What is the role of CAR (Chimeric Antigen Receptor) T Cell therapy in treating relapsed or refractory multiple myeloma?

CAR T Cell Therapy for Multiple Myeloma

For patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy (including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody), BCMA-directed CAR T-cell therapy with either idecabtagene vicleucel or ciltacabtagene autoleucel should be offered as a treatment option, with ciltacabtagene autoleucel showing superior response rates (97% ORR vs 73% ORR). 1

FDA-Approved BCMA-Directed CAR T-Cell Products

Two BCMA-targeting CAR T-cell therapies are currently approved in the United States for relapsed/refractory multiple myeloma:

Idecabtagene Vicleucel (ide-cel)

• Approved in 2021 for patients who have received ≥4 prior therapies including an anti-CD38 monoclonal antibody, proteasome inhibitor, and immunomodulatory drug 1
• In the pivotal phase II study (n=128), patients had received a median of 6 prior regimens and 94% had undergone hematopoietic cell transplantation 1
• Overall response rate of 73%, with 33% achieving complete response or better 1
• Median time to response was 1 month, with median time to CR of 2.8 months 1
• High response rates (>50%) observed across challenging subgroups including older patients, high-risk cytogenetics, pentarefractory disease, and high tumor burden 1

Ciltacabtagene Autoleucel (cilta-cel)

• Approved for patients with relapsed/refractory MM after ≥4 prior lines of therapy 1, 2
• In the CARTITUDE-1 trial (n=97), patients had received a median of 6 prior therapies with 88% being triple-class refractory 1
• Demonstrated superior overall response rate of 97%, with 67% achieving stringent complete response 1
• At 12.4 months median follow-up: PFS rate 77%, OS rate 89% 1
• At 18 months: PFS 66.0%, OS 80.9% with no new safety signals 1
• Two-year PFS of 60.5% demonstrates durability of response 1

CAR T-Cell Treatment Process

The multistep process takes several weeks and includes:

1. Leukapheresis: Collection of white blood cells (including T cells) from patient's blood 1
2. Manufacturing: T cells are isolated, activated, and transduced with CAR transgene via lentiviral or retroviral vector, then expanded 1
3. Lymphodepletion chemotherapy: Fludarabine and cyclophosphamide administered prior to infusion to prevent immunologic rejection and maximize CAR T-cell expansion 1
4. CAR T-cell infusion: Prepared cells are infused into the patient 1

Toxicity Profile and Management

Common Hematologic Toxicities

Idecabtagene vicleucel:

• Grade 3-4 neutropenia: 89-91% 1
• Grade 3-4 anemia: 60-70% 1
• Grade 3-4 thrombocytopenia: 52-63% 1

Ciltacabtagene autoleucel:

• Neutropenia: 95% 1
• Anemia: 68% 1
• Thrombocytopenia: 60% 1
• Leukopenia: 61%, lymphopenia: 50% 1

Cytokine Release Syndrome (CRS)

Idecabtagene vicleucel:

• CRS occurs in 84% of patients, but grade ≥3 CRS only in 5% 1

Ciltacabtagene autoleucel:

• CRS occurs in 95% of patients 1

CRS Management Algorithm: 1

Grade 1 (fever ≥38°C):

• For prolonged CRS >3 days in patients with symptoms, comorbidities, or elderly: consider tocilizumab 8 mg/kg IV (max 800 mg) 1
• Sepsis screen, empiric broad-spectrum antibiotics, consider G-CSF if neutropenic 1

Grade 2 (hypotension not requiring vasopressors OR hypoxia requiring low-flow oxygen):

• Tocilizumab 8 mg/kg IV (max 800 mg), repeat in 8 hours if no improvement; maximum 3 doses in 24 hours, 4 doses total 1
• For persistent refractory hypotension after 1-2 doses: dexamethasone 10 mg IV every 12-24 hours 1
• Manage as Grade 3 if no improvement within 24 hours after starting anti-IL-6 therapy 1

Grade 3 (hypotension requiring vasopressor with/without vasopressin AND/OR hypoxia):

• Tocilizumab as per Grade 2 1
• Dexamethasone 10 mg IV every 6 hours; if refractory, manage as Grade 4 1
• Transfer to ICU, obtain echocardiogram, hemodynamic monitoring 1
• Supplemental oxygen and symptomatic management of organ toxicities 1

Grade 4 (hypotension requiring multiple vasopressors OR hypoxia requiring positive pressure ventilation):

• Tocilizumab as per Grade 2 1
• Dexamethasone 10 mg IV every 6 hours 1

Infections

• Grade 3-4 infections occur in 44.8-69% of patients 1
• Empiric broad-spectrum antibiotics warranted in neutropenic patients 1

Emerging Data: Earlier Lines of Therapy

Recent randomized trials demonstrate benefit of CAR T-cell therapy in earlier disease settings:

• CARTITUDE-4: Showed improved progression-free survival with CAR T-cell therapy compared to standard of care in second-line therapy 2
• KarMMA-3: Demonstrated improved PFS in third-line therapy 2
• FDA expansion to earlier lines of therapy is anticipated based on these results 2

Critical Considerations for Patient Selection

Factors Associated with Inferior Outcomes

• Prior BCMA-directed therapy leads to inferior outcomes from subsequent CAR T-cell therapy 2
• Rapidly progressing advanced disease poses challenges for access and safety 2
• CD4+ CAR T-cell exhaustion with early expression of HAVCR2 and TIGIT markers associated with early relapse 3

Factors Associated with Durable Response

• Greater persistence of CAR T cells correlates with durable response 3
• Higher proportion of CD8+ T-effector memory cells predicts better outcomes 3
• Earlier use when T cells are healthier and myeloma less aggressive may improve outcomes 2

Sequencing Challenges

Critical sequencing principle: Avoid BCMA-directed bispecific antibodies (teclistamab, elranatamab) before CAR T-cell therapy, as prior BCMA-directed therapy compromises CAR T-cell efficacy 2

For patients relapsing after CAR T-cell therapy:

• BCMA expression often persists at relapse, indicating immune-intrinsic resistance mechanisms rather than antigen loss 3
• Retreatment with idecabtagene vicleucel showed 21% second response rate in 28 patients 1
• Bispecific antibodies and other novel strategies show promise for post-CAR T-cell failure 4

Common Pitfalls to Avoid

• Do not delay CAR T-cell therapy in eligible patients with rapidly progressive disease, as manufacturing takes several weeks and disease may progress during this time 1
• Do not use BCMA-directed bispecific antibodies before planned CAR T-cell therapy, as this compromises subsequent CAR T-cell efficacy 2
• Do not assume fever is required for grading CRS severity beyond Grade 1; hypotension or hypoxia drive grading in subsequent stages 1
• Do not underestimate infection risk: 44.8-69% develop grade 3-4 infections requiring aggressive prophylaxis and monitoring 1