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The combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, or VRd, successfully fended off a direct challenge to its position as standard of care in newly diagnosed multiple myeloma.

In the phase III ENDURANCE trial, which included over 1,000 standard and intermediate patients, those assigned to VRd had a median progression-free survival (PFS) of 34.4 months, as compared to 34.6 months with carfilzomib (Kyprolis), lenalidomide, and dexamethasone, or KRd (HR 1.04, 95% CI 0.83-1.31), reported Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota.

"Based on this data, the combination of bortezomib, lenalidomide, and dexamethasone should remain the standard of care for initial therapy of newly diagnosed symptomatic multiple myeloma," Kumar said during his presentation at the American Society of Clinical Oncology (ASCO) virtual meeting.

With a follow-up of 29 months, median overall survival (OS) was not reached in either arm, said Kumar, and the probability of survival at 3 years was 84% with VRd and 86% with KRd.

Findings from the trial were presented at the ASCO Plenary Session, featuring the top selected abstracts.

Carfilzomib is a next-generation proteasome inhibitor that outperformed bortezomib head-to-head in relapsed disease, and has been associated with deeper responses in newly diagnosed patients in phase II trials, said Kumar. In ENDURANCE, patients on KRd were more likely to achieve a very good partial response or better compared to those on VRd (74% vs 65%, P=0.002), with numerically higher rates of stringent complete response, complete response, and very good partial response.

While PFS was no different overall, it favored the VRd arm among the 31% of patients who were ages 70 and older (37 vs 28 months), and in those with normal cytogenetics.

In the KRd arm, those with abnormal cytogenetics and International Staging System (ISS) stage III disease showed a trend toward improved PFS, and more patients were able to complete their assigned induction therapy (61.6% vs 43.3% with VRd).

Of note, toxicity profiles between the two regimens were quite different. Rates of grade ≥3 non-hematologic toxicities were higher in the KRd group (48.3% vs 41.4% with VRd, P=0.024), as were rates of grade ≥4 non-hematologic toxicities (8.2% vs 4.0%, respectively, P=0.004).

And grade ≥3 peripheral neuropathy occurred more frequently with bortezomib (53.4% vs 24.4%, P<0.001), while cardiac, renal, and pulmonary adverse events of any grade were common with carfilzomib (16.1% vs 4.8%, P<0.001).

ASCO discussant Jesus Berdeja, MD, of the Sarah Cannon Research Institute in Nashville, said that while both regimens appear to be equivalent options for the frontline treatment of non-high-risk patients, the costs are higher with KRd, averaging roughly $315,000 per treatment course compared with about $215,000 with VRd.

"Comorbidities and toxicity profiles should guide the choice between the two regimens in any individual patients," he said, noting that bortezomib might be a more prudent choice for a patient with renal insufficiency, while carfilzomib might be better suited for a patient with neuropathy at baseline.

ENDURANCE (E1A11) was a phase III trial that randomized 1,087 patients 1:1 to VRd or KRd as initial treatment for newly diagnosed symptomatic multiple myeloma. Patients had a median age of 65, and were stratified by intent for transplant at disease progression. Patients with most high-risk features -- t(14;20), t(14;16), del(17p), etc. -- were excluded, though those with t(4;14) were allowed on trial.

Incidence of secondary primary cancers was similar with the two regimens, and quality of life appeared to be no different.

PFS was the primary endpoint of the first part of the trial. A second part of ENDURANCE, to be presented at a later date, will attempt to answer whether 2 years of lenalidomide maintenance or indefinite treatment until progression is superior, with OS as the second co-primary endpoint.

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