Page 236 - Haematologica Vol. 110 - January 2025

LETTER TO THE EDITOR
Comparing the clinical trial efficacy versus real-world effectiveness of treatments for multiple myeloma: a population-based study
Phase III randomized control trials (RCT) are the “gold standard” used to obtain marketing and regulatory approval for novel multiple myeloma (MM) treatments, inform pa- tients about treatment outcomes, and inform treatment guidelines. Yet, numerous indirect real-world (RW) and RCT comparisons have shown that RW patient tend to have inferior outcomes compared to RCT patients. However, to date, no study has directly quantified the differences in outcomes between RW and RCT patients with MM treat- ed with standard of care (SoC) therapies. Understanding and quantifying the difference in efficacy, the outcome in an “ideal” RCT setting, and effectiveness, the outcome in the “real life” clinical practice setting, is needed to con- textualize the generalizability of RCT data to the general population. To fill this knowledge gap, we conducted a population-based cohort study to compare and quantify the difference in the RW effectiveness versus RCT efficacy of SoC MM regimens with respect to the progression-free survival (PFS) and overall survival (OS).
The RCT cohort was identified from registrational phase III RCT which led to the public reimbursement of SoC regi- mens in Ontario between January 1, 2013 to December 31, 2021. Regimens included lenalidomide/dexamethasone (Rd) bortezomib/Rd (VRd) in patients with transplant-ineligi- ble newly diagnosed MM patients (TIE-NDMM). Relapsed refractory MM (RRMM) regimens included carfilzomib/Rd (KRd), carfilzomib/dexamethasone (Kd), daratumumab/Rd (DRd), daratumumab/bortezomib/dexamethasone (DVd), and pomalidomide/dexamethasone (Pd). The most recent published Kaplan-Meier PFS1-7 and OS1,2,7-11 curves were man- ually digitized using the WebPlotDigitizer software (version 4.6), then reconstructed using an established algorithm12 to provide individual patient-level estimates of PFS and OS for the experimental arm in the RCT cohorts.
RW data was obtained using from Ontario’s ICES adminis- trative database. Ontario has a universal, publicly funded healthcare system which provides access to chemotherapy, and the provincial administrative database captures virtu- ally all health care encounters and has a loss to follow-up rate of 0.25%. Treatment data was accessed through the Ontario Drug Benefit database for regimens containing only oral medications and the Cancer Activity Level Reporting database for treatment regimens containing injected or infused medications. Patients diagnosed with MM between January 1, 2013 to December 31, 2020 and initiating treat- ment with SoC regimens either at diagnosis or relapse were included in this study. Provincial reimbursement criteria
for SoC regimens mirrors the RCT inclusion criteria, with regards to the prior drug exposure and lines of therapy (see Online Supplementary Table S1). The data cut-off date was May 31, 2022.
We assessed the efficacy and effectiveness of RCT and RW data, respectively, by comparing the Kaplan-Meier survival curve estimates of PFS and OS. The RCT PFS was defined as the time from index regimen treatment to disease pro- gression, death, or last follow-up, whichever occurred first. In RW administrative database, the progression date could not be accurately determined and so time to next treatment (TTNT) was used as a surrogate for RW PFS. TTNT was defined as the time from initiation of index reg- imen to initiation of subsequent MM treatment, death, or last follow-up. In both RCT PFS and RW TTNT definitions, patients remaining on the index regimen at last follow-up were censored. OS was defined as the time from initia- tion of the index treatment to death or end of follow-up. Meta-analyses using random effects models were used to compare the PFS and OS outcomes of RW versus RCT pa- tients. Effect estimates for PFS and OS were summarized using hazard ratios (HR). The study was approved by the ethics committee of McMaster University.
Overall, 3,951 RW and 2,476 RCT MM patients, treated with seven SoC MM regimens, were included. Baseline charac- teristics of the RW and RCT cohorts are shown in Table 1. Overall, the RW cohort patients tended to be older than RCT patients. A minority of TIE-NDMM patients treated were initially started on a short course of single agent lenalidomide or bortezomib during the COVID-19 pandemic and then transitioned to the full triplet regimen. For RRMM SoC regimens, the time between MM diagnosis and index regimen treatment initiation was longer in the RCT versus RW cohorts. However, despite RW patients being treated with the SoC regimens earlier in their disease course, apart from RW patients treated with Pd, RW patients tended to have higher rates of previous lenalidomide and bortezomib exposure.
The RW had 51% increased risk of progression or death compared to RCT patients (pooled HR=1.51, 95% confidence interval [CI]: 1.03-2.21; P=0.034; Figure 1A). Six of the seven SoC regimens analyzed had a shorter mPFS in the RW co- hort compared to the RCT cohort (Table 2; Online Supple- mentary Figure S1). The disparate PFS outcomes were more apparent in patients treated with RRMM regimens (pooled HR=1.66, 95% CI: 0.99-2.80; P=0.056, absolute decrease in mPFS ranged from 7.2-18.3 months in the RW cohort) as
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