Daratumumab appears to be safe when used as consolidation therapy in patients with multiple myeloma, even soon after autologous stem cell transplant, and the agent has also demonstrated early efficacy in the setting of very good responders.
Daratumumab (Darzalex) appears to be safe when used as consolidation therapy in patients with multiple myeloma, even soon after autologous stem cell transplant (ASCT), and the agent has also demonstrated early efficacy in the setting of very good responders, according to findings from an interim analysis of the phase 2 DART4MM trial (NCT03992170).1
Results presented during the 2nd European Myeloma Network Meeting showed that 86% (n = 32) of 37 patients completed 6 months of therapy and reached the primary end point of the trial. Of 26 patients, 46% (n = 12) experienced minimal residual disease (MRD) negativity at 6 months. Notably, 52% (n = 12) of 23 patients who previously underwent ASCT had MRD negativity following 6 months of daratumumab and discontinued treatment.
“The data are very interesting. At 6 months, almost 50% of the patients are negative for MRD,” lead study author Alessandro Gozzetti, MD, PhD, who is also an associate professor of hematology at the University of Siena, said during a poster presentation on the data. “At 18 months, 4 patients were still MRD negative.”
Complete response (CR) is a prerequisite for durable responses, extended progression-free survival (PFS) and overall survival, as well as cure. With the emergence of novel agents in the multiple myeloma treatment paradigm, many patients are able to experience a stringent CR; however, these patients still relapse. As such, MRD negativity will serve as a primary end point for several future trials, according to the authors of the poster.
Notably, consolidation treatment with bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VMP) following ASCT has been shown to lead to increased CRs in patients who had previously experienced a very good partial response (VGPR), jumping from 15% to 49%. Moreover, this approach has been shown to lead to a doubling in PFS for patients with MRD negativity. In recent years, the ability to detect MRD has improved with the development of new next-generation sequencing tests.
Because daratumumab, as a single agent and in novel combinations, has been shown to result in impressive CRs and MRD negativity rates in this population, investigators set out to examine the impact of the agent on patients with multiple myeloma who have experienced a VGPR/CR and have MRD positivity following any first-line treatment. Patients could have previously undergone ASCT, received VMP, or lenalidomide (Revlimid) plus dexamethasone (Rd).
To be eligible for enrollment on the multicenter Italian trial, patients needed to be between the ages of 18 years and 85 years and able to adhere to the study visit schedule and other protocol requirements. Patients also needed to have greater than a VGPR and MRD positivity via next-generation flow (NGF) measured by a 2-tubes optimized 8-color antibody panel. They could not have received first-line treatment for their disease within 12 weeks of study treatment.
Participants started daratumumab at least 12 weeks after they had undergone ASCT and at least 4 weeks after they had received VMP. Patients received daratumumab at a weekly dose of 16 mg/kg for the duration of 8 weeks. Then, the agent will be given every 2 weeks for an additional 8 weeks in 50 patients with multiple myeloma who achieved a VGPR or better, defined per International Myeloma Working Group criteria, and have MRD positivity via NGF.
Notably, NGF was performed on marrow aspirate at time 0, at 2 months, and it will be done every 6 months for the duration of 2 years.
The primary end point of the trial was achievement of MRD negativity at the 6-month timepoint. If patients achieve MRD negativity, they are able to stop treatment. If they are still MRD positive at that timepoint, they will continue to receive treatment every 4 weeks for up to 2 years.
Recruitment for the trial began in December 2018 and a total of 79 patients were screened until January 2021 at 5 centers throughout Italy. At least 10 million cells were evaluated for sensitivity at flow for each sample. Of 82 patients, 49% (n = 40) MRD positive and eligible. Three patients were excluded from the trial protocol because of withdrawn consent.
The median age of study participants was 61 years (range, 48-78). Nineteen of the patients were male, while 18 were female. Thirty patients had undergone 1 ASCT, while 3 patients had undergone 2 of those procedures. Three patients previously received VMP, and 1 patient had prior carfilzomib (Kyprolis) plus Rd.
Moreover, 12 patients had International Staging System for Multiple Myeloma (ISS) stage I disease, 14 had ISS stage II disease, and 11 had ISS stage 3 disease. Cytogenetics/fluorescence in situ hybridization was performed at diagnosis in 34 of the patients; of these patients, 27 tested negative for 17p deletion, t(14)q, and 1q amplification; 3 were positive for t(4;14); 4 were positive for t(11;14); and 2 had del 17p; and 1 had del 13q.
Eighty-six percent (n = 32) of participants completed 8 weeks of treatment with daratumumab and underwent MRD evaluation.
Additional results indicated that at the 2-month timepoint, 68% (n = 26) of 36 patients were MRD positive and 32% (n = 10) were MRD negative; 1 patient had not been evaluable. At 12 months, 76% (n = 14) of patients had MRD positivity, while 24% (n = 4) achieved MRD negativity. At 18 months, 57% (n = 5) of 9 patients were MRD positive, while 43% (n = 4) were negative. Lastly, at the 24-month timepoint, 1 patient had MRD positivity, while the other patient had MRD negativity.
Regarding safety, 45% (n = 17) of all 37 patients experienced a grade 2 reaction during their first infusion of daratumumab; investigators promptly administered corticosteroids to these patients and temporarily interrupted administration of the study drug. Over 500 rapid infusions were delivered to a total of 24 patients. Notably, none of the patients experienced serious toxicities.