The importance of first-line therapy in multiple myeloma is that the first therapy typically achieves the most impact, and subsequent lines of therapy tend to be less effective, explained ENDURANCE study discussant Jesús G. Berdeja, MD, Director of Myeloma Research at the Sarah Cannon Research Institute, Nashville. In fact, he said, many patients do not go on to second- or third-line therapy.

Jesús G. Berdeja, MD

Carfilzomib is considered the standard treatment of relapsed multiple myeloma. Phase II studies suggested it might be preferable to bortezomib in combination therapy.

“The community was moving toward KRd [carfilzomib, lenalidomide, dexamethasone] as front-line therapy, feeling carfilzomib was better than bortezomib,” said Dr. Berdeja. “However, there has never been a trial comparing VRd [bortezomib, lenalidomide, dexamethasone] with KRd as front-line therapy until now. This is the first randomized trial of VRd vs KRd and includes patients with previously untreated multiple myeloma and no intent for upfront [autologous stem cell transplant].”

Dr. Berdeja continued: “We now have learned KRd is not superior to VRd as front-line treatment of patients with standard- and intermediate-risk multiple myeloma with deferred ASCT. We don’t know about high-risk patients, and definitions of high risk continue to evolve. I would encourage enrollment of high-risk patients in clinical trials of quadruplet regimens, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy.”

Beyond Efficacy: Toxicity and Cost

Dr. Berdeja cited important differences between the two regimens in terms of toxicity and cost, noting these considerations should drive treatment choice. “Cardiac, pulmonary, and renal adverse events were more common in the KRd arm, and peripheral neuropathy was more common in the VRd arm. Discontinuation of treatment due to toxicity is more common with VRd, and peripheral neuropathy is a significant side effect impacting patients’ quality of life and dose reductions,” he noted.

In terms of cost, VRd is the winner, Dr. Berdeja commented. The estimated cost of a planned regimen of VRd is $216,908 compared with $315,180 for KRd—a difference of $98,272 favoring VRd. The cost per cycle is $15,893 less with VRd.

“The implications for standard of care is that VRd and KRd are equivalent options in newly diagnosed multiple myeloma without high-risk features,” concluded Dr. Berdeja. “However, comorbidities and toxicity will guide the choice of therapy. VRd remains an excellent backbone for continued evaluation of additional agents.” 

DISCLOSURE: Dr. Berdeja has served as a consultant or advisor to Amgen, Bioclinica, Bristol-Myers Squibb, Celgene, Cancer Therapeutics, ­Janssen, Karyopharm Therapeutics, Kite Pharma, Legend Biotech, ­Porthema, Securabio, and Takeda and has received institutional research funding from AbbVie, Acetylon, Amgen, Bluebird Bio, Bristol-Myers Squibb, Celgene, Cellularity, Constellation, CRISPR Therapeutics, Curis, Genentech/Roche, Glenmark, Janssen, Kesios, Lilly, Novartis, Poseida Therapeutics, Sanofi, Takeda, Teva, and Vivolux.