas R. Chauncey