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SAN DIEGO -- Multiple myeloma patients in the clinic appear to benefit far less from standard treatments when compared with how the same regimens performed in randomized controlled trials (RCTs), according to a retrospective Canadian study.

In real-world myeloma patients treated with one of seven regimens for newly diagnosed or relapsed disease, progression-free survival (PFS) was 44% worse versus their RCT counterparts while overall survival (OS) was 75% worse, reported Alissa Visram, MD, MPH, of the Ottawa Hospital Research Institute in Ontario.

Crude PFS estimates showed absolute differences reaching as high as 18.3 months for patients treated with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) -- i.e., a median PFS of 8 months for the real-world group versus 26.3 months for the RCT group.

For OS, the differences for six of the seven regimens evaluated in the study favored the trial patients by more than 19 months, according to findings presented at the American Society of Hematology annual meeting.

"This is one of the largest, population-level studies highlighting the significant efficacy-effectiveness gap across multiple standard-of-care regimens for multiple myeloma," Visram said during a press briefing.

While it's known that efficacy (the outcomes in an ideal, clinical-trial setting) generally tends to be superior to effectiveness (outcomes in the real world), it hadn't been clear to what degree these benefits differ with regimens for myeloma specifically, she explained. Along with forming the basis for evidence-based treatment guidelines, clinicians rely on RCT data to counsel patients about the expected survival benefits of a particular regimen.

The seven standard-of-care treatments and corresponding registrational phase III trials included the following two regimens for newly diagnosed disease:

• Rd: lenalidomide plus dexamethasone;
• VRd: bortezomib (Velcade), lenalidomide, and dexamethasone;

And these five regimens for relapsed or refractory disease:

• KRd;
• Kd: carfilzomib plus dexamethasone; ENDEAVOR
• DVd: daratumumab (Darzalex), bortezomib, and dexamethasone;
• DRd: daratumumab, lenalidomide, and dexamethasone;
• Pd: pomalidomide (Pomalyst) plus dexamethasone;

Crude estimates showed that trial participants on Kd lived a median 37.9 months longer compared with the real-world patients, while those treated with VRd in trials lived at least 35.9 months longer, those on KRd in trials lived 26.7 months longer, and so on.

Understanding real-world effectiveness is important for policymakers and regulators, Visram noted, but also for patients and clinicians seeking to make informed treatment decisions.

"In clinical practice, when we're using these regimens, they're not behaving the way that we expect them to," she said. "I think the way that the study will change my clinical practice is that I'll probably present both numbers."

Importantly, real-world patients tended to be older than the trial participants, and there was a longer time between diagnosis and the start of regimens for relapsed disease in the real-world population.

The next steps will be to identify the key contributors to the efficacy-effectiveness gaps to work toward overcoming them, said Visram.

"Is it that our patients are older? Are they more frail? Is that it? Or are we using these regimens differently, are we quicker to dose-adjust our patients having more toxicity? What is driving the difference?" she said. "That's a question that patients will ask too."

Visram also suggested that the gap might narrow if RCTs become more pragmatic in their design and more inclusive in their eligibility criteria.

The current study included 3,951 adults with myeloma treated in Ontario from 2007 to 2020 with seven standard-of-care regimens, including 1,106 patients with newly diagnosed transplant-ineligible disease and 2,845 patients with relapsed disease. Researchers relied on the , which captures all patient records in Ontario's publicly funded healthcare system.

Three-fourths of the newly diagnosed patients were treated with Rd, and the rest received VRd. In the relapsed setting, 28% received DRd, 23% Pd, 22% DVd, 18% Kd, and 10% received KRd.

Using a meta-analysis, the researchers showed that across all regimens and disease settings, the real-world patients had worse PFS (HR 1.44, 95% CI 1.34-1.54) and OS (HR 1.75, 95% CI 1.63-1.88).

Newly diagnosed patients in the real world had a 16% greater risk for disease progression or death compared with their trial counterparts (HR 1.16, 95% CI 1.03-1.30) and a 76% higher risk for death (HR 1.76, 95% CI 1.55-2.01).

In the relapsed and refractory setting, PFS was 63% worse for real-world patients (HR 1.63, 95% CI 1.50-1.77), with the largest between-group differences seen with the two carfilzomib-based regimens. OS was 75% worse for the real-world group (HR 1.75, 95% CI 1.60-1.90), with the greatest difference observed with Kd (HR 3.25, 95% CI 2.75-3.85).

The only exception to the overall trend was with Pd, where there appeared to be a greater PFS benefit in the real-world population (median 5 vs 4 months) and no difference when it came to OS. "We think that this is because this is the only regimen where the prior treatment exposures are comparable between the real-world and trial patients," said Visram.

Safety data, as , suggested similar rates of hospital admissions between the two populations.

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