Frontline Daratumumab/VRd Regimen Improves sCR Rate in Transplant-Eligible Myeloma

Jan van de Winkel, PhD

The quadruplet regimen of daratumumab (Darzalex), lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone elicited a higher stringent complete response (sCR) rate compared with lenalidomide, bortezomib, and dexamethasone (VRd) alone in patients with transplant-eligible, newly diagnosed multiple myeloma, meeting the primary endpoint of the phase II GRIFFIN study.¹

Results demonstrated that the sCR rate with the daratumumab regimen was 42.4% versus 32.0% in the VRd arm (odds ratio [OR], 1.57; 95% CI, 0.87-2.82; P = .1359), which exceeded the statistical significance at a prespecified 2-side alpha level of 0.2. The quadruplet regimen also favored secondary endpoints of the trial, which included a minimal residual disease (MRD) analysis. The safety profile of the daratumumab regimen was consistent with that of each agent alone and coincided with prior data, according to a press release from Genmab, which sold the license to daratumumab to Janssen Biotech, Inc., in 2012.

A full efficacy and safety analysis is ongoing, and additional findings will be presented at an upcoming medical meeting.

"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, chief executive officer of Genmab, said in the press release. "This data also builds on the efficacy and safety data for daratumumab as a frontline treatment for transplant-eligible multiple myeloma patients 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."

In the open-label, parallel-assignment, phase II GRIFFIN trial (NCT02874742), 223 patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and autologous stem cell treatment were randomized to receive either daratumumab plus VRd or VRd alone. Patients must have also had an ECOG performance status between 0 and 2.

Lenalidomide is given orally at 25 mg on days 1 through 14 in 21-day cycles in cycles 1 to 6, followed by maintenance lenalidomide on days 1 to 21 in 28-day cycles in cycles 7 through 9. In cycle 10, lenalidomide’s dose is increased to 15 mg.

Bortezomib is administered subcutaneously at 1.3 mg/m2 on days 1, 4, 8, and 11 during cycles 1 to 6, and dexamethasone is given orally at 40 mg weekly (20 mg on days 1, 2, 8, 9, 15, and 16).

In the daratumumab arm, patients receive the monoclonal antibody intravenously at 16 mg/kg weekly during induction therapy, and every 3 weeks during consolidation treatment, following maintenance daratumumab every 4 or 8 weeks.

The primary endpoint is the number of patients who achieve sCR by the end of the consolidation therapy. Secondary endpoints are complete response rate, overall response rate, overall sCR, very good partial response rate (VGPR), MRD rate, duration of CR, duration of sCR, time to CR, time to sCR, time to VGPR, time to partial response, progression-free survival, overall survival, and duration of response.

Results of a safety run-in cohort of the 4-drug regimen in GRIFFIN were presented at the 2018 ASH Annual Meeting. Data showed that the combination of daratumumab and VRd led to a sCR or CR rate of 63% and a VGPR in all patients (n = 16) at the end of consolidation treatment.² MRD-negative disease was also achieved in half of the patients.

The safety run-in was conducted to determine the tolerability and dose-limiting toxicities of daratumumab with VRd in transplant-eligible patients with newly diagnosed disease who were aged between 18 and 70 years old.

All patients completed >9 cycles of treatment, including >3 cycles of maintenance therapy. At the time of data cutoff on October 24, 2018, the median number of cycles received was 17, which included 4 to 13 maintenance cycles. The median age was 62.5 years, 82% had an ECOG performance status of 0 or 1, 75% had stage I disease by the International Staging System, and 31% had 17p deletion.

At a median follow-up of 16.8 months, 94% of patients achieved sCR or CR, 19% achieved MRD negativity at the end of induction therapy, and 50% achieved it following consolidation therapy. All but 1 patient remained progression free on study treatment.

Regarding safety, all 16 patients experienced ≥1 treatment-emergent adverse event (TEAE), and TEAEs attributed to daratumumab occurred in 15 patients. Fourteen (88%) patients had grade 3/4 TEAEs, 10 (63%) of which were related to daratumumab. The most common hematologic TEAEs of any grade were neutropenia (75%), lymphopenia (75%), thrombocytopenia (50%), leukopenia (50%), and anemia (44%). Grade 3/4 hematologic TEAEs included neutropenia (31%), thrombocytopenia (25%), and lymphopenia (19%).

The most common nonhematologic TEAEs of any grade were diarrhea (56%), fatigue (56%), hypocalcemia (50%), and constipation (50%), most of which were grade 1/2. The most common grade 3/4 nonhematologic TEAEs were pneumonia (25%), hypophosphatemia (13%), and rash (13%).

Eleven patients (69%) had ≥1 serious AE, including 3 (19%) related to daratumumab. There were no treatment discontinuations due to AEs and no deaths due to serious AEs. Thirteen patients (81%) developed infections, the most common being upper respiratory tract infection in 6, pneumonia in 4, bronchitis in 2, and otitis and viral gastroenteritis in 2 each.

Moreover, daratumumab infusion reactions were reported in 4 (25%) patients, none of whom had grade 3/4 infusion reactions.

Also in the transplant-eligible setting, the FDA granted a priority review designation to a supplemental biologics license application for daratumumab in combination with bortezomib, thalidomide (Thalomid), and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT), based on encouraging sCR date from part 1 of the phase III CASSIOPEIA (MMY3006) trial.

In June 2019, the FDA approved the combination of daratumumab with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT.

References

1. Genmab Announces Positive Topline Results in the Phase II GRIFFIN Study of Transplant Eligible, Newly Diagnosed Patients with Multiple Myeloma Treated with Daratumumab in Combination with Lenalidomide, Bortezomib, and Dexamethasone. Genmab. Published July 8, 2019. https://bit.ly/32ffENb. Accessed July 8, 2019.
2. Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; dara‐vrd) vs. vrd in patients (pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT). Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 151.