What is the role of Chimeric Antigen Receptor T (CART) cell therapy in treating relapsed or refractory multiple myeloma, especially in older adults with significant comorbidities and previous exposure to lenalidomide, pomalidomide, and daratumumab?

Role of CAR-T Cell Therapy in Multiple Myeloma

CAR-T cell therapy, specifically idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), represents a highly effective treatment option for relapsed/refractory multiple myeloma patients who have received 4 or more prior therapies, including lenalidomide, pomalidomide, and daratumumab, with FDA approval based on superior efficacy even in heavily pretreated populations. 1

FDA-Approved CAR-T Products and Indications

Idecabtagene Vicleucel (ide-cel, bb2121)

• FDA-approved for adult patients with relapsed or refractory multiple myeloma after 4 or more prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody 1
• The KarMMa Phase 2 trial demonstrated 73% overall response rate with 33% complete response rate in 128 patients with median of 6 prior lines of therapy, where 94% were refractory to anti-CD38 antibody 1
• High rates of MRD negativity and manageable toxicities with promising progression-free and overall survival led to approval 1
• The phase 3 KarMMa-3 trial showed median progression-free survival of 13.3 months with ide-cel versus 4.4 months with standard regimens (hazard ratio 0.49, P<0.001) in triple-class-exposed patients 2
• 71% response rate with ide-cel compared to 42% with standard regimens, with 39% achieving complete response versus only 5% with standard therapy 2

Ciltacabtagene Autoleucel (cilta-cel)

• The CARTITUDE-1 trial evaluated 97 patients with median of 6 prior lines, 88% triple-class refractory 1
• Demonstrated 96.9% overall response rate with 34% MRD-negative complete response or stringent complete response 1
• Recently updated results showed 2-year progression-free survival of 60.5%, representing superior durability compared to ide-cel 1

Mechanism and Target Antigen

• Both products are BCMA-targeting CAR T-cell constructs administered after lymphodepleting chemotherapy 1
• BCMA (B-cell maturation antigen) promotes MM pathogenesis in the bone marrow microenvironment and is a specific MM target antigen 1
• Immunologically-based therapies targeting BCMA demonstrate promise independent of genetic heterogeneity and genetic risk, even in MM patients without other treatment options 1

Optimal Patient Selection for CAR-T

Ideal Candidates

• Patients with triple-class refractory disease (refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies) 1, 2
• Those who have received 2-4 prior regimens with disease refractory to the last regimen 2
• Patients with daratumumab-refractory disease (95% of KarMMa-3 patients had daratumumab-refractory disease) 2

Earlier Use Consideration

• The KarMMa-3 trial demonstrated benefit in patients with only 2-4 prior lines of therapy, suggesting CAR-T should be considered earlier than 4th line in appropriate candidates 2
• 66% of patients in KarMMa-3 had triple-class-refractory disease, indicating efficacy even in this challenging population 2

Safety Profile and Toxicity Management

Common Adverse Events

• Cytokine release syndrome (CRS) occurred in 88% of ide-cel patients, with only 5% grade 3 or higher 2
• Investigator-identified neurotoxic effects occurred in 15%, with 3% grade 3 or higher 2
• Grade 3-4 adverse events occurred in 93% of CAR-T patients versus 75% in standard regimen patients 2
• Toxicities were manageable in both the initial phase 1 study and subsequent trials 1

Meta-Analysis Safety Data

• Combined incidence of cytokine release syndrome was 82% (95% CI: 72-91%) across 21 trials with 761 patients 3
• Neurotoxicity incidence was 10% (95% CI: 5%-17%) 3

Efficacy Outcomes Across Studies

Response Rates

• Meta-analysis of 21 trials showed overall response rate of 87% (95% CI: 80-93%) 3
• Complete response rate of 44% (95% CI: 34-54%) 3
• MRD negativity rate within responders of 78% (95% CI: 65-89%) 3

Survival Outcomes

• Median progression-free survival: 8.77 months (95% CI: 7.48-10.06) across multiple studies 3
• Median overall survival: 18.87 months (95% CI: 17.20-20.54) 3
• Median duration of response: 10.32 months (95% CI: 9.34-11.31) 3

Positioning in Treatment Algorithm for Older Adults with Comorbidities

After Lenalidomide/Pomalidomide/Daratumumab Exposure

• CAR-T therapy is the preferred option after failure of triple-class therapy rather than continuing with additional chemotherapy combinations 1
• For patients who have exhausted lenalidomide, pomalidomide, and daratumumab, ide-cel or cilta-cel should be prioritized over belantamab mafodotin (which showed only 31-34% response rates with median PFS of 2.9-4.9 months) 1
• Superior to selinexor-dexamethasone, which showed only 26% response rate with median PFS of 3.7 months and median OS of 8.6 months 1

Considerations for Elderly Patients

• While age-specific data within CAR-T trials is limited, the manageable toxicity profile suggests feasibility in carefully selected older adults 1, 2
• The single infusion approach may be preferable to continuous chemotherapy regimens in frail patients who can tolerate lymphodepletion 2
• Patients must have adequate performance status to undergo lymphodepleting chemotherapy and CAR-T infusion 1

Post-CAR-T Relapse Management

Salvage Treatment Options

• Median overall survival from relapse post-CAR-T was 17.9 months (95% CI: 14.0-non-estimable) 4
• Overall response rate to first salvage regimen was 43.4% with median PFS of 3.5 months 4
• 44.3% of patients received T-cell-engaging therapy (bispecific antibody or subsequent CAR-T) as salvage 4
• Overall survival in patients receiving subsequent T-cell-engaging therapy was not reached after median follow-up of 21.3 months, indicating this is the preferred salvage approach 4

BCMA Re-targeting

• Continued expression of BCMA in some patients relapsing on BCMA-based therapies provides the option of continuing to target this antigen 1
• Bispecific antibodies (teclistamab, elranatamab, talquetamab) showed promising outcomes post-CAR-T failure 1

Critical Pitfalls to Avoid

Timing Errors

• Do not delay CAR-T referral until 5th or 6th line when patients have accumulated excessive toxicity and declining performance status—KarMMa-3 demonstrated benefit at 2-4 prior lines 2
• Do not continue ineffective chemotherapy combinations in triple-class refractory patients when CAR-T is available 1, 2

Patient Selection Errors

• Do not exclude patients solely based on age—focus on performance status and ability to tolerate lymphodepletion 2
• Do not use CAR-T in patients with plasma cell leukemia or extensive extramedullary disease without considering more intensive regimens first 5

Post-Treatment Management

• Do not abandon BCMA-targeting after CAR-T failure—bispecific antibodies maintain activity and should be prioritized as salvage 4
• Do not use single or doublet therapy when triplet T-cell engaging regimens are available post-CAR-T relapse 4

Comparison with Alternative BCMA-Targeted Therapies

Versus Belantamab Mafodotin

• Belantamab mafodotin (BCMA antibody-drug conjugate) showed only 31-34% response rates with median PFS of 2.9-4.9 months 1
• Failed to meet primary endpoint in DREAMM-3 trial (HR 1.03 versus pomalidomide/dexamethasone) and was withdrawn from market 1
• CAR-T demonstrates markedly superior efficacy with 71-97% response rates 1, 2

Versus Bispecific Antibodies

• Teclistamab showed 62% overall response rate with 9-month PFS of 58.5% in triple-class exposed patients 1
• While bispecifics avoid need for lymphodepletion and manufacturing delay, CAR-T products show deeper responses and longer durability 1, 3
• Bispecifics are excellent salvage options post-CAR-T failure 4