Background
Phase II randomized GRIFFIN tested whether adding daratumumab to bortezomib/lenalidomide/dexamethasone (RVd) deepens responses in transplant-eligible newly diagnosed multiple myeloma. 207 patients were randomized.
Interventions and follow up
Arm A (D-RVd): Daratumumab + RVd q21d x4 induction, then ASCT, then D-RVd q21d x2 consolidation, then daratumumab-lenalidomide maintenance.
Arm B (RVd): Same schedule without daratumumab.
Primary endpoint: Stringent complete response (sCR) rate by end of post-ASCT consolidation.
mFollow up: 13.5 months (primary); 22.1 months (updated); 36 months (extended).
Arm B (RVd): Same schedule without daratumumab.
Primary endpoint: Stringent complete response (sCR) rate by end of post-ASCT consolidation.
mFollow up: 13.5 months (primary); 22.1 months (updated); 36 months (extended).
Results
sCR (13.5 mo): 42.4% vs 32.0%; OR 1.57; 95% CI 0.87-2.82; P=.068.
sCR (22.1 mo): 62.6% vs 45.4%; OR 1.98; 95% CI 1.12-3.49; P=.0177.
MRD-negativity (10^-5, ITT, 22.1 mo): 51.0% vs 20.4%; OR 4.07; 95% CI 2.18-7.59; P<.0001.
MRD-negativity (10^-5, post-ASCT): 55.3% vs 25.6%; P<.0001.
ORR: 99.0% vs 91.8%; P=.0160.
≥VGPR: 90.9% vs 73.2%; P=.0014.
PFS: not reached in either arm; HR 0.46; 95% CI 0.21-1.01.
36-mo PFS: 88.9% vs 81.2%.
sCR (22.1 mo): 62.6% vs 45.4%; OR 1.98; 95% CI 1.12-3.49; P=.0177.
MRD-negativity (10^-5, ITT, 22.1 mo): 51.0% vs 20.4%; OR 4.07; 95% CI 2.18-7.59; P<.0001.
MRD-negativity (10^-5, post-ASCT): 55.3% vs 25.6%; P<.0001.
ORR: 99.0% vs 91.8%; P=.0160.
≥VGPR: 90.9% vs 73.2%; P=.0014.
PFS: not reached in either arm; HR 0.46; 95% CI 0.21-1.01.
36-mo PFS: 88.9% vs 81.2%.
Adverse events
Hematologic (grade 3/4, D-RVd vs RVd): neutropenia 41.4% vs 21.6%; lymphopenia 23.2% vs 21.6%; thrombocytopenia 16.2% vs 8.8%; leukopenia 16.2% vs 6.9%.
Infections: grade 3/4 pneumonia 8.1% vs 10.8%; daratumumab-associated infusion reactions were mostly grade 1/2.
Overall: No new safety concerns; the daratumumab arm had higher cytopenias without excess treatment-related mortality.
Infections: grade 3/4 pneumonia 8.1% vs 10.8%; daratumumab-associated infusion reactions were mostly grade 1/2.
Overall: No new safety concerns; the daratumumab arm had higher cytopenias without excess treatment-related mortality.
Conclusions
Adding daratumumab to RVd improved depth of response (sCR and MRD-negativity) in transplant-eligible NDMM, with responses deepening over continued therapy and a manageable safety profile.
Key Limitations
Phase II with sCR (not survival) as primary endpoint; the ISS stage I proportion was higher and high-risk cytogenetics lower than in some other trials. The RVd-arm MRD-negativity rate was lower than reported in IFM 2009. The phase III PERSEUS study (SC daratumumab + VRd) provides confirmatory data.
Clinical Context
GRIFFIN, alongside the confirmatory phase III PERSEUS trial, supports daratumumab-based quadruplet induction (Dara-RVd) as a preferred regimen for transplant-eligible NDMM per ASCO/ESMO and IMWG guidance.
36-mo update (Laubach, ASH 2021): MRD-negativity 10^-5 (ITT) 64.4% vs 30.1%, P<.0001; MRD 10^-6 35.6% vs 14.6%, P=.0007; sustained MRD-negativity (≥12 mo) 44.2% vs 12.6%, P<.0001.
Dosing: daratumumab IV 16 mg/kg weekly C1-4, then per schedule; lenalidomide 25 mg D1-14 (induction/consolidation), 10-15 mg maintenance; bortezomib SC 1.3 mg/m2; dexamethasone per protocol.
36-mo update (Laubach, ASH 2021): MRD-negativity 10^-5 (ITT) 64.4% vs 30.1%, P<.0001; MRD 10^-6 35.6% vs 14.6%, P=.0007; sustained MRD-negativity (≥12 mo) 44.2% vs 12.6%, P<.0001.
Dosing: daratumumab IV 16 mg/kg weekly C1-4, then per schedule; lenalidomide 25 mg D1-14 (induction/consolidation), 10-15 mg maintenance; bortezomib SC 1.3 mg/m2; dexamethasone per protocol.