Peter Voorhees, MD
Peter Voorhees, MD, a multiple myeloma specialist at Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Durham, North Carolina, introduced the plenary presentation of the phase III IsKia trial by Gay et al and further commented on the study for The ASCO Post.
An important predecessor to the IsKia trial was the randomized phase II GRIFFIN trial, led by Dr. Voorhees, which showed the benefit of daratumumab added to bortezomib, lenalidomide, and dexamethasone (Dara-VRd) over VRd (hazard ratio [HR] = 0.45) in transplant-eligible patients with newly diagnosed multiple myeloma.1 “Not only did we show an improvement in depth of response with the addition of daratumumab, but we showed a 55% reduction in the risk of disease progression or death with the quadruplet,” he noted.
“In the FORTE trial, Dr. Gay and her colleagues famously established the efficacy of carfilzomib, lenalidomide, and dexamethasone followed by transplant maintenance therapy for newly diagnosed patients.2 Building on that experience, the phase II MASTER3 and CONCEPT4 trials evaluated the addition of daratumumab and isatuximab, respectively, to the KRd backbone in this group of patients. Remarkably, the MRD negativity rates were quite high (80% and 67.7%, respectively), and compared favorably to what we saw with the quadruplet in GRIFFIN (63%),” he said.
“The IsKia trial is the first randomized, phase III study establishing the efficacy of a KRd-based quadruplet in transplant-eligible patients with newly diagnosed myeloma, as determined by improvement in the rates of measurable residual disease (MRD) negativity with the addition of the anti-CD38 monoclonal antibody isatuximab. Longer follow-up will be required to see if progression-free survival will be better with the addition of isatuximab,” he commented.
Surrogate Endpoints
Addressing the use of MRD as an endpoint, Dr. Voorhees emphasized the increasing difficulty in discerning overall survival differences among the wealth of new treatments for this disease. A hypothetical phase III study of daratumumab plus RVd vs RVd plus a bispecific monoclonal antibody, for example, would need to enroll more than 1,700 patients, take 4.4 years to accrue, and require 9.5 years to reach its final progression-free survival analysis.
“With front-line quadruplets yielding unprecedented progression-free survival, building on this success using the same surrogate endpoint is becoming increasingly impractical. Clearly, we need a surrogate endpoint for longitudinal outcomes that reads out earlier than progression-free survival if we are going to continue to make progress,” he said.
“As such, there is intense interest in using MRD, but to use MRD as a primary endpoint for registrational studies, we need to better understand the strength of the relationship between MRD and longitudinal outcomes,” he said. “The i2TEAMM initiative is an international collaboration of myeloma investigators collecting patient-level data on MRD and longitudinal outcomes to determine if MRD can become a new surrogate endpoint for registrational trials, thereby facilitating further progress for this group of patients.”
DISCLOSURE: Dr. Voorhees has served as a consultant to AbbVie, BMS, GSK, Janssen, Karyopharm, and Regeneron; has served on advisory boards for AbbVie, BMS, and Sanofi; and has received research funding from AbbVie, GSK, Janssen, and Nervianos Medical Sciences.
REFERENCES
1. Voorhees PM, Kaufman JL, Laubach J, et al: Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood 136:936-945, 2020.
2. Gay F, Musto P, Rota-Scalabrini D, et al: Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): A randomised, open-label, phase 2 trial. Lancet Oncol 22:1705-1720, 2021.
3. Costa LJ, Chhabra S, Medvedova E, et al: Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol 40:2901-2912, 2022.
