The addition of subcutaneous daratumumab to bortezomib, lenalidomide, and dexamethasone (VRd) induction and consolidation therapy and to lenalidomide maintenance therapy confers a significant benefit to transplant-eligible patients with newly diagnosed (ND) multiple myeloma (MM). Pieter Sonneveld, MD, PhD, professor of hematology at the Erasmus MC Cancer Institute in the Netherlands, reported the improvement in progression-free survival (PFS) in The New England Journal of Medicine. The paper includes the first interim analysis (47.5 months of follow-up) of the PERSEUS trial.
The phase III trial randomized 709 transplant-eligible patients with ND MM to receive subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). Unlike previous studies of treatments for transplant-eligible patients with ND MM, the PERSEUS trial did not have a second randomization to maintenance therapy, so patients in the D-VRd group received daratumumab throughout the maintenance phase. The authors noted in their discussion that this aspect of the trial design may have confounded the ability to determine the independent contribution of each treatment component to the efficacy of each phase of treatment. Dr. Sonneveld also noted that because the trial was conducted in European countries and Australia, fewer than 2% of the participants were Black.
The treatment arm achieved the primary endpoint of PFS at four years with 84.3% of patients in the D-VRd group and 67.7% in the VRd group experiencing PFS (p<0.001). This 58% reduction in the risk of progression and death occurred across prespecified subgroup analyses, suggesting a consistent benefit even in patients with International Staging System stage III disease and those with high cytogenetic risk. The percentage of patients with a complete response (CR) or better was also higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, p<0.001).
The investigators found that 75.2% of patients in the D-VRd group had a measurable residual disease (MRD)-negative status assessed at a sensitivity threshold of 10-5, whereas only 47.5% of patients in the VRd group achieved that status (p<0.001). The percentage of patients with MRD-negative status assessed at a sensitivity threshold of 10-6 was 65.1% in the D-VRd group and 32.2% in the VRd group. The researchers also found that the safety profile of daratumumab combined with VRd was consistent with the known safety profiles for daratumumab and VRd in this patient population.
Dr. Sonneveld explained that although the results were consistent with previous studies, “the magnitude of the difference surprised us.” He also pointed out that while the phase II GRIFFIN trial administered daratumumab intravenously, patients in the phase III trial received daratumumab subcutaneously — a route that was “much easier on the patient.” Moreover, while patients in the phase II trial received VRd in three-week cycles, the phase III trial used four-week intervals. The phase III protocol was thus much easier on the patients than the phase II protocol.
During the maintenance phase, the investigators gave patients who had received at least 24 months of maintenance therapy and attained a CR or better and sustained MRD-negative status for at least 12 months the option of discontinuing daratumumab. According to Dr. Sonneveld, 64% of patients were able to stop treatment with daratumumab, and these patients continued with just lenalidomide, resuming daratumumab only if they became positive again. “We are following these patients very closely because the results have thus far been so good,” he said.
While approved for two indications, daratumumab has not yet been approved by the U.S. Food and Drug Administration and the European Medicines Agency for use in this combination for patients with MM. Dr. Sonneveld hopes approval for the new indication will be granted in 2024. “This treatment is going to be standard of care for patients with MM,” he predicted.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma [published online ahead of print, 2023 Dec 12]. N Engl J Med. doi: 10.1056/NEJMoa2312054.
Perspectives
The outcomes of patients with transplant-eligible ND MM has significantly improved over the past decade with use of immunomodulatory agents (IMiDs), proteasome inhibitors (PI), and corticosteroids in combination with autologous hematopoietic cell transplantation (AHCT) and prolonged maintenance until disease progression.1,2 The introduction of monoclonal antibodies (mAbs) resulted in improvement in overall survival (OS) and unprecedented PFS benefit in the relapsed setting.3,4
Based on these encouraging data, several trials evaluated addition of anti-CD38 mAbs to the triplets for transplant-eligible patients with ND MM. The phase III CASSIOPEIA trial confirmed improved depth of response and PFS with addition of daratumumab (an anti-CD38 mAb) to the backbone of thalidomide, bortezomib, and dexamethasone with AHCT compared to the triplet.5 In the U.S., the phase II randomized GRIFFIN study evaluated D-VRd compared to VRd with a primary endpoint of stringent CR rate by the end of consolidation after AHCT. The study met its primary endpoint and showed encouraging PFS benefit compared to the triplet, although the study was not powered for this endpoint.6
The phase III PERSEUS trial was powered to detect a difference in risk of disease progression or death with the quadruplet and used subcutaneous daratumumab, which has previously shown equivalent efficacy as intravenous daratumumab in combination with enhanced ease of administration. As expected, the results showed an improved PFS at 48 months of 84% in the D-VRd group and 68% in the VRd group (hazard ratio = 0.42; p<0.001) without significant additional toxicities.7
These results have generated additional high-level evidence to support the use of anti-CD38 mAbs for induction in patients with transplant-eligible ND MM, which has been practice changing for some and practice affirming for others already using quadruplets in induction based on prior studies. In MM, initial therapy is of paramount importance, and using our most efficacious agents early in the disease course in the best combinations has helped patients live longer in remission and take advantage of progress made downstream at the time of relapse. Saving potent agents for later at the time of relapsed disease often means that some patients may never receive these agents because of known attrition with each line of therapy.8
Additionally, outcomes of patients with ND MM are heterogeneous, and several markers of prognosis and risk have emerged to identify patients at greatest risk of poor outcomes, including those with two or more high-risk features as well as those patients with MRD. MRD is emerging as one of the most important dynamic markers of prognosis in myeloma and is being evaluated as a surrogate endpoint for drug development. The addition of anti-CD38 mAbs significantly improves MRD negativity at single time points as well as incidence of sustained MRD negativity, translating into improved patient outcomes with differences between the curves visible as early as six months into therapy, which continue to widen over time.
However, despite a reduction in the number of patients with early progression events with quadruplets, those with two or more high-risk cytogenetic abnormalities and persistent residual disease remain a challenge. Additional strategies, including immunotherapeutic approaches, may modify the natural history of these challenging subsets. For others, the incorporation of risk-adapted therapy offers a glimmer of hope toward functional cure.
Susan Bal, MD
Assistant Professor
Division of Hematology Oncology
University of Alabama at Birmingham
Birmingham, Alabama
References
- Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147.
- Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320.
- Sonneveld P, Chanan-Khan A, Weisel K, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41(8):1600-1609.
- Dimopoulos MA, Oriol A, Nahi H, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41(8):1590-1599.
- 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. The Lancet. 2019;394(10192):29-38.
- Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945.
- Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma [published online ahead of print, 12 Dec 2023]. N Engl J. Med. doi: 10.1056/NEJMoa2312054.
- Fonseca R, Usmani SZ, Mehra M, et al. Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma. BMC Cancer. 2020;20(1):1087.
