Ajay K. Nooka, MD, MPH
THE ASCO POST asked Ajay K. Nooka, MD, MPH, Associate Professor, Division of Bone Marrow Transplant at Winship Cancer Institute, Emory University, to comment on studies involving daratumumab.
“After the phase III SWOG S0777 trial demonstrated a survival benefit with a 3-drug induction regimen (bortezomib, lenalidomide, and dexamethasone [VRd]) over a 2-drug regimen (lenalidomide and dexamethasone [Rd]) among newly diagnosed patients,1 there was greater enthusiasm for using quadruplet therapies among newly diagnosed transplant-eligible patients, to derive a better depth of response,” Dr. Nooka said. “In this context, the elusive fourth agent— daratumumab, a CD38 monoclonal antibody—seemed to fit snugly as the placeholder in the quadruplet induction therapies for myeloma. A higher minimal residual disease (MRD)-negativity rate and an acceptable nonoverlapping toxicity profile have made daratumumab an ideal partner to the existing backbone three-drug induction regimens. At the 2018 American Society of Hematology (ASH) Meeting & Exposition, we heard the results of several studies of daratumumab added to initial therapy among newly diagnosed patients with myeloma.”
The phase II Griffin trial has finished accrual of more than 200 transplant-eligible newly diagnosed patients, and the results are awaited. The study is evaluating daratumumab plus VRd (D-VRd) vs VRd, with the primary endpoint of stringent complete response after consolidation. At the ASH meeting, Voorhees et al presented the safety run-in portion of the study among 16 patients, showing a good safety profile, a 100% rate of very good partial response or better, and a complete response rate of 63%.2 Moreover, “using a much better tool to evaluate the depth of response, MRD negativity (for the threshold of 10–5) was seen in 50% of the patients. These are impressive responses, and yet the regimen had no negative impact on the stem cell yield,” Dr. Nooka noted.
IN A SIMILAR VEIN, a nonrandomized phase II trial by Kumar et al evaluated daratumumab in combination with ixazomib, lenalidomide, and dexamethasone among 40 patients.3 Very good partial responses or better were achieved by 69%, with 19% being complete responses, he continued. “Although the regimen was extremely well tolerated and did not impact stem cell collection, the response rates seem lower in this trial than what is expected, partly because of the evaluation of response by a more sensitive technique—mass spectrometry—as compared to the electrophoretic methods,” Dr. Nooka pointed out.
He said he would like to see the encouraging results for D-VRd in the safety run-in period also reflected in the entire Griffin cohort, when that analysis is done. He also hopes to see strong results from the phase III Cassiopeia study, which is evaluating daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) vs VTd for a similar endpoint. A company press release has stated the study met its primary endpoint, but results have not yet been presented or published.
For transplant-ineligible patients, daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) was evaluated in the phase III ALYCONE trial, whose strong initial results were previously reported by Mateos et al.4 The 1-year update presented by Dimopoulos et al at the ASH meeting showed a 57% reduction in the risk of disease progression or death with D-VMP, vs VMP, based on a 30-month progression-free survival of 60% vs 28%, respectively; MRD-negativity rates were also much higher at 27% vs 7%.5 “But while the addition of daratumumab to VMP is U.S. Food and Drug Administration–approved for the treatment of transplant-ineligible patients with newly diagnosed myeloma, in the United States the VMP backbone is not the most preferred regimen for patients who are not eligible for transplant,” he said.
In this context, results of the phase III MAIA trial, presented at the ASH meeting by Facon et al,6 “were appropriate and timely,” Dr. Nooka added. The MAIA trial randomly assigned 737 newly diagnosed transplant-ineligible patients to receive daratumumab plus lenalidomide and dexamethasone (D-Rd) or Rd, with the primary endpoint being progression-free survival. The D-Rd arm demonstrated a 30-month progression-free survival of 71% vs 56% with Rd—a 44% reduction in risk—with MRD negativity (at 10-5 sensitivity) achieved by 24% vs 7%, respectively.
“ALTHOUGH THE DATA are more compelling for the use of daratumumab in the induction regimens and practice-changing for transplant-ineligible patients in the United States, the benefit seems to be limited to patients at standard risk. Those at higher risk did not get the benefit of adding daratumumab in both the Alcyone and MAIA trials,” Dr. Nooka noted.
“What I would like to see next is the addition of daratumumab to the ‘VRd-lite’ regimen for transplant-ineligible high-risk patients, and a trial evaluating the addition of daratumumab to bortezomib or ixazomib (ie, a chemotherapy-free regimen) in newly diagnosed transplant-ineligible patients,” he said. ■
DISCLOSURE: Dr. Nooka has served on advisory boards for and has received fees and honoraria from Janssen, Takeda, Celgene, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Adaptive, and Spectrum Pharmaceuticals.
1. Durie BG, Hoering A, Abidi MH, et al: Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomized, open-label, phase 3 trial. The Lancet 389:519-527, 2017.
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 with newly diagnosed multiple myeloma eligible for high‐dose therapy and autologous stem cell transplantation. 2018 ASH Annual Meeting & Exposition. Abstract 151. Presented December 1, 2018.
3. Kumar SK, Kapoor P, Laplant B, et al: Phase 2 trial of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with newly diagnosed multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 304. Presented December 2, 2018.
4. Mateos M-V, Dimopoulos MA, Cavo M, et al: Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 378:518-528, 2018.
5. Dimopoulos M, Mateos M-V, Cavo M, et al: One-year update of a phase 3 randomized study of daratumumab plus bortezomib, melphalan and prednisone versus bortezomib, melphalan and prednisone in patients with transplant-ineligible newly diagnosed multiple myeloma: Alcyone. 2018 ASH Annual Meeting & Exposition. Abstract 156. Presented December 1, 2018.
6. Facon T, Kumar S, Plesner T, et al: Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma ineligible for transplant. 2018 ASH Annual Meeting & Exposition. Abstract LBA2. Presented December 4, 2018.
Kenneth Shain, MD, PhD
DARATUMUMAB APPEARS to be the “gift that keeps on giving” to the myeloma community. “It seems we can add daratumumab to almost anything and make the regimen better. It’s got good activity and a good safety profile,” said Kenneth Shain, MD, PhD, Director of the...!-->!-->