The 4-drug regimen of daratumumab in combination with bortezomib, lenalidomide, and dexamethasone induced a high percentage of stringent complete responses compared with VRd alone in patients with newly diagnosed multiple myeloma who are eligible for high-dose chemotherapy and an autologous stem cell transplantation, according to topline results of the GRIFFIN trial. This met the primary endpoint of the phase II trial.
Jan van de Winkel, PhD
The 4-drug regimen of daratumumab (Darzalex) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induced a high percentage of stringent complete responses (sCRs) compared with VRd alone in patients with newly diagnosed multiple myeloma who are eligible for high-dose chemotherapy and an autologous stem cell transplantation (ASCT), according to topline results of the GRIFFIN (MMY2004) trial. This met the primary endpoint of the phase II trial.1
Stringent complete responses were seen in 42.4% of patients treated with the 4-drug regimen compared with a sCR rate of 32.0% seen in those treated with the triplet (odds ratio, 1.57; 95% CI, 0.87-2.82;P= .1359). This exceeded the preset statistical significance at the 2-sided alpha level of 0.2.
Although further analysis of the trial is ongoing, positive trends have also been seen for the secondary endpoints favoring daratumumab in combination with VRd.
The safety profile of the combination of daratumumab plus VRd was considered consistent with prior reports of the experience with each individual agent.
“The data from the phase II GRIFFIN trial underlines the potential of daratumumab when used in combination with VRd and supports Janssen’s decision to start the PERSEUS and CEPHEUS phase III studies of daratumumab in combination with VRd for certain frontline multiple myeloma indications,” Jan van de Winkel, PhD, CEO of Genmab, said in a statement. “These data also build on the efficacy and safety data for daratumumab as a frontline treatment for transplant-eligible [patients with] multiple myeloma as seen in the CASSIOPEIA phase III study in which newly diagnosed patients with multiple myeloma who were candidates for ASCT were treated with daratumumab combined with an immune-modulatory drug and a proteasome inhibitor.”
The license for daratumumab was sold to Jansen Biotech in 2012. Daratumumab continues to be investigated in a number of trials for multiple myeloma in various settings.
The ongoing GRIFFIN trial is a randomized, open-label, parallel-assignment trial investigating the addition of daratumumab to the VRd regimen for patients with newly diagnosed multiple myeloma (NCT02874742). The trial enrolled 223 patients who were eligible for high-dose chemotherapy and ASCT and these patients were randomized to receive either daratumumab plus VRd or VRd alone.
In the investigational arm, daratumumab was given intravenously at 16 mg/kg weekly on days 1, 8, and 15 of cycles 1 through 4 and then every 3 weeks on day 1 of cycles 5 and 6, followed by maintenance with daratumumab every 4 or 8 weeks.
The primary endpoint of the trial is the percentage of patients who achieve a sCR, as defined by the International Myeloma Working Group criteria, by the completion of ASCT consolidation treatment. Secondary endpoints include the overall complete response (CR) rate, the overall response rate, the rate of patients who achieve a very good partial response (VGPR) or better, the rate of patients with minimal residual disease, time to progression, progression-free survival, overall survival, time to response, and duration of response.
The trial began with a phase I safety run-in including 16 patients. Results of the safety lead-in were presented at the 2018 ASH Annual Meeting.2
The median age of the 16 patients was 62.5 years; 50% were male and 63% had an ECOG performance status of 1. As of the data cutoff, patients had received a median of 11 cycles of treatment with the 4-drug regimen (range, 9-12), including 3 to 6 maintenance cycles.
All of the patients achieved a VGPR or better, with 63% achieving a CR or sCR. Eight patients achieved MRD negativity. The investigators noted that responses continued to deepen during maintenance therapy.
At a median follow-up of 15.6 months, 94% of patients remained progression free on the study treatment.
Each patient experienced at least 1 treatment-emergent adverse event (AE) with serious AEs seen in 10 patients (63%), 3 of which experienced at least 1 serious AE related to daratumumab treatment. No deaths due to serious AEs were reported and no patients discontinued treatment due to an AE.
Grade 3/4 AEs were seen in 14 patients (88%), with 11 (69%) considered related to daratumumab. The most common grade 3/4 AEs were neutropenia, pneumonia, thrombocytopenia, lymphopenia, febrile neutropenia, leukopenia, and hypophosphatemia. Additionally, 12 patients (75%) experienced infections and daratumumab infusion reactions were noted in 5 patients (31%).