Bortezomib, thalidomide, and dexamethasone (VTd) is an acceptable, effective standard-of-care induction treatment in Europe for patients with newly diagnosed myeloma who are eligible for autologous stem cell transplantation. CASSIOPEIA is a two-part, open-label, randomized, phase III trial in transplant-eligible patients with newly diagnosed myeloma.
CASSIOPEIA: The Sum of Its Parts
In part 1 of CASSIOPEIA,1 1,085 patients were randomly assigned 1:1 to induction (four cycles) and consolidation (two cycles) with daratumumab and VTd (D-VTd; 543 patients) or VTd (542 patients), and transplantation was sandwiched in between. The primary endpoint of part 1 was stringent complete response, assessed 100 days after transplantation, which favored the D-VTd group (29%) over the VTd group (20%; odds ratio [OR] = 1.60, P = .0010). At a median follow-up of 44.5 months from first randomization, the median progression-free survival was not reached in the D-VTd arm and 51.5 months in the VTd arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.47–0.72, P < .0001). Based on these results, the European commission approved D-VTd in January 2020 for treatment of newly diagnosed patients who are eligible for transplantation.
It is unclear whether there is a relative benefit to a fixed duration of daratumumab maintenance given every 8 weeks compared with the current standard of care—lenalidomide maintenance until disease progression.— Ajay K. Nooka, MD, MPH, FACP
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Part 2 of CASSIOPEIA—summarized in this issue of The ASCO Post2—evaluated the role of daratumumab as a maintenance agent. Patients who had a partial response or better in part 1 were randomly assigned 1:1 to receive daratumumab at 16 mg/kg intravenously every 8 weeks or observation for 2 years. Stratification factors were induction treatment and depth of response in part 1. The primary endpoint for part 2 was progression-free survival from second randomization. Overall, 458 patients (84% of the original cohort) in the D-VTd group and 428 patients (79%) in the VTd group underwent second randomization. At a median follow-up of 35.4 months from second randomization, median progression-free survival was not reached in the daratumumab maintenance arm vs 46.7 months in the observation group (HR = 0.53, 95% CI = 0.42–0.68, P < .0001), showing superiority of the addition of daratumumab as maintenance therapy.
When the study was designed, there was not as much information available as there is now regarding the role of maintenance therapy in myeloma, the duration that maintenance should be offered, and the optimal dosing frequency schedule during the maintenance phase. That may explain the reduced frequency of therapy in the CASSIOPEIA trial compared with the currently used daratumumab frequency with long-term dosing. Per the trial design, during induction and consolidation, patients received a total of 16 doses of daratumumab, which is similar to the dose frequency for patients receiving daratumumab in the maintenance phase.
Key Findings From Prespecified Subgroups
In evaluating progression-free survival in prespecified subgroups, two important findings are evident. First, patients who received D-VTd as induction and consolidation did not seem to benefit much with daratumumab as maintenance compared with observation (HR = 1.05, 95% CI = 0.73–1.51). Patients who received VTd as induction and consolidation seemed to derive the most benefit with daratumumab as maintenance (HR = 0.34, 95% CI = 0.24–0.47). In this subgroup, daratumumab may have “made up” the benefit when given later as maintenance, which suggests that patients who have not received daratumumab in induction or consolidation may be salvaged with daratumumab as maintenance.
In essence, the progression-free survival for patient groups that received daratumumab in induction and consolidation or in maintenance is similar. The patients who had dismal outcomes are the ones who did not receive daratumumab in induction and consolidation or as maintenance. These findings also highlight the beneficial effects of maintenance even among patients who receive effective induction treatments such as a combination of an immunomodulatory agent and a proteasome inhibitor (VTd).
Second, the high-risk group that did not benefit from the addition of daratumumab in part 1 seemed to attain benefits with daratumumab maintenance (HR = 0.43, 95% CI = 0.25–0.73). The patient selection in which patients achieved a partial response or better and underwent the second randomization makes it more likely that high-risk patients have been selected out prior to the second randomization. However, those high-risk patients who benefited from the addition of daratumumab seemed to gain a longer-term benefit.
The results of CASSIOPEIA part 2 show that daratumumab maintenance improved outcomes, similar to what we had seen with earlier studies using lenalidomide3,4 and ixazomib,5 as post-transplantation maintenance strategies in myeloma compared with observation. It is unclear whether there is a relative benefit to a fixed duration of daratumumab maintenance given every 8 weeks compared with the current standard of care—lenalidomide maintenance until disease progression. The ongoing GRIFFIN, PERSEUS, and AURIGA studies will shed further light to determine the optimal post-transplantation maintenance strategies using daratumumab with or without lenalidomide.
Dr. Nooka works in the Department of Hematology and Medical Oncology and is Medical Director, Winship Data and Technology Applications Shared Resource, Winship Cancer Institute, Emory University School of Medicine.
DISCLOSURE: Dr. Nooka has served on advisory boards for Janssen, GlaxoSmithKline, Takeda, Oncopeptides, Sanofi Genzyme, Karyopharm, Bristol Myers Squibb, Adaptive Biotechnology, Beyond Springs, and Amgen; has received research funding from Amgen, Janssen, and Takeda; and has received travel and accommodation expenses from GlaxoSmithKline.
1. Moreau P, Attal M, Hulin C, et al: Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet 394:29-38, 2019.
2. Moreau P, Hulin C, Perrot A, et al: Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): An open-label, randomised, phase 3 trial. Lancet Oncol 22:1378-1390, 2021.
3. McCarthy PL, Holstein SA, Petrucci MT, et al: Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol 35:3279-3289, 2017.
4. Jackson GH, Davies FE, Pawlyn C, et al: Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 20:57-73, 2019.
5. Dimopoulos MA, Gay F, Schjesvold F, et al: Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): A double-blind, randomised, placebo-controlled phase 3 trial. Lancet 393:253-264, 2019.
As reported in The Lancet Oncology by Philippe Moreau, MD, of the University Hospital Hôtel-Dieu, Nantes, and colleagues, an interim analysis of part 2 of the phase III CASSIOPEIA trial has showed significantly prolonged progression-free survival with maintenance daratumumab vs observation...