Daratumumab Plus RVd Improves Clinical Outcomes in Transplant-Eligible, Newly Diagnosed Multiple Myeloma

Douglas W. Sborov, MD, MS

The addition of daratumumab (Darzalex) to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) induction and consolidation treatment and lenalidomide maintenance therapy (D-RVd/D-R) resulted in high minimal residual disease (MRD) rates and prolonged progression-free survival (PFS) in patients with transplant-eligible, newly diagnosed multiple myeloma, according to data from the final analysis of the phase 2 GRIFFIN trial (NCT02874742).¹

Data presented at the 19th International Myeloma Society (IMS) Annual Meeting showed that at a median follow-up of 49.6 months, D-RVd/D-R (n = 104) resulted in a clinically meaningful 55% reduction in the risk of disease progression or death vs RVd/R (n = 103) in this patient population (HR, 0.45; 95% CI, 0.21-0.95; P = .0324). The median PFS had not yet been reached in either treatment arm. Separation of the PFS curves occurred beyond 1 year of maintenance treatment.

The PFS benefit was observed in the D-RVd arm vs the RVd arm, irrespective of whether lenalidomide was continued per standard of care (SOC) following the completion of study treatment.

Additionally, by the end of the study, 64% of patients in the D-RVd arm had achieved MRD negativity threshold of 10-5 vs 30% of those in the RVd arm.

“Ultimately, these data support the use of D-RVd induction and consolidation and D-R maintenance as a new SOC in transplant-eligible patients with newly diagnosed multiple myeloma,” said Douglas W. Sborov, MD, MS, lead study author and associate professor in the Division of Hematology and Hematologic Malignancies in the Department of Internal Medicine at the University of Utah School of Medicine in a presentation of the data.

GRIFFIN enrolled patients with transplant-eligible, newly diagnosed multiple myeloma who were between the ages of 18 and 70 years, had an ECOG performance status of 0 to 2, and creatinine clearance of at least 30 mL/min.

Participants were randomly assigned 1:1 to the D-RVd arm or the RVd arm. For induction treatment, those in the investigative arm received intravenous daratumumab at 16 mg/kg on days 1, 8, and 15; oral lenalidomide at 25 mg on days 1 to 14; subcutaneous bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11; and oral dexamethasone on days 1, 2, 8, 9, 15, and 16.

Following transplant, these patients received 2 cycles of consolidation treatment with daratumumab at 16 mg/kg on day 1; lenalidomide at 25 mg on days 1 to 14; bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11; and dexamethasone at 20 mg on days 1, 2, 8, 9, 15, and 16. For maintenance treatment, they received daratumumab at 16 mg/kg on day 1 every 4 weeks or every 8 weeks; and lenalidomide at 10 mg on days 1 to 21 for cycles 7 to 9, and at 15 mg on days 1 to 21 for cycles 10 and on.

Those in the control arm received induction treatment with RVd, given at the same dose and schedule as those in the investigative arm. Following transplantation, they received consolidation treatment with RVd at the same dose and schedule as the investigative arm, and then went on to receive maintenance treatment with lenalidomide alone. For cycles 7 to 9, lenalidomide was given at a dose of 10 mg for days 1 to 21; in cycles 10 and thereafter, the agent was given at 15 mg.

Patients were permitted to continue lenalidomide after the completion of planned study treatment in accordance with local SOC, Sborov noted.

Key stratification factors comprised disease stage per International Staging System (ISS) criteria (I vs II vs III) and creatinine clearance (30 to 50 mL/min vs > 50 mL/min).

Stringent complete response rate (sCR) served as the primary end point of the trial, and other end points included MRD negativity, objective response rate, very good partial response rate or better, complete response (CR), PFS, and overall survival (OS).

Data from the primary analysis of the trial, which had a median follow-up of 13.5 months, showed that D-RVd elicited a significantly improved sCR rate vs RVd by the end of consolidation treatment, at 42.4% and 32.0%, respectively (1-sided P = .0680), which met the prespecified 1-sided alpha of 0.10.²

At the IMS Annual Meeting, investigators reported data from the final analysis of the trial, which occurred after all participants had at least 1 year of long-term follow-up after the completion of maintenance treatment.

The demographic and clinical characteristics were well balanced between the arms. The median age of patients in the D-RVd arm was 59 years (range, 29-70) vs 61 years (range, 40-70) in the RVd arm. “The majority of patients had ISS I and II disease, and less than 20% of patients in both arms had evidence of conventional high-risk features,” Sborov said. He added that 35% of those in the D-RVd arm and 29% of those in the RVd arm had tumors with gain 1q.

During maintenance treatment, 15% of those in the D-RVd arm and 21% of those in the RVd arm discontinued D-R or lenalidomide maintenance treatment. Notably, more patients in the RVd arm discontinued due to disease progression vs those in the D-RVd arm, at 8% and 3%, respectively.

Following study treatment completion, 61% of those who received D-RVd and 41% of those given RVd continued to receive lenalidomide in accordance with local SOC. The median duration of continued lenalidomide treatment in the investigative and control arms was 16.9 months (range, 2-26) and 14.8 months (range, 1-25), respectively.

At all timepoints, response rates were “consistently higher in those patients treated with D-RVd [vs RVd],” Sborov noted. By the end of the study, 83% of those who received D-RVd experienced a CR or better vs 60% of those who were given RVd. CR or better rates improved over time, with the deepest responses occurring at the end of study maintenance treatment.

MRD negativity rates also improved over time, and were consistently higher in the D-RVd arm vs the RVd arm. These rates deepened throughout the study maintenance period; 14% of those in the D-RVd arm vs 10% of those in the RVd arm converted from MRD-positive status at the end of the consolidation period to MRD-negative status by the end of the 2-year maintenance period.

The median time to negative status was 8.5 months in the D-RVd arm vs 34.6 months in the RVd arm at the 10-5 threshold. Moreover, at the 10-6 threshold, time to negative status was 33.9 months and not reached in the D-RVd and RVd arms, respectively.

At the time of the final analysis, the median OS was not yet reached in either arm. A total of 14 patients had died; 7 deaths occurred in the D-RVd arm, and 7 deaths occurred in the RVd arm. Nine of these deaths were because of disease progression, 5 of which occurred in the D-RVd arm.

“OS data are not mature and longer follow-up would be required to evaluate this end point,” Sborov noted.

The median event-free survival (EFS) was also examined in the intention-to-treat population.

“D-RVd prolonged EFS vs RVd, which an early separation of the curves, suggesting suboptimal efficacy of the RVd-only regimen,” Sborov said. In the D-RVd arm, the median EFS had not yet been reached vs 50.5 months in the RVd arm (HR, 0.45; 95% CI, 0.28-0.74; P = .0011).

With the longer-term follow-up, no unexpected safety signals were reported. Rates of treatment-emergent adverse effects (TEAEs) that resulted in discontinuation were comparable between the D-RVd (n = 99) and RVd (n = 102) arms, at 33% and 31%, respectively.

The most common grade 3 or 4 hematologic TEAEs experienced in the D-RVd and RVd arms, respectively, were neutropenia (46% vs 23%), thrombocytopenia (16% vs 9%), leukopenia (17% vs 8%), anemia (9% vs 6%), and lymphopenia (23% vs 23%).

The most frequent nonhematologic TEAEs that were grade 3 or 4 in severity included fatigue (7% vs 6%), upper respiratory tract infection (4% vs 2%), diarrhea (7% vs 5%), peripheral neuropathy (7% vs 9%), nausea (2% vs 1%), constipation (2% vs 1%), pyrexia (3% vs 3%), insomnia (2% vs 1%), back pain (2% vs 1%), arthralgia (1% vs 2%), peripheral edema (2% vs 3%), headache (5% vs 1%), vomiting (3% vs 0%), muscle spasms (2% vs 5%), and dyspnea (3% vs 5%).

TEAEs led to death in 2 patients (1 in each treatment arm); however, neither case was related to study treatment.

The most common infection in both treatment arms was upper respiratory tract infection, and the highest incidence of infections occurred in earlier cycles of treatment and in the maintenance period. Five patients in the D-RVd arm and 2 patients in the RVd arm had COVID-19 infections. Infections led to treatment discontinuation in 2% of those in the D-RVd arm and 3% of those in the RVd arm.

During the discussant portion of the plenary session, Philippe Moreau, MD, IMS vice president and a professor of clinical hematology and head of the Hematology Department at the University Hospital of Nantes, said that although the data from the final analysis of GRIFFIN are positive, it is important to ask: Is this a game changer?

“In your conclusion, you mentioned that D-RVd, followed by transplantation and lenalidomide maintenance is a new SOC…but we should be very cautious [when determining a new] SOC,” Moreau said. “In my opinion, a SOC should be approved; daratumumab plus VTd [bortezomib, thalidomide (Thalomid), and dexamethasone] is the only quadruplet combination that is approved in the setting of stem cell transplantation.”

Moreau noted that daratumumab plus VTd has demonstrated a PFS benefit and a trend toward better OS in more than 1000 patients in the phase 3 CASSIOPEIA trial (NCT02541383). In GRIFFIN, “when comparing the 2 arms [there are] very, very few deaths and that’s very good,” Moreau noted. He added that although there is a numerical PFS benefit with D-RVd over RVd, the P value is .03.

“When looking more carefully at the data, [in particular] at the RVd arm, 32% of patients did not receive maintenance [therapy] as opposed to almost all patients [(87%) having been] treated with maintenance in the D-RVd arm,” Moreau explained. He added that if more patients received maintenance in the RVd arm, potentially fewer relapse events may have occured and “the PFS benefit would not have been that important; and the P value may have changed. So, I think this is a very important bias for the study.”

He added that there was an imbalance in continued lenalidomide maintenance following study maintenance completion in the RVd arm. “This is also introducing another bias, in my opinion,” he said.

Moreau did note that the PFS with D-RVd was “one of the best ever reported,” adding, “When we are comparing the response rates of GRIFFIN and [those in] CASSIOPEIA, the CR or better rate after induction, after consolidation, are identical, maybe slightly higher with D-RVd [vs D-VTd].”

He added that the results regarding MRD negativity were also “good news” and comparable to what was observed in CASSIPOEIA, which was 34.6% (95% CI, 30.6%-38.8%) among 543 patients who received D-VTd. “We confirm with [GRIFFIN] that the quadruplet is potentially very important,” Moreau said.

Regarding safety, Moreau added that D-RVd may be associated with slightly less peripheral neuropathy than what has been observed with D-VTd, underscoring the potential of the combination in the paradigm.

References

1. Sborov DW, Laubach J, Kaufman JL, et al. Daratumumab (dara) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057
2. 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(suppl 8):936-945. doi:10.1182/blood.2020005288