Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark RCTs in Relapsed/Refractory Multiple Myeloma

Structured Abstract BACKGROUND There is growing concern in oncology about randomized clinical trial (RCT) eligibility limiting generalizability to real-world populations. PURPOSE Utilizing a large US electronic health record database, we investigated real-world generalizability of recent RCTs in relapsed and/or refractory multiple myeloma (RRMM). PATIENTS AND METHODS RRMM patients initiating second-to-fourth-line therapy with the control arm of the following RCTs were retrospectively identified and categorized as “RCT-eligible” vs “RCT-ineligible” based on eligibility criteria: (1) lenalidomide/dexamethasone (Rd): ASPIRE, TOURMALINE-MM1, POLLUX, ELOQUENT-2; (2) bortezomib/dexamethasone (Vd): CASTOR, ENDEAVOR. Predictors of RCT ineligibility and overall survival (OS) were analyzed using logistic regression and Cox regression. RESULTS Variation in individual trial ineligibility rates was noted with up to 72.3% (range: 47.9—72.3%) of patients not meeting eligibility criteria for one of the 6 hallmark RCTs (n=788 Rd; n=477 Vd). Other malignancies, cardiovascular disease, acute infections, and renal dysfunction were common reasons for ineligibility. Advanced age, Charlson comorbidity score of ≥2, later therapy lines (3-4), and refractory status to prior line were independently predictive of RCT-ineligibility. RCT-ineligible vs RCT-eligible patients had significantly higher mortality risk (Rd: HR=1.46; Vd: HR=1.51). CONCLUSION The majority of real-world RRMM patients were ineligible for hallmark RCTs. Eligibility rates varied across RCTs, underlining the flawed nature of cross-study comparisons without RCT validation. OS was significantly affected by inability to meet criteria highlighting limited generalizability of RCT results. Greater efforts should be made to broaden eligibility criteria to reflect real-world clinical characteristics to narrow the gap between RCT efficacy and observed effectiveness in real-world MM patients.