Study Finds Huge Gap Between Clinical Trial Data and Real-World Outcomes in Multiple Myeloma

Patients treated in real-world settings for multiple myeloma had death rates 75% higher than those in clinical trials, according to data from a 13-year period presented during the 65th American Society of Hematology (ASH) in San Diego, California.¹

The study’s authors said the findings show the limitations of using clinical trial data in isolation when predicting outcomes for patient groups that are typically absent from trial populations, including those excluded due to their health status.

Alissa Visram, MD | Image credit: Ottawa Hospital Research Institute

“The criteria for clinical trial eligibility are often quite stringent, so the results are not always generalizable,” lead author Alissa Visram, MD, of Ottawa Hospital Research Institute, said in a statement released by ASH. “It’s not a surprise that real-world patients don’t do as well as those in clinical trials, but our study is the first to quantify the difference. It suggests we need to change our frame of reference and better contextualize what outcomes we would expect our patients to have.”²

Although there have been many advances in multiple myeloma in the past 20 years, the disease remains incurable and challenging to diagnose, because its early symptoms often go unrecognized. Data from the American Society of Clinical Oncology estimate that 35,730 adults in the United States will be diagnosed with the blood cancer in 2023, and that 12,590 deaths will occur. The 5-year survival rate for multiple myeloma is 58%.³

For the study presented at ASH, investigator compared rates of death, progression-free survival (PFS) and adverse events (AEs) reported in phase 3 clinical trials for 7 common multiple myeloma regimens with the outcomes experienced by 3951 patients receiving the same regimens in the health system of Ontario, Canada, that nation’s largest province, from 2007 through 2020.

Only regimens with corresponding registrational phase 3 randomized clinical trials that led to regimens receiving public reimbursement in Ontario were included in the study. These treatments included: lenalidomide (Revlimid)/dexamethasone (Rd) and bortezomib (Velcade) plus Rd for newly diagnosed patients who were ineligible for a stem cell transplant; and carfilzomib (Krypolis)-Rd, carfilzomib-dexamethasone, daratumumab (Darzalex)-Rd, daratumumab plus Vd and pomalidomide (Pomalyst)-dexamethasone for patients with relapsed multiple myeloma.

Results. The authors found that multiple myeloma patients treated in a real-world practice had worse progression-free survival compared with clinical trial patients for 6 of the 7 regimens studied, with a pooled HR of 1.44 (95% CI, 1.34.-1.54) in the meta-analysis. Real-world patients also had worse overall survival compared with clinical trial patients in 6 of 7 regimens, with a pooled HR of 1.75 (95% CI, 1.63-1.88) in the meta-analysis. Of note, the patients in the real-world group had higher rates of prior lenalidomide use compared with the trial patients.

Among the regimens, only pomalidomide-dexamethasone performed as well as or slightly better in the real world than in clinical trials. In the statement from ASH, investigators said this may be due to its use in a real-world patient population “with similar or slightly fewer exposures to prior therapies.”

Although the authors noted the study was not designed to determine what caused the differences in outcomes, they discussed some factors likely behind the results. Real-world patients were on average older and had more comorbidities than those in clinical trials, factors previously seen in comparisons between patients in clinical trials and real-world settings. For this reason, Visram said, patients in the real-world settings may not have tolerated treatments well as those in the trial settings. Investigators also noted:

Clinical trials typically take place in medical centers that are more likely to see patients with rare diseases; thus, clinicians are more familiar with administering complex regimens and addressing toxicities.

Historically marginalized groups are often disproportionately excluded from clinical trials and may lack resources to visit clinics or adhere to regimens, which can lead to poorer outcomes.

“As clinicians, we need to acknowledge that outcomes might not be as good in the real world,” Visram said in the statement. “We often use clinical trial results to explain to patients what to expect with treatment, but it’s important to understand that you may be doing more harm if you don’t know whether this [clinical trial result] is actually applicable to your patient.”

Investigators called for more work to better understand the factors that lead to gaps between clinical trial results and those in real-world settings.

References

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. Presented at: 65th American Society of Hematology Annual Meeting and Exposition, San Diego, CA: December 9-12, 2023; Abstr 541. https://doi.org/10.1182/blood-2023-189506
2. Studies uncover drivers of health disparities and opportunities to enhance equity. News release. PRNewswire. December 9, 2023. Accessed December 16, 2023. https://prn.to/48iAXyP
3. Multiple myeloma: statistics. Cancer.net. Updated March 2023. Accessed December 16, 2023. https://www.cancer.net/cancer-types/multiple-myeloma/statistics