Blood
Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.
Abstract
Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10-5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.
Related Questions
Are you still recommending autologous stem cell transplantation (ASCT) for all eligible myeloma patients who achieve remission after induction with a quadruplet regimen?
Our institution still recommends upfront autologous transplant for most fit patients. We appreciate the recent results from CEPHEUS and BENEFIT, but if we believe that achieving MRD negativity is important, the addition of autologous transplant improves the rate of MRD negativity, which ultimately s...
How do you modify Daratumumab-RVD relative to the protocols used in trials when used as a first-line agent to transplant-eligible patients with myeloma?
My modifications based off the GRIFFIN trial (Voorhees et al., PMID 32325490) are as follows: If patients have high burden disease and no underlying neuropathy, I will start with twice-weekly bortezomib (days 1, 4, 8, 11) but will change the dexamethasone to 20 mg days 1, 4, 8, 11, and 15 using the ...
Do you recommend utilizing daratumumab in the maintenance phase after a quadruplet induction for transplant eligible multiple myeloma?
Great question as always - both the Phase 2 GRIFFIN study (Dara-VRd vs VRd using IV Dara and 21-day induction cycles) and the Phase 3 PERSEUS study (Dara-VRd vs VRd using subQ dara and 28-day induction cycles) went on to use dara + lenalidomide for all patients in the post-transplant maintenance set...
What induction regimen do you choose for high risk newly diagnosed multiple myeloma in light of the recent high risk focused studies?
Two things are clear from the slew of high-risk enrichment studies and subgroup analyses that have been done. In the age of upfront quadruplet therapy with an anti-CD38 monoclonal antibody, outcomes for patients with one high-risk cytogenetic abnormality are very good, even in the absence of prolong...
What post-auto maintenance therapy do you recommend for patients with high-risk multiple myeloma?
This is tough. You want each particular risk group to correspond to a maintenance treatment that is likely to benefit the patient - not too much nor too little. The definition of high risk has changed from one single characteristic or one cytogenetic abnormality to a more additive model such as the ...
How do you now approach treatment sequencing in MM in light of the DETERMINATION trial data?
There are two questions that come to mind re: DETERMINATION with respect to sequencing.1) To do early transplant or not?2) To do indefinite lenalidomide maintenance? My views on question #1 are evolving, but here is how I have unpacked it and stated elsewhere on theMednet. REASONS TO DO TRANSPLANT: ...
What factors do you look at while deciding between a daratumumab-based quadruplet induction versus standard triplet induction such as VRd for newly diagnosed MM?
This is becoming an increasingly thorny issue. A few guidelines to keep in mind:1) Dara-VRd has only been studied (thus far) in transplant-eligible patients. So this discussion of Dara-VRd vs. VRd is hard to apply to patients without intent for transplant. 2) When you look at the CASSIOPEIA and GRIF...
How do you determine when to use a maintenance regimen vs continuous 3-drug regimen in a transplant-ineligible MM patient after response to first line therapy?
After completing initial therapy (which may or may not include high dose melphalan and auto SCT), I typically use maintenance lenalidomide. I consider “dual maintenance,” which is combining lenalidomide and a proteasome inhibitor, for patients with high risk FISH: t(4;14), t(14;16), and del17p. 1q g...
How would you manage multiple myeloma with a suboptimal response to frontline quadruplet therapy?
A suboptimal response, i.e. less than PR, to 4-drug induction is likely a poor prognostic sign, I just don't know how poor. This does not mean that you should follow induction with a tandem autologous transplant, CART, or bispecific as we don't know whether it's better than just moving forward with ...
Is there a role for MRD monitoring in the decision to switch from a triplet regimen to maintenance therapy in transplant-ineligible myeloma patients?
There is no role for MRD monitoring in the decision to switch from 3-drug therapy to maintenance, yet. First, MRD status is not the only variable to consider. It's ideal to personalize ongoing therapy as high-risk myeloma may require 3-drug therapy to remain in control, and low-risk disease may stay...
When would you add daratumumab to a PI/IMiD/dex backbone for first-line treatment of transplant-eligible multiple myeloma?
Short answer - in patients with low risk disease.Long answer - CASSIOPEIA enrolled fit patients below 65 years of age with adequate kidney function (greater than or equal to 40 mL/min/1.73 m2) with predominantly stage 1 & 2 disease by the revised international staging system (91% in Dara-VTd, 90% VT...