Short answer: GRIFFIN was a randomized phase 2 trial of 207 transplant-eligible patients with newly diagnosed multiple myeloma. Adding daratumumab to lenalidomide, bortezomib and dexamethasone (D-RVd versus RVd) deepened responses at every time point: MRD negativity at 10^-5 reached 64% vs 30% by the end of the study, and complete response or better reached 83% vs 60%. At a median follow-up of 49.6 months, progression-free survival favored D-RVd (HR 0.45), although the trial was not powered for survival endpoints and overall survival was immature. GRIFFIN is the phase 2 foundation that PERSEUS later confirmed in a larger phase 3 trial.
Author and disclosure: Roupen Odabashian, MD, FRCPC, Oncologist and founder of MeDucation AI. I am the founder of MeDucation AI, which sells hematology and oncology board preparation. I have no other financial relationships relevant to the studies discussed here. This article is educational and is not a substitute for individualized clinical judgment or tumor board discussion.
What was the GRIFFIN trial design?
GRIFFIN enrolled adults with newly diagnosed, transplant-eligible multiple myeloma. A 16-patient safety run-in cohort received the quadruplet first, and the randomized phase 2 portion then assigned 207 patients to D-RVd (n = 104) or RVd alone (n = 103). Both arms followed the same structure: four induction cycles, high-dose melphalan with autologous stem cell transplant, two consolidation cycles, and then 24 months of maintenance. The control arm received lenalidomide maintenance alone, whereas the daratumumab arm received daratumumab plus lenalidomide maintenance. The primary endpoint was the stringent complete response (sCR) rate by the end of consolidation. The primary analysis was reported at a median follow-up of 13.5 months, and the investigators later reported updated and final analyses.
What were the key response results?
Outcome | D-RVd | RVd |
|---|---|---|
sCR by end of consolidation (primary endpoint) | 42.4% | 32.0% (one-sided P = 0.0680) |
sCR after 24 months of maintenance | 66.0% | 47.4% |
MRD negativity at 10^-5 (end of maintenance, ASH 2021 update) | 64.4% | 30.1% |
MRD negativity at 10^-5 (final analysis, by end of study) | 64% | 30% |
MRD negativity at 10^-6 (overall) | 35.6% | 14.6% |
Sustained MRD negativity for at least 12 months | 44.2% | 12.6% |
Complete response or better (final analysis) | 83% | 60% |
The pattern to remember is that the response gap widened with time on treatment. The primary endpoint at the end of consolidation showed a modest difference, but the deepening of response during daratumumab plus lenalidomide maintenance produced the larger separation seen in the later analyses.
Did D-RVd improve progression-free survival?
The trial suggested it did, with an important caveat. At the ASH 2021 update, estimated 36-month PFS was 88.9% with D-RVd vs 81.2% with RVd, and the authors described the result as a trend because the study was not powered for PFS. At the final analysis (median follow-up 49.6 months), median PFS was not reached in either arm and the hazard ratio favored D-RVd (HR 0.45, 95% CI 0.21 to 0.95, P = 0.0324). Overall survival was not mature: 14 patients had died, 7 in each arm, and 9 of those deaths were from disease progression. For board purposes, a PFS signal from a phase 2 trial that was not powered for it does not establish a survival benefit.
What toxicities did GRIFFIN report?
Adverse event (grade 3 or 4) | D-RVd | RVd |
|---|---|---|
Neutropenia | 46% | 23% |
Thrombocytopenia | 16% | 9% |
Leukopenia | 17% | 8% |
Peripheral neuropathy | 7% | 9% |
Discontinuation for treatment-emergent adverse events | 33% | 31% |
Hematologic toxicity was higher with the quadruplet, particularly neutropenia, while neuropathy was not increased. COVID-19 infections were reported in 5 patients on D-RVd and 2 on RVd. Treatment-emergent adverse events caused one death in each arm, and neither was considered related to study treatment.
How does GRIFFIN connect to PERSEUS?
PERSEUS tested the same idea in a phase 3 setting. It randomized 709 transplant-eligible patients with newly diagnosed myeloma to subcutaneous daratumumab plus VRd, with daratumumab and lenalidomide maintenance, or to VRd with lenalidomide maintenance. At a median follow-up of 47.5 months, estimated 48-month PFS was 84.3% with D-VRd vs 67.7% with VRd (HR 0.42). The key teaching point is that GRIFFIN raised the signal with deep MRD negativity as a surrogate, and PERSEUS then showed a clear PFS benefit in a trial powered for it. Note that GRIFFIN used intravenous daratumumab, whereas PERSEUS used the subcutaneous formulation.
What should you remember for the boards?
Daratumumab targets CD38, and this can interfere with pretransfusion testing by causing a positive indirect antiglobulin test, so notify the blood bank before transfusion.
Daratumumab can also interfere with serum immunofixation by appearing as an IgG kappa band, which can complicate confirming a complete response in patients with IgG kappa myeloma.
Infusion reactions occur mainly with the first infusion, which is why premedication is used.
MRD negativity and sustained MRD negativity are used as markers of depth of response and are associated with longer progression-free survival in myeloma studies.
Expect higher rates of neutropenia and infection with quadruplet therapy than with RVd alone, so supportive care and infection prophylaxis matter.
To practice this kind of question, see Oncology Board Review Question Banks Compared or the broader plan in How to Pass the ABIM Medical Oncology Boards. For the full exam approach, read Oncology Board Review 2026.
Frequently asked questions
What did the GRIFFIN trial show?
Adding daratumumab to RVd in transplant-eligible newly diagnosed myeloma increased sCR and MRD negativity rates, with a progression-free survival signal favoring D-RVd (HR 0.45) at 49.6 months of median follow-up.
Is GRIFFIN a phase 3 trial?
No. GRIFFIN was a randomized phase 2 trial of 207 patients and was not powered for PFS or overall survival. The phase 3 confirmation came from PERSEUS.
What was the primary endpoint of GRIFFIN?
The primary endpoint was the stringent complete response rate by the end of consolidation, which was 42.4% with D-RVd and 32.0% with RVd.
What is the difference between GRIFFIN and PERSEUS?
GRIFFIN was a phase 2 trial using intravenous daratumumab, while PERSEUS was a phase 3 trial of 709 patients using subcutaneous daratumumab and showing 48-month PFS of 84.3% vs 67.7%.
Does daratumumab affect blood bank testing?
Yes. Because daratumumab binds CD38 on red cells, it can cause a positive indirect antiglobulin test, so the blood bank should be told before any transfusion.
References
Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936 to 945. doi:10.1182/blood.2020005288
Voorhees PM, Rodriguez C, Reeves B, et al. Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN. Blood Adv. 2021;5(4):1092 to 1096. doi:10.1182/bloodadvances.2020003642
AJMC. Final analysis of phase 2 GRIFFIN shows daratumumab improves PFS after 4 years. ajmc.com
Targeted Oncology. Dara-RVd reduces risk of progression or death in transplant-eligible NDMM. targetedonc.com
Urban Health Today. Long-term follow-up from GRIFFIN confirms durability of daratumumab responses in transplant-eligible myeloma. December 2021. urbanhealthtoday.com
The ASCO Post. PERSEUS: daratumumab regimen significantly improves progression-free survival in newly diagnosed multiple myeloma. January 2024. ascopost.com
ClinicalTrials.gov. GRIFFIN, NCT02874742. clinicaltrials.gov
