Real-World Applicability of Commercial Chimeric Antigen Receptor T Cell Therapy Among Older Adults with Relapsed and/or Refractory Multiple Myeloma

Introduction: In 2021, the US FDA approved idecabtagene vicleucel, the first Chimeric Antigen Receptor-T cell (CAR-T) therapy for patients with relapsed/refractory multiple myeloma (MM) who had received at least four prior lines of therapy. Approval was based on phase II KARMMA trial of this drug showing a response rate of 73% and median progression free survival of 8.8 months; efficacy parameters considered transformative in this setting. Other CAR-T cell therapies are being tested in similar population. However, it is unknown what proportion of real world MM patients, particularly older adults, would be eligible for this treatment.

Methods: We used the Flatiron Health Electronic Health Record (EHR) derived de-identified database to select patients newly diagnosed with MM from January 2011 to December 2016. We limited our cohort to those who received ≥1 line of myeloma treatment within 90 days of diagnosis. Lines of therapy (LoT) were ascertained using Flatiron oncologist-defined rules based on the addition of new anti-myeloma agents and gap periods during which no treatment was received. All patients were followed up to the initiation of fifth-line therapy, death or their last structured visit, whichever came earlier. We computed the cumulative incidence of initiating LoT therapy with death prior to fifth-line as the competing risk, remaining patients were censored at their last structured activity in the EHR. For patients initiating fifth LoT, we assessed their CAR-T eligibility using the following key inclusion criteria per the KARMMA trial (ECOG 0-1, GFR >45 ml/min, ANC > 1250 /mm3, Platelet >75k/mm3, ALT/AST <2.5 x upper limit, Bilirubin <2x upper limit, and active treatment for secondary cancer) extracting relevant variables within 90 days of the start of fifth line therapy. Differences in cumulative incidence rates were compared using univariate Fine-Gray's test. All p-values were two sided and the level of significance was 0.05.

Results: A total of 4522 eligible patients were identified. The cohort was representative of population of MM patients and patterns of MM therapy in the US with a median age at diagnosis of 69 y (IQR 61-77) and 49% with age 70y or older, 54% males, and 63% non-Hispanic whites. Overall, 20% had ISS III disease, with 11% high risk cytogenetics 31% receiving initial therapy with proteasome inhibitor and immunomodulatory-based triplet therapy and 28% receiving stem cell transplant. In the overall cohort, the cumulative incidence of starting fifth LoT 8y from diagnosis was 28%, while the cumulative risk of death before initiating 5 ^th LoT was 53% (Figure). However, achievement of 5 ^th line therapy at 8y was much lower for older adults (35% for age<70y vs 20% for age ≥70y; p value <0.01, Figure), while the risk of death before achieving 5 ^th line therapy was higher among older patients (37% for age<70y vs 69% for age≥70y; p value <0.01). Among the patients reaching 5 ^th line therapy, only 44% would be eligible for CAR-T therapy based on the aforementioned eligibility criteria, which translates to about 8.9% of all newly diagnosed older adults ≥70y.

Conclusion: Less than 10% of newly diagnosed older adults with MM are expected to be eligible for CAR-T therapy based on the current FDA approval and eligibility criteria. Meanwhile a much higher proportion of patients die before reaching CAR-T eligibility. These findings highlight the need to explore CAR-T cell therapy in earlier lines of disease and in a population that better represents real world patients to expand the applicability of this novel treatment.

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