The combination of carfilzomib (Kyprolis) with lenalidomide (Revlimid) and dexamethasone (KRd) as induction therapy does not improve outcomes in patients newly diagnosed with multiple myeloma compared with the current standard of care with bortezomib (Velcade), lenalidomide, and dexamethasone (VRd).
Data from the phase 3 ENDURANCE clinical trial presented at the ASCO 2020 virtual annual meeting showed comparable progression-free survival (PFS) between the 2 regimens, despite previous data suggesting higher efficacy with KRd.
Although treatment with KRd was associated with a higher rate of very good partial responses, reflecting a better depth of response, the carfilzomib-containing regimen also had increased cardiopulmonary and renal adverse reactions. The follow-up data showed no difference in overall survival (OS) between the 2 groups.
“Based on these data, the combination of bortezomib, lenalidomide, and dexamethasone should remain the standard of care for initial therapy of newly diagnosed symptomatic multiple myeloma,” said Shaji K. Kumar, MD, Consultant, Division of Hematology, Mayo Clinic, Rochester, MN.
“VRd should also be considered the backbone for adding new drugs, such as monoclonal antibodies, in the development of normal regimens for myeloma induction therapy,” Dr Kumar added.
The initial therapy of multiple myeloma has changed dramatically over the past decade with the introduction of several new drugs and drug combinations. Currently, the combination of the proteasome inhibitor bortezomib, the immunomodulatory drug lenalidomide, and dexamethasone is considered the standard of care in the front-line treatment of newly diagnosed symptomatic disease.
In a phase 3 clinical trial, the next-generation proteasome inhibitor carfilzomib was more effective than bortezomib in patients with relapsed multiple myeloma. Dr Kumar and colleagues designed the ENDURANCE study to examine whether replacing bortezomib with carfilzomib in the triplet combination would improve the efficacy of initial therapy for patients with newly diagnosed disease who were not candidates for an immediate upfront stem-cell transplant.
Comparable Survival, Increased Toxicity
As Dr Kumar reported, the median PFS was 34.4 months with VRd compared with 34.6 months with KRd. A subgroup analysis of PFS also showed comparable performance in the majority of the subgroups, with a trend toward improved PFS with the KRd regimen in patients with abnormal cytogenetics. In patients aged ≥70 years, however, the median PFS was 37 months with VRd and 28 months with KRd.
“Almost 85% of patients achieved a partial response or better across the study, and the overall response rate was comparable between the VRd and the KRd groups,” said Dr Kumar. “However, when you look at the deeper responses, a significantly higher proportion of patients in the KRd arm achieved a very good partial response or better compared to patients in the VRd arm.”
At a median follow-up of 29 months, the OS was identical between the VRd and KRd arms, at approximately 85%.
However, the data also revealed differences in treatment-related adverse events. Grade ≥3 nonhematologic toxicity was significantly higher in the KRd arm than in the VRd arm.
Specifically, dyspnea, hypertension, heart failure, and acute kidney injury were more common in the KRd group, whereas neurologic toxicity and peripheral neuropathy were significantly higher in patients receiving VRd.
Grade ≥3 cardiac, pulmonary, and renal adverse events were also significantly higher in the KRd arm than in the VRd arm, Dr Kumar reported.
Jesús G. Berdeja, MD, Director, Multiple Myeloma Research, Sarah Cannon Research Institute, Nashville, TN, who discussed the results said that based on these data, VRd and KRd are equivalent options for the front-line treatment of patients with newly diagnosed multiple myeloma and no high-risk features.
“Comorbidities and toxicity profiles should guide the choice between the 2 regimens in any individual patient,” said Dr Berdeja. “For example, patients with renal insufficiency should favor the bortezomib arm, while patients with baseline peripheral neuropathy should consider treatment with the carfilzomib triplet.”
“It’s also worth noting that VRd is less costly than KRd, and it remains an excellent backbone for continued evaluation of additional agents,” he concluded.