How effective is chimeric antigen receptor T‑cell (CAR‑T) therapy in adults with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (e.g., bortezomib), an immunomodulatory drug (e.g., lenalidomide), and an anti‑CD38 monoclonal antibody (e.g., daratumumab)?

CAR T-Cell Therapy Success in Relapsed/Refractory Multiple Myeloma

CAR T-cell therapy demonstrates exceptional efficacy in heavily pretreated multiple myeloma, with overall response rates of 73-97% and complete response rates of 33-67%, representing the most effective treatment option for patients who have failed at least four prior therapies including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. 1, 2

FDA-Approved CAR T-Cell Products and Their Efficacy

Ciltacabtagene Autoleucel (Cilta-cel)

Ciltacabtagene autoleucel is the superior CAR T-cell product based on response rates, achieving a 97% overall response rate with 67% of patients reaching stringent complete response in the CARTITUDE-1 trial. 1, 2 The trial enrolled 97 patients with a median of 6 prior therapies, with 88% being triple-class refractory. 1

• After 12.4 months median follow-up, progression-free survival rate was 77% with an 89% overall survival rate. 1
• Updated 18-month data showed durable responses with 66% progression-free survival and 80.9% overall survival. 1
• The 2-year progression-free survival reached 60.5%, demonstrating sustained disease control. 1
• 34% of patients achieved MRD-negative complete response or stringent complete response. 1

Idecabtagene Vicleucel (Ide-cel)

Idecabtagene vicleucel showed strong but slightly lower efficacy in the KarMMa Phase 2 trial with 128 patients who had a median of 6 prior lines of therapy. 1, 2

• Overall response rate was 73% with 33% achieving complete response or better. 1, 2
• All 16 evaluable responders achieved MRD-negative status (≤10⁻⁴ nucleated cells). 3
• Median progression-free survival was 11.8 months (95% CI, 6.2-17.8). 3
• The estimated 1-year overall survival rate was 65% in earlier phase I/II data. 1

Comparative Efficacy Across Studies

A systematic review and meta-analysis of 23 studies including 350 RRMM patients treated with CAR T-cell therapy revealed pooled efficacy outcomes: 4

• Pooled overall response rate: 77%
• Pooled complete response rate: 37%
• MRD negativity rate within responders: 78%
• Pooled relapse rate among responders: 38%
• Median progression-free survival: 8 months
• Pooled survival rate at last follow-up (median 12 months): 87%

BCMA-targeted CAR T-cell therapy demonstrated superior efficacy compared to other antigen targets. 4

Safety Profile and Toxicity Management

Hematologic Toxicities

Severe cytopenias are nearly universal and represent the most common grade 3-4 adverse events. 2

With idecabtagene vicleucel: 2

• Grade 3-4 neutropenia: 89-91%
• Grade 3-4 anemia: 60-70%
• Grade 3-4 thrombocytopenia: 52-63%

With ciltacabtagene autoleucel: 1, 2

• Neutropenia: 95%
• Anemia: 68%
• Thrombocytopenia: 60%
• Leukopenia: 61%
• Lymphopenia: 50%

Cytokine Release Syndrome (CRS)

CRS occurs in the vast majority of patients but is predominantly low-grade and manageable. 2

• Idecabtagene vicleucel: 84% any grade CRS, with only 5% grade ≥3. 2
• Ciltacabtagene autoleucel: 95% any grade CRS. 1, 2
• In the phase 1 bb2121 study, 76% experienced CRS, with 70% grade 1-2 and only 6% grade 3. 3

The pooled grade 3-4 CRS rate across all CAR T-cell studies was 14%. 4

Neurologic Toxicities

Neurologic adverse events are less common than CRS but require vigilant monitoring. 3

• The pooled grade 3-4 neurologic toxicity rate was 13%. 4
• In the bb2121 study, 42% experienced neurologic toxicities, with 39% grade 1-2 and only 3% grade 4 (reversible). 3

Infectious Complications

Grade 3-4 infections occur in 44.8-69% of patients, necessitating aggressive antimicrobial prophylaxis and monitoring. 2

Treatment-Related Mortality

Treatment-related deaths are uncommon but can occur. In CARTITUDE-1, there were 6 deaths due to treatment-related adverse events out of 97 patients. 1 One study reported a death from hemophagocytic lymphohistiocytosis syndrome secondary to severe CRS. 5

Clinical Positioning and Patient Selection

The NCCN Guidelines designate both idecabtagene vicleucel and ciltacabtagene autoleucel as preferred options for patients with relapsed/refractory multiple myeloma after at least 4 prior therapies including an anti-CD38 monoclonal antibody, proteasome inhibitor, and immunomodulatory drug. 1

Key Considerations for Patient Selection

• Patients must have adequate organ function to tolerate lymphodepletion chemotherapy and potential toxicities. 2
• The CAR T-cell manufacturing process takes several weeks, requiring bridging therapy for patients with rapidly progressive disease. 2
• Avoid prior BCMA-directed therapy (including bispecific antibodies) as this significantly compromises CAR T-cell efficacy. 6
• Earlier use in the disease course may yield better outcomes when T cells are healthier and disease burden is lower. 6

Emerging Data on Earlier Lines of Therapy

Recent randomized trials demonstrate superior progression-free survival with CAR T-cell therapy in earlier disease settings. 6

• CARTITUDE-4 showed improved outcomes in second-line therapy
• KarMMa-3 demonstrated benefit in third-line therapy
• These results suggest FDA approval expansion to earlier lines is anticipated. 6

Common Pitfalls and Caveats

Critical pitfall: Using BCMA-directed bispecific antibodies before CAR T-cell therapy leads to inferior CAR T-cell outcomes. 6 Sequencing decisions must prioritize CAR T-cell therapy in appropriate candidates before considering bispecific antibodies.

Relapse remains common despite high initial response rates, with 38% of responders eventually relapsing. 4 Six of 15 complete responders in the bb2121 study experienced relapse. 3

Rapidly progressive disease poses challenges as the manufacturing timeline (several weeks) may allow disease progression requiring bridging therapy. 2

Post-CAR T-cell relapse represents an unmet clinical need with limited effective salvage options, particularly after BCMA-directed therapy. 7