<scp>Real‐world</scp> applicability of commercial chimeric antigen receptor T‐cell therapy among older adults with relapsed and/or refractory multiple myeloma
Authors: Smith Giri, Susan Bal, Kelly N. Godby, Gayathri Ravi, Deanna Clark, Clare Ubersax, Abigail Cooley, Priscila White, Sunil Rangarajan, Grant R. Williams, Luciano J. Costa
Journal: American Journal of Hematology (2022)

Despite significant advances in the treatment of multiple myeloma (MM), most patients inevitably relapse and ultimately succumb to their disease. In particular, the treatment of patients who are triple-class refractory (TCR, i.e., refractory to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody) remains a significant challenge with a median overall survival of 9 months and limited therapeutic options available.1, 2 In 2021, the US Food and Drug Administration approved Idecabtagene vicleucel, the first chimeric antigen receptor-T-cell (CAR-T) therapy, for patients with relapsed/refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy. Approval was based on the single arm phase II KARMMA study among 128 patients with heavily pretreated MM (84% TCR) demonstrating an overall response rate of 73%, complete response rate of 33%, and a median progression-free survival of 8.8 months; efficacy parameters considered transformative in this setting.3 While the FDA approval of CAR-T therapy among patients with RRMM represents a significant addition to the therapeutic arsenal, its immediate benefit in real-world patients with MM, particularly older adults, is unknown. Published real-world evidence suggests that 32–61% and 14–38% of patients with symptomatic MM receive second- and third-line therapy, respectively.4 Furthermore, the very reeligibility criteria used by the phase II KarMMa study may further limit the number of patients who are considered for this therapy. We used the Flatiron Health Electronic Health Record (EHR)-derived deidentified database, a longitudinal database comprising patient-level structured and unstructured data, curated via technology-enabled abstraction, originating from approximately 280 cancer clinics across the United States (≈800 sites of care). Our primary study cohort included adults ≥18 years diagnosed with MM from January 2011 and December 2016, who received ≥1 line of therapy (LoT) within 90 days of diagnosis. We applied oncologist-defined, rule-based LoT algorithms, anchored to the addition of new anti-myeloma agents and gap periods during which no treatment was received. The primary outcome of interest was eligibility for CAR-T based on the current FDA approval, defined as a) patients who are initiating fifth line of therapy and b) meeting criteria for CAR-T therapy based on the key eligibility criteria used by the KarMMa (ECOG performance status (PS) 0-1, glomerular filtration rate > 45 mL/min, absolute neutrophil count ≥1250/mm3, platelet count ≥ 75 k/mm3, alanine aminotransferase/aspartate aminotransferase ≤2.5× upper limit, direct bilirubin ≤2× upper limit, and no active treatment for secondary cancer).3 The latter was defined based on documented ECOG PS or laboratory values within 90 days prior to initiation of the 5th LoT, whereas receipt of an anticancer agent not approved for MM during the fifth line was considered as evidence of active treatment for secondary cancer. All patients were followed up to the initiation of fifth-line therapy, death, or their last structured visit, whichever came earlier. Death was ascertained using a previously validated composite mortality variable using patient-level structured (EHR data, obituaries, and Social Security Death Index) and unstructured EHR data.5 Real world overall survival (rwOS) was defined as time from the date of diagnosis (index date) to death or last structured activity in the electronic health record. We computed the cumulative incidence of initiating fifth-line therapy with death prior to fifth-line as the competing risk, remaining patients were censored at their last structured activity in the EHR. We computed differences in cumulative incidence rates using univariate Fine-Gray's test. All p-values were two sided, and the level of significance was chosen as 0.05. Institutional Review Board approval of the study protocol was obtained prior to study conduct and included a waiver of informed consent. We selected 4522 eligible patients during the study period. The overall cohort had 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 International Staging System-stage 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. Over a median follow-up of 4.6 years, 2117 (46.8%) patients died, with a median rwOS of the entire cohort of 4.9 (95% CI 4.6–5.2) years. During this time period, a total of 656 (14.5%) of the initial cohort patients started fifth-line therapy, whereas 1793 (39.6%) died prior to starting fifth-line therapy. When accounting for death as a competing risk, the cumulative incidence of starting fifth-line therapy 8 years from diagnosis was 28% in the overall cohort (Figure 1A). However, achievement of 5th-line therapy at 8 years was much lower for older adults (35% for age < 70 years vs 20% for age ≥ 70 years; p value < .01, Figure 1B), while the risk of death before achieving 5th line-therapy was higher among older patients (37% for age < 70 years vs 63.2% for age ≥ 70 years; p value < .01). Among the patients initiating 5th-line therapy, only 44% would be eligible for CAR-T therapy based on the aforementioned eligibility criteria, which would translate to about 15.4% and 8.8% of newly diagnosed patients with MM <70 and ≥70 years, respectively. Our study highlights that only a small proportion of patients with RRMM, particularly those ≥70 years at the time of diagnosis, are actually likely to benefit from the current CAR-T FDA approval. Ongoing studies are currently looking at these therapies in earlier lines of therapy so that more patients can potentially be benefited. Our findings are overall consistent with a recent study by Fonseca et al showing high attrition rates across lines of therapy among patients with newly diagnosed MM, with only 8% of nontransplant patients and 22% of total transplant patients receiving a fifth-line therapy, although we report slightly higher proportions.4 This difference is likely explained by the use of competing risk framework in our analysis, which takes into account the high number of deaths occurring prior to the initiation of fifth-line therapy. With the incorporation of CD38 monoclonal antibodies into earlier regimens, it is quite likely that most patients will have TCR myeloma by second or third line of therapy, and there is a large unmet need for novel therapies in this population. Therefore, approvals should be defined based on development of TCR rather than based on a set number of lines of therapy. Furthermore, our findings that majority of patients reaching 5th LoT would not meet eligibility criteria for CAR-T therapy calls upon studying the efficacy and safety of these therapies among patients with broader set of eligibility criteria than used by KarMMa study. The real-world data on the outcomes of patients who actually obtained commercial CAR-T will further clarify the eligibility criteria and outcomes of these heavily pretreatment patients. Lastly, clinical trials should continue to test CAR-T therapies in earlier lines of therapy, and results from several of these trials (NCT04855136, NCT03651128, and NCT04181827) are eagerly awaited. Our study has several limitations. While not nationally representative, our data originated from 280 cancer clinics (≈800 practice sites), predominantly community cancer centers across 44 states in the United States. Our study cohort was derived from patients diagnosed in the pre-CART era, and it is possible that a greater proportion of patients may receive a 5th LoT than those reported in our study. Despite having more recent data (2016–2021), we were forced to select an earlier time-period to allow sufficient follow-up and more accurately ascertain the proportion of patients receiving 5th LoT. Since, our results were heavily influenced by high attrition rates; these findings may not only be unique to CART but for any novel therapies for MM approved in the later lines of therapy. Patients who transfer their care to a different practice site may have lost to follow-up, leading to an underestimation of the proportion of patients starting a LoT. Data on comorbidity and organ function (other than renal/hepatic) was not available; therefore, we were not able to adjudicate treatment ineligibility based on cardiac or pulmonary status as originally defined in KARMMA study.6 Lastly, eligibility status on some patients (≈20%) starting fifth-line therapy could not be determined due to missing data on performance status or laboratory data, and we restricted our analysis to complete cases only. To summarize, less than 10% of older adults with newly diagnosed MM patients 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. Smith Giri: Carevive Systems: Honoraria, Research Funding; Pack Health LLC: Research Funding; Sanofi: Research Funding. Susan Bal: Adaptive Biosciences: Consultancy; Amyloid Foundation: Research Funding. Luciano J. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Sanofi: Consultancy, Honoraria, Speakers Bureau Janssen: Research Funding, Speakers Bureau; Abbvie: Consultancy. The data that support the findings of this study are available from Flatiron Health (https://flatiron.com). Restrictions apply to the availability of these data, which were used under license for this study. Data are available at https://flatiron.com with the permission of Flatiron Health. The data that support the findings of this study are available from Flatiron Health (https://flatiron.com). Restrictions apply to the availability of these data, which were used under license for this study. Data are available at https://flatiron.com with the permission of Flatiron Health.