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

Abstract

Despite randomized clinical trials (RCTs) of novel agents showing prolonged survival for patients with relapsed/refractory multiple myeloma (RRMM), we have found that most patients with RRMM receiving routine care will not be eligible for these trials. Furthermore, survival has been significantly worse for patients with RRMM not meeting the eligibility criteria, resulting in a gap between RCT efficacy and real-world effectiveness. Background: Concern has been increasing in oncology regarding randomized clinical trial (RCT) eligibility limiting the generalizability of the findings to real-world populations. Using a large US electronic health record database, we investigated the real-world generalizability of the findings from recent RCTs for relapsed and/or refractory multiple myeloma (RRMM). Patients and Methods: Patients with RRMM initiating second-to fourth-line therapy with the control arm of the following RCTs were retrospectively identified and categorized as "RCT eligible" or "RCT ineligible" according to the eligibility criteria: (1) Rd (lenalidomide, dexamethasone)-ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2; and (2) Vd (bortezomib, dexamethasone)-CASTOR and ENDEAVOR. Predictors of RCT ineligibility and overall survival were analyzed using logistic regression and Cox regression analysis. Results: Variations in the individual trial ineligibility rates were noted, with up to 72.3% (range, 47.9%-72.3%) of patients not meeting the eligibility criteria for 1 of the 6 hallmark RCTs (n ¼ 788 for Rd; n ¼ 477 for Vd). Other malignancies, cardiovascular disease, acute infection, and renal dysfunction were the common reasons for ineligibility. Advanced age, Charlson comorbidity score of ! 2, later therapy lines (3-4), and refractory status to the previous line were independently predictive of RCT ineligibility. RCT-ineligible versus RCT-eligible patients had a significantly greater mortality risk (hazard ratio, Rd, 1.46; Vd, 1.51). Conclusion: Most real-world patients with RRMM were ineligible for the hallmark RCTs. The eligibility rates varied across the RCTs, underlining the flawed nature of cross-study comparisons without RCT validation. Overall survival was significantly affected by the inability to meet the criteria, highlighting the limited generalizability of the RCT results. Greater efforts are required to broaden the eligibility criteria to reflect real-world clinical characteristics and narrow the gap between RCT efficacy and the observed effectiveness in real-world patients with RRMM.

Real-world outcomes and factors impacting treatment choice in relapsed and/or refractory multiple myeloma (RRMM): a comparison of VRd, KRd, and IRd

“…Given the known differences in a real-world RRMM population vs. those meeting the strict eligibility criteria within clinical trials [12], we conducted a subgroup analysis in real-world patients treated in earlier LOTs (i.e. LOT 2 or 3) who are more representative of the clinical trial population.…”

“…Patients with missing data were categorized separately. A modified frailty score based on Palumbo et al [14] was employed utilizing age and CCI score only (Online Appendix Further, given the age of the studied population and mix of cardiovascular comorbidities that affect treatment choice, an expanded definition of cardiovascular disease was employed [12]. Presence of cardiovascular disease was captured via ICD-9/10 coding for myocardial infarction (MI), angina, coronary artery disease (CAD), arrhythmia, sick sinus syndrome, or heart failure (HF); however, to ensure only severe (i.e.…”

“…Presence of cardiovascular disease was captured via ICD-9/10 coding for myocardial infarction (MI), angina, coronary artery disease (CAD), arrhythmia, sick sinus syndrome, or heart failure (HF); however, to ensure only severe (i.e. uncontrolled or symptomatic cases) were recorded, identification required 1 inpatient encounter coded as primary or discharge or any two outpatient encounters with primary diagnosis codes that were 60 to 365 days apart, with the first one occurring within 6 months prior to start of the index regimen [12]. Presence of uncontrolled hypertension (HTN) was identified via 1 inpatient or 2 outpatient ICD-9/10 codes for HTN that were 60 to 365 days apart with an accompanying blood pressure measurement ≥160/100 mmHg (corresponding to Common Terminology Criteria for Adverse Events grade ≥3) based on the most recent measurement within 14 days prior to index regimen [12].…”

“…In patients with MM, advanced age and higher comorbidity burden are factors that are under-represented in clinical trials. A recent real-world analysis reported that up to 75% of patients with RRMM engaged in routine care in the US do not meet the eligibility criteria of hallmark clinical trials of approved or recommended regimens in this setting and that 3-year OS was significantly and negatively impacted by the inability to meet eligibility requirements [12]. Greater comorbidities and poorer performance status result in worse treatment outcomes [13].…”

Quality of life is maintained with ixazomib maintenance in post‐transplant newly diagnosed multiple myeloma: The TOURMALINE‐MM3 trial

“…35 It is acknowledged that the characteristics of the TOURMALINE-MM3 population may limit the generalisability of the findings to a wider real-world population-a known limitation of randomised controlled trials in MM more generally. 36 A…”