Daratumumab Boosts Outcomes in Transplant-Eligible Myeloma

Published: Tuesday, Dec 10, 2019

Peter M. Voorhees, MD, Levine Cancer Institute

Peter M. Voorhees, MD

Adding an anti-CD38 antibody to a 3-drug chemotherapy-free regimen led to deeper and more frequent responses in patients with transplant-eligible, newly diagnosed multiple myeloma, according to updated results from the randomized GRIFFIN trial.1

After a median follow-up of 22.1 months, the stringent complete response (sCR) rate was 45.4% with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) and 62.6% with daratumumab (Darzalex) and RVd (D-RVd). The addition of daratumumab essentially doubled the likelihood of achieving sCR (odds ratio [OR] 1.98; 95% CI, 1.12-3.49; P = .0177).

The overall CR rate (sCR + CR) also improved with D-RVd (79.8% vs 60.8%; P = .0045), and the proportion of patients achieving minimal residual disease (MRD) negativity was twice as high with D-RVd. At 24 months, both regimens led to rates of progression-free survival (PFS) exceeding 85% and rates of overall survival (OS) exceeding 90%, Peter M. Voorhees, MD, of the Levine Cancer Institute in Charlotte, North Carolina, reported at the 61st American Society of Hematology Annual Meeting and Exposition.

“The benefit of daratumumab continues with longer follow-up, as D-RVd shows continued improvement of stringent complete response and MRD negativity beyond posttransplant consolidation,” said Voorhees. “The overall safety profile of D-RVd is consistent with previous reports of daratumumab plus standard of care.”

“These results support D-RVd as a potential new standard of care for transplant-eligible newly diagnosed multiple myeloma,” he added. “We need to confirm that the MRD negative rates that were seen in the daratumumab arm are sustained. Most importantly, we need to make sure this improved depth of response translates into an improvement in progression-free survival.”

The addition of daratumumab to other recognized standards of care has improved depth of response, MRD negativity, and progression-free survival across subsets of patients with multiple myeloma. The backbone of the current regimen being examined was first studied by the Intergroupe Francophone du Myélome in a trial known as the IFM 2009 study that showed RVd plus early stem cell transplantation improved PFS as compared with RVd therapy alone.2 The addition of daratumumab to a similar regimen of bortezomib, thalidomide, and dexamethasone had previously demonstrated improved response rates and PFS as induction and consolidation therapy for transplant-eligible patients with newly diagnosed myeloma in the phase III CASSIOPEIA trial.3

Patients being treated in the GRIFFIN trial are receiving induction, consolidation, and maintenance therapy with or without daratumumab

Investigators at 35 sites in the United States randomized 207 patients 1:1 to 4 induction cycles of either D-RVd or RVd. Following stem-cell mobilization and transplantation, patients received an additional 2 cycles of consolidation therapy. Finally, the patients received as many as 26 cycles of maintenance therapy consisting of lenalidomide with or without daratumumab.

The study population had a median age of about 60 years with one-fourth of the patients being ≥65. On average, <1 month had passed since myeloma diagnosis, and about 85% of the patients had standard-risk cytogenetics.

The primary end point was a superior sCR rate with D-RVD regimen at the end of consolidation therapy, which met the preset 1-sided a of 0.1 (42.4% vs 32.0%; OR, 1.57; 95% CI, 0.87-2.82; 1-sided P = .068). Higher rates of sCR were also observed following induction therapy (12.1% vs 7.2%) and the end of transplantation (21.2% vs 14.4%). The addition of daratumumab led to significantly higher MRD-negativity rates in all patients (51.0% vs 20.4%; P <.0001) and in those with achieving a CR or better (47.1% vs 18.4%; P <.0001).

The 12-month PFS rates were 96.9% with daratumumab and 95.3% with RVd alone, and the 24-month PFS rates were 95.8% and 89.8%, respectively. The 12- and 24-month rates of OS were 99.0% and 95.8% with daratumumab versus 97.9% and 93.4% with RVd alone.

With respect to safety, treatment-emergent adverse events were observed in both groups. Infections of any grade were more common with D-RVd (91% vs 62%), primarily because of a high rate of grade ≤2 upper respiratory tract infections, Voorhees. Rates of grade 3/4 infections were similar in the 2 groups (23% vs 22%), as was the rate of any-grade pneumonia (13% vs 15%).

The addition of daratumumab did not adversely affect stem-cell harvesting, transplantation, or time to engraftment of neutrophils or platelets.

Voorhees said the ongoing phase III PERSEUS trial (NCT03710603) is evaluating subcutaneous daratumumab plus RVd in transplant-eligible patients with myeloma.

References  

  1. Voorhees PM, Kaufman JL, Laubach, JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Blood. 2019;134(suppl 1;abstract 691). doi: 10.1182/blood-2019-123456.
  2. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi: 10.1056/NEJMoa1611750.
  3. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.
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