In an update of the phase 2 GRIFFIN study, the addition of daratumumab to the standard regimen of lenalidomide/bortezomib/dexamethasone (RVd) led to rapid and deep responses that increased with longer duration of treatment in newly diagnosed patients who were eligible for autologous stem-cell transplantation (ASCT), according to Peter Voorhees, MD, the study’s presenting author. Daratumumab, a monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens such as RVd.
ASCT has been established as an important standard of care for eligible patients with newly diagnosed multiple myeloma. Previous research shows that RVd induction improves overall response, depth of response, progression-free survival (PFS), and overall survival (OS) in these patients in the nontransplant setting, and that it has notable activity in the setting of frontline ASCT.
Other research has demonstrated that the addition of daratumumab to lenalidomide and dexamethasone (Rd) or bortezomib and dexamethasone (Vd)-based therapy significantly improved depth of response, minimal residual disease (MRD) negativity, and PFS in newly diagnosed as well as relapsed/refractory patients, and that RVd plus early ASCT versus RVd alone significantly improves PFS.
“Median PFS continues to improve in multiple myeloma, highlighting the pressing need for surrogate end points that are predictive of longitudinal outcomes of PFS and OS,” he said.
In that regard, research has shown that achievement of stringent complete response (sCR) and MRD-negativity after ASCT are associated with better PFS and OS.
The GRIFFIN study evaluated the addition of daratumumab to the RVd backbone plus ASCT in transplant-eligible newly diagnosed multiple myeloma patients. At ASH, Dr Voorhees presented updated efficacy and safety data from the study after a median follow-up of 22.1 months.
The study randomized 207 newly diagnosed transplant-eligible patients (median age, 60 years) to standard-of-care RVd with or without daratumumab. Patients were International Staging System stage I (48%), stage II (37%), and stage III (14%); approximately 15% had high cytogenetic risk as defined by the presence of del(17p), t(4;14), or t(14;16).
Patients received 4 induction cycles, high-dose therapy, ASCT, 2 consolidation cycles, and 24 months of maintenance with RVd with or without daratumumab. The primary end point was the sCR rate by the end of consolidation. MRD-negativity, a secondary end point, was assessed by next-generation sequencing.
“The study met its primary end point, with D-RVd improving the sCR rate by the end of consolidation,” Dr Voorhees reported, noting the sCR rate of 42.4% with D-RVd and 32.0% with RVd represented a 57% increase (P = .1359) in this favorable outcome. “This was, technically speaking, statistically significant as defined by the protocol,” he said.
With longer follow-up, responses have deepened over time in both arms of the study, but patients in the daratumumab arm continue to perform better. Response rates and depths were greater for D-RVd at all time points, including end of induction, end of ASCT, end of consolidation, and clinical cutoff.
At the time of clinical cutoff, rates of complete response or better were close to 80% in the D-RVd arm, in contrast with 61% in the standard-of-care arm, with sCR rates of 62.6% versus 45.4%.
MRD-negative rates at clinical cutoff were 51.0% with daratumumab versus 20.4% with standard of care; rates were 47.1% and 18.4% in patients achieving both MRD-negativity and at least a complete response, respectively.
“If we just look at patients who achieved complete response, a higher proportion of patients in the daratumumab arm were MRD-negative, suggesting that the quality of complete responses was better in the daratumumab arm,” he noted. MRD assessments will be updated at 12 and 24 months of maintenance.
D-RVd also resulted in durable estimated PFS and OS (>95%) at 2 years. “Looking at initial progression-free and overall survival rates, suffice it to say that both groups of patients are doing incredibly well,” said Dr Voorhees. At 2 years, PFS is 95.8% in the daratumumab arm versus 89.8% in the RVd arm, and OS is 95.8% versus 93.4%. Median PFS and OS have not been reached in either arm.
More grade ≥3 neutropenia (41% vs 22%) and thrombocytopenia (16% vs 9%) were observed in the D-RVd arm. Any-grade infection rates were higher for D-RVd versus RVd (91% vs 62%), largely due to grade 1 and 2 upper respiratory tract infections, but grade 3 and 4 infection rates were similar, as were rates of any-grade pneumonia. There were no treatment-related deaths.
Stem-cell mobilization and ASCT were feasible with D-RVd, without a significant effect on hematopoietic reconstitution.
“These data demonstrate that adding daratumumab to RVd significantly improves response rates and depth of response, including continued improvement of sCR and MRD-negativity rates beyond post-ASCT consolidation,” Dr Voorhees concluded. “As seen in other randomized studies, continued use of daratumumab improved the depth of response.”
He added that early adopters of therapy have “good ammunition” to support D-RVd as a potential new standard of care in transplant-eligible, newly diagnosed multiple myeloma patients, but he argues that further research is needed, particularly in regard to confirming that the increased MRD-negative rate seen in the daratumumab arm translates to a sustained improvement in MRD-negativity, and most importantly, that the improved depth of response eventually translates to an improvement in PFS.
Voorhees P, et al. ASH Abstract 691.