Patients with multiple myeloma treated in the “real world” had worse outcomes than patients who received the same treatment on clinical trials, according to research presented at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition.¹ In a pooled analysis of clinical trial efficacy vs real-world effectiveness for seven myeloma regimens, median progression-free survival was 44% worse and median overall survival was 75% worse for patients not enrolled in trials, according to Alissa Visram, MD, MPH, a hematologist at the Ottawa Hospital Research Institute, Ontario, Canada.

“For six of the seven standard-of-care regimens, the median progression-free survival was at least 3 to 18 months longer in the clinical trial cohort, and median overall survival was at least 19 months longer,” Dr. Visram said. “These real-world studies of effectiveness are going to become increasingly relevant, as we evaluate complex treatments that are associated with significant toxicity and financial burden.”

Alissa Visram, MD, MPH

As the investigators noted, improvements in outcomes of patients depend on using regimens of proven efficacy in large phase III randomized controlled trials, but many real-world patients would not have met stringent trial inclusion criteria. Reported outcomes from large trials are used by clinicians in counseling patients about the expected benefits of treatment, but the efficacy seen in the ideal clinical trial setting is often superior to the effectiveness observed in “real patients.” The magnitude of this “efficacy-effectiveness” gap in myeloma is unknown. “Understanding the effectiveness of treatments is important for policymakers who regulate the use of drugs but also for patients and clinicians to make informed treatment decisions,” Dr. Visram stated.

Study Populations

The findings were based on reported outcomes of phase III registrational trials that led to reimbursement of myeloma regimens under Ontario’s public health-care program as of 2020. These outcomes were compared with those reported in a database of more than 13 million health records at the Institute for Clinical Evaluative Sciences.

Treatments included two regimens for newly diagnosed, transplant-ineligible patients—lenalidomide plus dexamethasone [Rd] and Rd plus bortezomib—and five for relapsed or refractory disease—Rd plus carfilzomib; carfilzomib plus dexamethasone; Rd plus daratumumab; daratumumab, bortezomib, and dexamethasone; and pomalidomide plus dexamethasone. Although cyclophosphamide, bortezomib, and dexamethasone is a commonly used induction regimen in Canada, its approval was based on phase II data, and therefore that regimen was not included in this study.

Hazard Ratios Determined

The hazard ratios for the 3,951 patients treated with standard-of-care regimens in the pooled meta-analysis compared with the selective group of clinical trial patients was 1.44 (95% confidence interval [CI] = 1.34–1.54) for progression-free survival and 1.75 (95% CI = 1.63–1.88) for overall survival. The differences were most apparent in patients treated with regimens for relapsed or refractory disease, for whom the real-world population had higher rates of exposure to lenalidomide. The only regimen on which real-world patients seemed to fare better was pomalidomide plus dexamethasone, which was the only treatment where prior treatment exposure was comparable between the populations.

In response to the findings, Dr. Visram said she will counsel her patients by providing both the randomized trial’s “best-case scenario” numbers and the “real-world” numbers. Her team now hopes to learn which factors are key to the efficacy-effectiveness gap for their Ontario population. However, “what we really need is for future trials to be more pragmatic in their trial design and more inclusive in their trial eligibility to see if this reduces the efficacy-effectiveness gap,” she added. 

DISCLOSURE: Dr. Visram reported financial relationships with Apotex, Janssen, and Sanofi.

REFERENCE

1. Visram A, Chan KKW, Seow H, et al: Comparison of the efficacy in clinical trials versus effectiveness in the real world of treatments for multiple myeloma: A population-based cohort study. 2023 ASH Annual Meeting & Exposition. Abstract 541. Presented December 10, 2023.