For newly treated patients with standard- and intermediate-risk multiple myeloma who are not slated for immediate autologous stem cell transplantation (ASCT), the triplet regimen of carfilzomib/lenalidomide/dexamethasone (KRd) failed to improve progression-free survival vs the current standard-of-care regimen of bortezomib/lenalidomide/dexamethasone (VRd). These results of the phase III ENDURANCE trial were presented at the Plenary Session of the ASCO20 Virtual Scientific Program.¹

These results were somewhat surprising, as phase II studies suggested carfilzomib might outperform bortezomib. Once again, this is a reminder that phase II data do not always pan out in phase III trials.

Shaji K. Kumar, MD

“There was no improvement in progression-free survival by replacing bortezomib with carfilzomib in the current standard initial treatment of newly diagnosed patients with standard- or intermediate-risk myeloma, even though we observed a very good partial response rate with the carfilzomib combination,” stated lead author Shaji K. Kumar, MD, of Mayo Clinic, Rochester, Minnesota. “Thus far, there is no difference in overall survival between the two regimens. Based on these data, VRd should remain the standard of care for initial therapy of newly diagnosed symptomatic multiple myeloma, where an early transplant is not planned, and should be considered the backbone for novel regimens as well as the control arm for clinical trials.”

Dr. Kumar commented on toxicity: “The side-effect profiles of the two regimens were different, with a higher rate of peripheral neuropathy seen with VRd and higher rates of cardiac, pulmonary, and renal toxicities seen with KRd.

VRd has been the standard of care for newly diagnosed patients for several years. In a phase III trial, carfilzomib—a proteasome inhibitor like bortezomib—was superior to bortezomib in the relapsed setting, and a phase II trial suggested this might be the case in newly diagnosed patients, Dr. Kumar noted.

ENDURANCE Details

The ENDURANCE trial consisted of two parts. Part 1 evaluated induction therapy with VRd vs KRd in newly diagnosed patients with multiple myeloma. Part 2 randomly assigned patients from both arms again to two different duration of maintenance lenalidomide (every 4 weeks for 2 years or every 4 weeks until disease progression). During his presentation at ASCO20, Dr. Kumar reported results of part 1.

To be eligible for enrollment in ENDURANCE, patients had to have newly diagnosed symptomatic multiple myeloma with no intent for immediate upfront ASCT. Patients with high-risk features were excluded, with the exception of t(4;14), which some consider to be a high-risk feature. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1; they also had to have adequate hematologic parameters and no organ failure. Peripheral neuropathy, heart failure, and myocardial infarction were exclusion criteria.

At baseline, both arms were well balanced for disease characteristics. Nearly one-third of patients were 70 years of age or older, and almost 12% were black. Nearly 10% had t(4;14). “The percentage of black patients [who are at higher risk] was much higher than in typical phase III trials,” Dr. Kumar noted.

Patients were randomly assigned 1:1, and 1,053 of them started treatment. Induction therapy with VRd was given every 3 weeks, for a total of 12 cycles, and KRd was given every 4 weeks, for a total of 9 cycles. Induction therapy was completed by 43% of those assigned to VRd vs 61.6% of the KRd group.

Progression-free survival was analyzed at the second interim analysis, when 79% of planned events had occurred from the time of induction randomization. At that time, the results were released for futility.

Key Findings

Progression-free survival was almost identical in the two arms. Median progression-free survival was 34.4 months with VRd vs 34.6 months with KRd, at a median estimated follow-up of 15 months. For patients aged 70 or older, median progression-free survival was 31.7 months and 28 months with KRd. When censored for ASCT or alternative therapy, median progression-free survival was almost identical: 31.7 months and 32.8 months, respectively.

A subgroup analysis showed both regimens performed equally well in the majority of subgroups. However, there was a trend toward improved progression-free survival with KRd in patients with abnormal cytogenetics, whereas older patients seemed to do better with VRd.

Almost 85% of both treatment arms had an objective response. However, deeper responses were observed in KRd-treated patients. The rate of very good partial responses was higher with KRd (74% vs 65%, respectively, P = .002).

At the time of the presentation during ASCO20, 13.6% of patients in both arms had died, and overall survival seemed to be almost identical. Median overall survival has not yet been reached.

A similar percentage of patients in both treatment arms proceeded to ASCT: 28% in the VRd arm and 26.8% in the KRd arm. The median time to transplantation was 6.5 months and 8.5 months, respectively.

Adverse Events

The rate of grade 3 or higher treatment-related nonhematologic adverse events was 41% with VRd and 48% with KRd. The rates of peripheral neuropathy, fatigue, and diarrhea were higher in the VRd arm, whereas dyspnea, hypertension, heart failure, and acute kidney injury were more frequent in the KRd arm.

Significantly higher rates of cardiac, pulmonary, and renal toxicities were observed with KRd (P < .001), and a significantly higher rate of peripheral neuropathy was found with VRd (P < .001). The incidence of secondary primary cancers was about 3% in both arms. 

DISCLOSURE: The study was funded by the National Cancer Institute and conducted by the ECOG-ACRIN Cancer Research Group. Dr. Kumar has served as a consultant or advisor to Cellectar Biosciences, GeneCentrix, and Oncopeptides; has served as an institutional consultant or advisor to AbbVie, Amgen, Bluebird Bio, Celgene, Genentech/Roche, Janssen Oncology, Kite Pharma, Merck, Molecular Partners, and Takeda; and has received institutional research funding from AbbVie, CARsgen Therapeutics, Celgene, Janssen Oncology, Kite Pharma, MedImmune, Merck, Novartis, Roche/Genentech, Sanofi, Takeda, and TeneoBio.

REFERENCE

1. Kumar SK, Jacobus SJ, Cohen AD, et al: Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma: Results of ENDURANCE (E1A11) phase III trial. ASCO20 Virtual Scientific Program. Abstract LBA3. Presented May 31, 2020.