Daratumumab regimen increases response in transplant-eligible multiple myeloma
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ORLANDO — The addition of daratumumab to lenalidomide, bortezomib and dexamethasone significantly improved rates of stringent clinical response and minimal disease negativity among patients with transplant-eligible newly diagnosed multiple myeloma, according to results of the randomized phase 2 GRIFFIN study presented at ASH Annual Meeting and Exposition.
The depth of responses improved with longer therapy duration.
The results support the regimen as a potential new standard of care for this patient population, according to investigators.
“We saw a dramatic improvement in stringent complete response, an effective doubling of minimal residual disease negativity and excellent safety, but the most important message is how the quality of responses were much higher with the integration of daratumumab and improved over time,” researcher Paul G. Richardson, MD, director of clinical research at Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and a HemOnc Today Editorial Board Member, told Healio.
Daratumumab (Darzalex; Genmab, Janssen Oncology) — a human immunoglobulin G1 kappa monoclonal antibody that binds to CD38 — is approved in the United States for six indications in multiple myeloma
Randomized studies showed daratumumab-based regimens significantly improved response rates, depth of response and PFS among patients with newly diagnosed multiple myeloma, as well as those with relapsed or refractory disease.
The RVd regimen — which consists of lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Takeda) and dexamethasone — followed by high-dose therapy, autologous stem cell transplant and consolidation is a standard regimen in the United States for newly diagnosed multiple myeloma.
The GRIFFIN study evaluated the addition of daratumumab to RVd for patients with newly diagnosed disease who were eligible for autologous stem cell transplant.
The analysis included 207 patients (median age, 60 years; range, 29-70; 57% men) who had stage I (48%), stage II (37%) or stage III (14%) multiple myeloma by International Staging System (ISS) criteria. Approximately 90% of patients had ECOG performance status of 0 or 1.
Thirty patients (15%) had high cytogenetic risk — determined by fluorescent in situ hybridization — due to deletion 17p, t(4;14) translocation or t(14;16) translocation.
Researchers randomly assigned patients to RVd with daratumumab (n = 104) or without (n = 103). Investigators stratified randomization by ISS stage and creatinine clearance. Treatment groups were well-balanced for baseline demographics and disease characteristics.
All patients received four induction cycles, high-dose therapy, autologous stem cell transplant, two consolidation cycles, and 24 months of maintenance therapy.
During the 21-day induction and consolidation cycles, patients received lenalidomide dosed at 25 mg orally on days 1 to 14, subcutaneous bortezomib dosed at 1.3 mg/m2 on days 1, 4, 8 and 11, and 40 mg dexamethasone on days 1, 2, 8, 9, 15 and 16.
Patients assigned daratumumab received 16 mg/kg via IV on days 1, 8 and 15 of the induction cycles, and on day 1 of the two consolidation cycles.
During maintenance — administered in 28-day cycles — patients received 10 mg lenalidomide on days 1 to 21. If tolerated in the first 3 months, the dose was increased to 15 mg in months 4 through 24.
Those assigned daratumumab received 16 mg/kg via IV every 8 weeks during maintenance, or every 4 weeks per patient decision allowed after study amendment.
Stringent complete response by the end of consolidation per International Myeloma Working Group criteria served as the primary endpoint.
Researchers used next-generation sequencing to assess minimal residual disease, defined as 10-5 per International Myeloma Working Group criteria. Secondary endpoints included rates of minimal residual disease negativity, complete response, overall response, and very good partial response.
Median follow-up was 22.1 months.
The study achieved its primary endpoint, as the addition of daratumumab to RVd improved the stringent complete response rate by the end of consolidation (42.4% vs. 32%; OR = 1.57; 95% CI, 0.87-2.82). Researchers observed improvement in all patient subgroups with the exception of those with ISS stage III disease or high cytogenetic risk.
Responses with daratumumab deepened over time, with stringent complete response rates favoring daratumumab at the end of induction (12.1% vs. 7.2%), after autologous stem cell transplant (21.2% vs. 14.4%) and at clinical cutoff (62.6% vs. 45.4%).
By the end of consolidation, a higher percentage of patients assigned daratumumab achieved response (99% vs. 92%), very good partial response or better (91% vs. 73%), and complete response or better (52% vs. 42%).
“The response rates from RVd alone are still very promising and consistent with earlier data,” Richardson told Healio. “The message is that they are enhanced by the addition of daratumumab in terms of quality of response.”
Next-generation sequencing showed a higher percentage of patients assigned daratumumab achieved minimal residual disease negativity at a sensitivity of 10-5 (51% vs. 20.4%). Minimal residual disease assessments will be updated at 12 and 24 months of maintenance.
PFS and OS data are immature but show an “outstanding early signal,” Richardson said. After median follow-up of 22.1 months, researchers estimated better 24-month PFS (95.8% vs. 89.8%) and 24-month OS (95.8% vs. 93.4%) with daratumumab.
The results showed stem cell mobilization and autologous stem cell transplant are feasible with the daratumumab regimen, with no significant effect on hematopoietic reconstitution.
Researchers reported no significant difference between the daratumumab and RVd-alone groups with regard to median stem cell yield (8.1 x 106 cells/kg vs. 9.4 x 106 cells/kg), median time to platelet engraftment (13 days vs. 12 days) or median time to neutrophil engraftment (12 days vs. 12 days).
The safety profile of daratumumab plus RVd appeared consistent with prior studies of daratumumab in combination with other standard-of-care regimens.
Grade 3 or grade 4 treatment-emergent adverse events that occurred more frequently among daratumumab-treated patients included neutropenia (41% vs. 22%), lymphopenia (23% vs. 22%), thrombocytopenia (16% vs. 9%), leukopenia (16% vs. 7%) and anemia (9% vs. 6%).
Researchers reported no difference in rates of grade 3 or grade 4 infections between treatment groups. Forty-two percent of daratumumab-treated patients experienced infusion-related reactions, but most were grade 1 or grade 2.
“When you combine daratumumab with the triplet, you have to be aware of pulmonary issues and infection,” Richardson told Healio. “At the same time, those are manageable if you are proactive.”
The findings from this study should serve as a basis for regulatory filing seeking approval of this regimen, Richardson said.
“We also will be looking at RVd plus daratumumab in the nontransplant settings,” he said. “If we’re achieving such high quality of response with this regimen among transplant-eligible patients, the key next question becomes: How much does transplant really add?” – by Mark Leiser
Reference: Voorhees PM, et al. Abstract 691. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosure: Richardson reports research funding from or advisory/board of directors roles with Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm Therapeutics, Oncopeptides, Sanofi and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.