Key Clinical Summary

• CAR T-cell therapies and bispecific antibodies continue to expand treatment options across multiple myeloma, lymphoma, and acute leukemia, with growing evidence supporting earlier-line use.
• Safety innovations—including optimized bridging therapy, infection prophylaxis, and toxicity-mitigation strategies—are improving the feasibility of T-cell–engaging therapies.
• Sequencing challenges remain, particularly around post–B-cell maturation antigen (BCMA) therapy in myeloma and post–bispecific CAR T use across hematologic malignancies.

Introduction

In a panel presentation at 67th ASH Annual Meeting and Exposition, leading experts discussed significant advances in immunotherapies for leukemia, lymphoma, and multiple myeloma. The session underscored how CAR T-cell therapies and bispecific antibodies are reshaping survival expectations, expanding to earlier treatment lines, and improving outcomes through better toxicity management. Speakers Doris Hansen, MD, H. Lee Moffitt Cancer Center & Research Institute; Sonali Smith, MD, University of Chicago; and Nicolas Boissel, MD, PhD, Hopital Saint-Louis, Paris, highlighted new data, emerging technologies, and ongoing challenges in sequencing and access.

Session Highlights

Multiple Myeloma

Dr Hansen reviewed progress in BCMA-directed therapies. Two approved CAR T-cell products, ide-cel and cilta-cel, continue to demonstrate deep, durable responses, with cilta-cel producing a 5-year median overall survival (OS) in late-line patients. Phase 3 trials (KARMA-3 and CARTITUDE-4) showed superior progression-free survival (PFS), higher measurable residual disease (MRD) negativity, and improved survival with CAR T vs standard therapy, especially when used earlier. Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and Parkinsonian-like neurotoxicity remain concerns but are increasingly mitigated using improved bridging therapy and early-intervention protocols such as dexamethasone-based management within the Citadel study.
Bispecific antibodies—including teclistamab (TEC), elranatamab, and talquetamab (TAL)—show response rates up to 72% in triple-class refractory disease. Dr Hansen emphasized sequencing challenges: Prior BCMA exposure reduces CAR T efficacy, while talquetamab maintains activity post-CAR T (median PFS ~13 months). Emerging bispecific combinations (eg, TEC + TAL in redirect-1) show high efficacy in extramedullary disease.

Lymphoma

Dr Smith discussed rapid advances in CD19-directed CAR T and CD20×CD3 bispecific antibodies. Next-generation CAR constructs (dual-antigen CD19/CD20 targeting, armored CARs secreting IL-18, and 48-hour manufacturing platforms) are improving durability and reducing toxicity. In diffuse large B-cell lymphoma (DLBCL), bispecific-chemo combinations—such as glofitamab + GemOx—demonstrate superior overall survival vs chemotherapy alone, with manageable CRS rates.

Access remains a barrier: Only 5.4% of eligible third-line DLBCL patients in a Surveillance, Epidemiology, and End Results (SEER)-Medicare analysis received CAR T. Shorter manufacturing times and community-feasible bispecifics may help close this gap.

Acute Leukemia

Dr Boissel highlighted dramatic improvements in B-cell acute lymphoblastic leukemia (B-ALL) through CD19/CD22-directed immunotherapies. Blinatumomab improves OS in frontline consolidation (E1910 study), while inotuzumab provides high complete response (CR) and MRD negativity rates, especially in older adults.

In T-ALL, novel CD7-directed CAR Ts—using gene editing or protein-trapping strategies—achieve > 90% response rates with encouraging MRD negativity. Acute Myeloid Leukemia (AML) remains challenging; CD33-directed ADCs (gemtuzumab ozogamicin) offer benefit only in favorable-risk subsets, and CAR T studies continue to explore ways to overcome myeloid-specific toxicities and a suppressive microenvironment.

According to Dr Hansen, earlier-line CAR T-cell use may narrow the gap between high- and standard-risk myeloma, particularly when bridging therapy is optimized. She emphasized the importance of preventing neurotoxicity through early detection of rapid CAR T expansion. Dr Smith noted that access, not biology, remains the largest barrier in DLBCL immunotherapy. She highlighted evidence that distance from treatment centers and logistical hurdles significantly reduce CAR T uptake. Dr Boissel stressed that MRD assessment methods and sensitivity requirements remain unresolved in the immunotherapy era, particularly post-CAR T. He emphasized that sequencing bispecifics before CAR T in leukemia may impair outcomes due to potential T-cell exhaustion, although mechanisms remain under investigation.

Implications for Practice

These data reinforce the trend toward earlier integration of T-cell–engaging therapies, refinement of toxicity-mitigation strategies, and evidence-driven sequencing to preserve T-cell fitness. Clinicians should consider earlier CAR T-cell referral, vigilant infection prophylaxis, and individualized therapy selection based on antigen exposure and MRD status. Payers and pathway developers should anticipate expanded indications and shifting treatment algorithms.

Conclusion

Immunotherapies across hematologic malignancies continue to advance rapidly, offering deeper remissions and evolving toward curative potential. Ongoing trials—including in vivo CAR T platforms and frontline bispecific combinations—promise to further refine sequencing and expand access across patient populations.

Reference

Hansen DK, Smith S, Boissel N. Invasion of the immunotherapies: where we are and where we are going in leukemia, lymphoma, and myeloma. Presented at: ASH 2025; December 6-9; Orlando, FL.