IMWG Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma

The management of relapsed or refractory multiple myeloma presents a significant clinical challenge, despite recent advancements in treatment modalities. Novel immunotherapies, particularly chimeric antigen receptor (CAR) T-cell therapies targeting B-cell maturation antigen (BCMA), have demonstrated promising results in improving overall response rates and extending survival. However, the implementation of CAR T-cell therapy is hindered by unique toxic effects, necessitating optimized management strategies. This consensus statement, developed by an international panel of multiple myeloma experts, aims to provide comprehensive recommendations for the selection of suitable patients, bridging therapy, lymphodepletion, response assessments, and toxicity management in the context of CAR T-cell therapy for relapsed or refractory multiple myeloma.

Key Points:

1. Epidemiology and Treatment Landscape: Approximately 176,404 new cases of multiple myeloma and 117,077 myeloma-related fatalities were estimated globally in 2020. Advances in treatment, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, have significantly improved patient survival.
2. Unmet Need: Despite therapeutic advancements, resistance to treatment remains a significant challenge, leading to poor prognosis for many patients with highly refractory disease.
3. Novel Immunotherapies: CAR T-cell therapies targeting BCMA have shown high objective response rates and extended median overall survival in relapsed or refractory multiple myeloma patients.
4. Clinical Trials: Large randomized trials, such as KarMMa-3 and CARTITUDE 4, have demonstrated the superiority of CAR T-cell therapy over standard triplet therapy in terms of overall response rate and progression-free survival.
5. Toxicity Management: Optimized management of unique toxic effects associated with CAR T-cell therapy is crucial for its widespread implementation. Deaths from all-cause adverse events were higher in the CAR T group, emphasizing the importance of tailored toxicity management strategies.
6. Patient Selection: Regulatory approvals vary between regions, with the FDA requiring at least four previous lines of therapy for cilta-cel and ide-cel, while the EMA approves them for patients with at least three previous lines. Drug class refractoriness may be more prognostic than the number of therapy lines.
7. Future Directions: Ongoing clinical trials are exploring the use of CAR T-cell therapy in frontline treatment and investigating allogeneic CAR T-cell options as potential off-the-shelf alternatives. Rapid manufacturing CAR T cells offer a promising strategy to improve patient access to therapy.
8. CAR T-cell therapy has shown promise in patients with relapsed and refractory multiple myeloma, with high response rates and extended overall survival. ​
9. Three BCMA-targeted CAR T-cell therapies have been approved: ide-cel, cilta-cel, and eque-cel. ​
10. Infection screening is essential before initiating CAR T-cell therapy, including evaluation for viral infections, hepatitis, and reactivation of cytomegalovirus and Epstein-Barr virus. ​
11. Repeat dosing of the same CAR T-cell therapy is not recommended, but CAR T-cell treatment targeting a different antigen or binding domain could be considered. ​
12. Close monitoring of organ function and comorbidities, such as cardiopulmonary fitness and renal function, is important for eligibility and safety during CAR T-cell therapy. ​
13. Antimicrobial prophylaxis and immunoglobulin replacement may be considered to prevent infections and manage hypogammaglobulinemia. ​
14. Vaccination strategies for patients undergoing CAR T-cell therapy are still being studied, and live vaccines should be avoided. ​
15. Management of toxic effects, such as cytokine release syndrome and immune effector cell-associated neurologic syndrome, should follow regulatory guidelines and consider early intervention and escalation of therapy when necessary. ​
16. Haematological toxicity, including cytopenias, is common with CAR T-cell therapy and requires aggressive supportive care and close monitoring of blood counts. ​
17. Referral logistics should prioritize early referral and consider disparities in patient access to care.
18. The guidelines aim to provide a harmonized approach to the management of CAR T-cell therapy in clinical practice for relapsed and refractory multiple myeloma. ​

Authors:

Prof Yi Lin MD PhD, Prof Lugui Qiu MD, Prof Saad Usmani MD MBA, Prof Chng Wee Joo MD, Prof Luciano Costa MD PhD, Benjamin Derman MD, Prof Juan Du MD PhD, Prof Hermann Einsele MD FRCP, Prof Carlos Fernandez de Larrea MD PhD, Prof Roman Hajek MD PhD, Prof P Joy Ho, Efstathios Kastritis MD, Joaquin Martinez-Lopez, Prof Maria-Victoria Mateos MD PhD, Prof Joseph Mikhael MD, Prof Philippe Moreau MD, Chandramouli Nagarajan MBBS FRCP, Prof Ajay Nooka MD MPH, Prof Michael O'Dwyer MD, Prof Fredrik Schjesvold MD PhD, Surbhi Sidana MD, Prof Niels WCJ van de Donk MD PhD, Prof Katja Weisel MD, Prof Sonja Zweegman MD PhD, Prof Noopur Raje MD, Paula Rodriguez Otero MD PhD, Prof Larry D Anderson Jr MD PhD, Prof Shaji Kumar MD, Prof Tom Martin adon behalf of theInternational Myeloma Working Group

Citation:

The Lancet Oncology, 2024,ISSN 1470-2045,
https://doi.org/10.1016/S1470-2045(24)00094-9