Daratumumab With VRd Induced VGPR in 100% of Patients With Multiple Myeloma

Peter Voorhees, MD

In a study of transplant-eligible patients with newly diagnosed multiple myeloma (MM), daratumumab (Darzalex) added to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induced at least a very good partial response (VGPR) in all patients, including a stringent complete response (sCR) or CR in 63% of patients (n = 16), at the end of consolidation therapy. In addition, half of the patients achieved minimum residual disease (MRD) negativity after consolidation in the safety run-in to the phase II Griffin study, reported Peter Voorhees, MD, at the 2018 American Society of Hematology Annual Meeting.

 

“The depth of response improved with consolidation and continued to deepen over time,” said Voorhees, associate professor, University of North Carolina Lineberger Comprehensive Cancer Center, Charlotte. He said the combination of daratumumab and VRd (D-VRd) was “well tolerated and effective in transplant-eligible patients with newly diagnosed MM.”

He added, “It does not appear that adding daratumumab to a VRd backbone negatively impacts stem cell collection and engraftment.” All 16 patients underwent successful stem cell mobilization with subsequent transplant. The median stem cell yield was 8.05 x 10⁶CD34-positive cells, the median time to neutrophil engraftment was 13.0 days, and the median time to platelet engraftment was 13.5 days.

Daratumumab, a human IgGκ monoclonal antibody that targets CD38, is already approved in many countries as monotherapy and in combination with standard of care regimens in relapsed/refractory MM, as well as in combination with bortezomib, melphalan, and prednisone in transplant-ineligible patients with newly diagnosed MM. Daratumumab-based combinations in these settings have been shown to reduce the risk of progression or death and to induce deep and durable responses.

“We know that attaining a CR is important to improve long-term outcome after autologous stem cell transplantation [ASCT], whether that’s measured by sCR or MRD negativity,” said Voorhees. The VRd triplet followed by high-dose therapy (HDT), ASCT, and consolidation has yielded high rates of response and progression-free survival (PFS) in newly diagnosed MM. Numerous phase III studies have shown that the addition of daratumumab to other standard of care regimens has improved the depth of responses, leading to improved PFS in patients with relapsed/refractory MM or newly diagnosed MM.

These observations led the investigators to conduct a safety run-in of the open-label study to determine the tolerability of D-VRd before proceeding with a larger randomized phase II study comparing D-VRd with VRd in transplant-eligible patients with newly diagnosed MM. The run-in included patients 18 to 70 years old with documented MM who were naïve to systemic therapy and eligible for ASCT. Patients received 4 cycles of D-VRd every 21 days as induction therapy followed by ASCT, and upon recovery, 2 more cycles of D-VRd every 21 days as consolidation therapy, followed by maintenance therapy with daratumumab and lenalidomide every 28 days during cycles 7 through 32. The dosage of daratumumab was 16 mg/kg on days 1, 8, and 15 of the induction phase and 16 mg/kg on day 1 of the consolidation phase. During the maintenance phase, patients received daratumumab as in the consolidation phase and lenalidomide, 10 mg, on days 1 to 21 of cycles 7 to 9, and 15 mg on days 1 to 21 beginning at cycle 10 if tolerated. The purpose of the run-in was to assess dose-limiting toxicities during cycle 1 of D-VRd.

All 16 patients completed at least 9 cycles of treatment, including at least 3 cycles of maintenance. At the time of data cutoff (October 24, 2018), the median number of cycles received was 17, which included 4 to 13 maintenance cycles. Median age of patients 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 del17p.

With a median follow-up of 16.8 months, 100% of patients reached VGPR or better and 63% achieved sCR or CR per investigator assessment by the end of consolidation. The depth of responses continued to improve during maintenance, with 94% achieving sCR or CR. Some 19% achieved MDR negativity at 10-5 by next generation sequencing at the end of induction and 50% achieved it at the end of consolidation. Fifteen of the 16 (94%) of patients remain progression free on study treatment.

All 16 patients experienced at least 1 treatment-emergent adverse event (TEAE), with TEAEs attributed to daratumumab in 15 patients. Fourteen (88%) patients had grade 3/4 TEAEs, with 10 (63%) 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%) . The vast majority of those were grade 1/2. The most common grade 3/4 nonhematologic TEAEs were pneumonia (25%), hypophosphatemia (13%), and rash (13%). Eleven patients (69%) had at least 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.

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

“I am happy to report that the randomized phase II portion of the trial, which includes 222 patients, finished enrollment in April of this year, and we should have data on that in 2019,” Voorhees said.

Reference:

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; Dec. 1-4, 2018; San Diego. Abstract 151.