The combination of daratumumab plus lenalidomide (D-R) resulted in more patients with newly diagnosed multiple myeloma (NDMM) converting from measurable residual disease (MRD)-positive to MRD-negative status following transplantation, compared with those treated with lenalidomide (R) alone. These results, from the phase III AURIGA study, were published recently in Blood.
“This clinical trial established for the first time a direct comparison between D-R compared with R alone as maintenance after stem cell transplantation in patients with MM. D-R maintenance statistically improved the primary endpoint, MRD-negative conversion rate, at a threshold of 10-5 cells at 12 months, to 50% versus 18% for R alone. This benefit improved over the 36-month study duration. This MRD-negative conversion rate was noted in all clinically relevant subgroups, including patients with high-risk myeloma,” said study author Ashraf Z. Badros, MBChB, director of MM service at the University of Maryland Greenebaum Comprehensive Cancer Center and professor of medicine at the University of Maryland School of Medicine in Baltimore.
Progression-free survival (PFS) favored the combination maintenance therapy, with a 47% reduction in the risk of death or progression (hazard ratio = 0.53). The estimated 30-month PFS rates were 82.7% for the combination and 66.4% for R.
The investigators of the AURIGA study hypothesized that adding daratumumab to lenalidomide maintenance therapy could increase deeper responses in patients with NDMM who had a very good partial response (VGPR) but remained MRD positive following a transplant.
Patients were randomized 1:1 to either D-R maintenance therapy or R alone and stratified by cytogenetic risk per investigator assessment. High risk was defined as the presence of one or more cytogenetic abnormalities, del(17p), t(4;14), or t(14;16). The 200 patients were all newly diagnosed and anti-CD38-naïve; they had received at least four cycles of standard induction that did not include daratumumab and had achieved a VGPR or better and were MRD positive. All patients were randomized to the study within 12 months of diagnosis and within six months of transplant.
All patients received 10 mg of R daily over a 28-day cycle. After three cycles, the dose could be increased to 15 mg if tolerated and at the discretion of the investigator and based on MRD status. Patients in the D-R arm also received subcutaneous 1,800 mg D co-formulated with recombinant human hyaluronidase PH20 weekly during cycles 1 and 2, every two weeks during cycles 3 through 6, and every four weeks from cycle 7 on. Treatment was planned for a maximum duration of 36 cycles or until disease progression.
The MRD-negative conversion rate, at a threshold of 10-6 cells, was also higher for the D-R therapy at 23.2% compared with 5.0% for R alone (p=0.0002).
At the 32.3-months median follow-up, D-R also achieved a higher overall MRD-negative conversion rate, at a threshold of 10-5 cells, of 60.6% compared with 27.7% with R alone (p<0.0001), as well as a higher complete response (CR) rate of 75.8% compared with 61.4% for R alone (p=0.0255).
Patients receiving D-R had higher incidences of grade 3 or 4 cytopenias compared with the R-alone group (54.2% vs. 46.9) and a higher rate of infections (18.8% vs. 13.3%).
“This is not a registration trial, so we do not have conclusive data to establish a standard of care. However, the results of this trial as well as other trials support the addition of D not only for induction and consolidation but also to the standard-of-care R maintenance,” Dr. Badros said.
This combination of D-R maintenance therapy is also being investigated in the SWOG DRAMMATIC trial that is enrolling more than 1,500 patients with MM and using MRD to guide the maintenance therapy duration. Another trial, based in Germany, is also investigating this question.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Badros A, Foster L, Anderson LD, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study [published online ahead of print, 2024 Sept. 27]. Blood. doi: 10.1182/blood.2024025746.
Perspectives
Recent advancements in myeloma therapeutics have significantly improved survival outcomes.1 Post-transplant maintenance therapy has been shown to enhance PFS,2 and ongoing studies are exploring further improvements for transplant-eligible patients with NDMM. In the AURIGA study, patients who were MRD positive post-transplant were randomized to receive maintenance therapy using daratumumab plus lenalidomide (D-R) or standard-of-care (SOC) lenalidomide (R) alone. The primary outcome, conversion to MRD (10-5)-negative status at 12 months, was achieved in roughly half of the D-R group compared with 18.8% (p<0.0001) in the R-only group. At a median follow-up of 32.2 months, the MRD-negative responses deepened further, with 60.6% of the D-R group MRD negative compared with 27.7% (p=<0.0001) in the R-only group. There was a PFS benefit at 30 months (82.7% vs. 66.4%) in favor of the D-R group, and this benefit was seen across patients with standard and high-risk MM. No new safety concern was identified in the D-R group. The findings are encouraging and underscore the potential of MRD status-based patient selection for maintenance therapy.
MRD testing is not routinely performed for all patients in clinical practice; all post-transplant patients are offered SOC maintenance or the option to participate in clinical trials if available. The AURIGA study findings are reassuring, as responses based on International Myeloma Working Group 2016 criteria favored the D-R group (≥CR 75.8% vs. 61.4%) with a higher number of VGPR patients achieving CR and stringent CR in the D-R cohort. Patients who remained MRD positive at 12 months showed inferior PFS compared with those who became MRD negative. Despite the use of protocol-based intervention, surprisingly, nearly half of the patients in the D-R group and 80% in the R group failed to achieve MRD-negative status at 12 months. This resistant cohort needs to be further investigated to better understand the underlying factors and optimize treatment strategies. In the PERSEUS trial, the MRD-negative rate for D-bortezomib, lenalidomide, and dexamethasone (VRd) followed by D-R was 65% at 12 months.
Anti-CD38 antibody with VRd is considered a contemporary standard induction regimen for transplant-eligible NDMM. As CD38-targeting antibodies are increasingly incorporated into induction regimens, the number of CD38-naïve patients is rapidly decreasing, particularly in North America. The SWOG 1803 is a phase III randomized study investigating D-R versus R alone.3 Importantly, this study does not exclude CD38-exposed patients. Additionally, maintenance therapy using newer agents like iberdomide and elranatamab compared with R alone are being investigated in randomized prospective studies.
The AURIGA study included CD38-naïve patients, while several recent prospective trials (e.g., GRIFFIN, PERSEUS, and CASSIOPEIA) tested four drug combinations based on CD38-targeting antibodies in transplant-eligible patients, and trials like IMROZ, CEPHEUS, and BENEFIT tested four drug combinations in transplant-ineligible patients, all showing improved outcomes for NDMM. Despite the positive PFS signal with daratumumab monotherapy maintenance compared to observation in part II of the CASSIOPEIA trial,4 an important question remains: What is the additional benefit of anti-CD38 antibody plus lenalidomide compared with lenalidomide alone as post-transplant maintenance therapy in transplant-eligible patients with NDMM who receive CD38-targeted antibody with VRd during pretransplant remission induction therapy?
COI disclosure: Dr. Anwer served as advisor and speaker for Bristol Myers Squibb, Celgene, and Caribou Biosciences. Received research funding from Allogene Therapeutic, Celgene, GlaxoSmithKline, Bristol Myers Squibb, and Caribou Biosciences.
Faiz Anwer, MD
Associate Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Director, Inpatient Lymphoma Myeloma Service
Taussig Cancer Center
References
- Lytvynova O, Jwayyed J, Pastel D, et al. Insights from clinical trials: evidence-based recommendations for induction treatment of newly diagnosed transplant-eligible multiple myeloma. Antibodies (Basel). 2024;13(4):80.
- Wahab A, Rafae A, Faisal MS, et al. Advances in maintenance strategy in newly diagnosed multiple myeloma patients eligible for autologous transplantation. Expert Rev Hematol. 2020;13(12):1333-1347.
- Krishnan A, Hoering A, Hari P, et al. Phase III study of daratumumab/rhuph20 (nsc-810307)+ lenalidomide or lenalidomide as post-autologous stem cell transplant maintenance therapy in patients with multiple myeloma (mm) using minimal residual disease to direct therapy duration (DRAMMATIC study): SWOG s1803. Blood. 2020;136:21-22.
- Moreau P, Hulin C, Perrot A, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024;25(8):1003-1014.
