Quadruplet Trials Form New Standard in Transplant-Eligible Multiple Myeloma

Susan Bal, MD

Assistant Professor-Medicine

The University of Alabama at Birmingham, School of Medicine

Birmingham, AL

Targeted Oncology: What was the significance of the GRIFFIN trial (NCT02874742)in patients with newly diagnosed multiple myeloma?

The GRIFFIN trial…was the United States randomized phase 2 trial. It had roughly 100 patients in each arm, and what we saw was that daratumumab [Darzalex] plus lenalidomide [Revlimid] maintenance after induction and consolidation with Dara-VRd [daratumumab, bortezomib (Velcade), lenalidomide, and dexamethasone] resulted in a high rate of stringent complete remission [sCR], which was the primary end point of this study. Looking at the sCR after maintenance [at most recent follow-up], it was [67% vs 48% for VRd (bortezomib, lenalidomide, and dexamethasone)].¹ The rate of sCR across the board across different high-risk features favored the Dara-VRd.²

For a while, there was a lot of thought that daratumumab works, but doesn’t work for high-risk patients. There are a couple of meta-analyses published by different groups that put that to dust. Daratumumab helps everybody. Daratumumab helps a little bit better in the patients in whom everything works better. Standard-risk patients benefit from daratumumab a bit more than in high-risk patients, but that’s because standard-risk patients benefit from everything a little bit more than high-risk patients. That dust settled and we published a meta-analysis.³

What is the quality of life in patients treated on the GRIFFIN trial?

Some patient-reported outcomes showed that initially the global health status and physical functioning were low, but as they get into month 6, month 12, and month 18, they looked pretty good. Pain and fatigue were initially pretty bad. Then of course after you get to the month 6 timepoint, when patients are responding, they’ll [respond] better and they feel better.⁴

What did the final analysis of GRIFFIN show, and what phase 3 data on this regimen are now available?

The final analysis was shared at the International Myeloma Society Annual Meeting and was published in October of 2023. With about 4 years of follow up, the 4-year progression-free survival rate was 87% for Dara-VRd vs 70% for VRd.⁵ This is almost identical to what was shared in the abstract for the Perseus [NCT03710603] data.⁶ [The phase 3 Perseus trial] data look very consistent with what has been shown so far. We do not have overall survival data [for GRIFFIN]. It started in 2019, so it’s too immature for survival.

What did the phase 2 MASTER trial (NCT03224507) show regarding minimal residual disease (MRD) negativity in patients treated for multiple myeloma?

I was one of the investigators for MASTER and it was a very innovative trial led by Luciano Costa, MD. [It asked] if patients get to MRD negativity, do patients need ongoing therapy, and can we cure patients with multiple myeloma? That’s the premise of the study. We did 4 cycles of Dara-KRd [daratumumab, carfilzomib (Kyprolis), lenalidomide, and dexamethasone], and then we checked MRD status. All patients get autologous stem cell transplant [ASCT], so it’s important to remember that MASTER does not answer the question of should we do ASCT or not, because all patients regardless of their MRD status went ahead and got ASCT. Then subsequent to ASCT, they get another MRD [test]. and if their first MRD and second MRD are both negative, they can go on observation. If they’re not MRD negative, but they get to MRD negativity after ASCT, then as long as they can get 4 more cycles and get to MRD negativity, they do that. We keep repeating blocks of 4 cycles until we get a total of 12 cycles and if by then you have not reached MRD negativity you continue on lenalidomide maintenance and you’re off protocol.

But overall, this is a study that was associated with what’s one of the highest rates of MRD negativity, 80% across the board for all comers.⁷ There was a large proportion of patients who were able to discontinue therapy as of the final manuscript publication. Some of those patients, particularly those with ultra–high-risk disease, have had disease resurgence. The 3-year PFS rate looks very promising at 88% [for 0 high-risk cytogenetics, 79% for 1 high-risk feature, and 50% for those with 2-plus] high-risk features.⁸ So this approach is doable. It’s feasible, it works for standard-risk patients as well as patients with 1 high-risk feature, but those who have 2 or more high-risk features, those are really where nothing seems to help and a lot of people will criticize this trial saying that it happened, because they stopped treatment. I would beg to differ, because if you look at the patients on GRIFFIN, who are getting daratumumab/lenalidomide, the patients with ultra­–high-risk progressed there too. So I think this is just a population of high unmet need.

Maybe these are the patients who need to get chimeric antigen receptor T-cell therapy and bispecifics early so that we can salvage them. But I think those are the patients who need ASCT the most and they should certainly get ASCT.

_References:

_{1. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837. doi:10.1016/S2352-3026(23)00217-X}

_{2. Chari A, Kaufman JL, Laubach JP, et al. Daratumumab plus lenalidomide, bortezomib, and dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients (pts): final analysis of GRIFFIN among clinically relevant subgroups. Blood. 2022;140(suppl_1):7278-7281. doi: 10.1182/blood-2022-162339}

_{3. Giri S, Grimshaw A, Bal S, et al. Evaluation of daratumumab for the treatment of multiple myeloma in patients with high-risk cytogenetic factors: a systematic review and meta-analysis. JAMA Oncol. 2020;6(11):1759-1765. doi:10.1001/jamaoncol.2020.4338}

_{4. Silbermann R, Laubach J, Kaufman JL, et al. Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: patient reported outcomes from GRIFFIN. Blood. 2022;140(suppl_1):1146-1149. doi:10.1182/blood-2022-162313}

_{5. Sborov DW, Laubach J, Kaufman JL, et al. Daratumumab (dara) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057}

_{6. Sonneveld P, Dimopolous MA, Boccadoro M, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib, lenalidomide, and dexamethasone (VRd) Versus Vrd alone in patients (Pts) with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem cell transplantation (ASCT): primary results of the Perseus trial. Blood. 2023;142(suppl_2):LBA-1. doi:10.1182/blood-2023-191911}

_{7. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935}

_{8. Costa L, Medvedova E, Chhabra S, et al. S203: Quadruplet induction therapy, ASCT and MRD-modulated consolidation and treatment cessation in newly diagnosed multiple myeloma: final analysis of the MASTER trial. Hemasphere. 2023;7(Suppl):e1332195. doi:10.1097/01.HS9.0000967724.13321.95}