Phase 2 and 3 Transplant-Eligible NDMM Data Build Evidence for Quadruplet Therapy

Laahn Ho Foster, MD

Associate Professor

University of Virginia School of Medicine

Charlottesville, VA

Targeted Oncology: What led to the development of quadruplet therapy for patients with transplant-eligible newly diagnosed multiple myeloma (NDMM)?

LAAHN HO FOSTER, MD: The GRIFFIN study [NCT02874742]…showed early data on a quadruplet therapy for transplant eligible patients. This was a phase 2 trial with dara-RVd [daratumumab (Darzalex), lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone] vs RVd [lenalidomide, bortezomib, and dexamethasone]. In induction, they received 4 cycles, [autologous stem cell] transplant, and consolidation for another couple cycles; then in the maintenance setting, the patients who were on the dara-RVd arm received daratumumab and lenalidomide. The daratumumab continued for almost 3 years, then it was stopped after that, but the lenalidomide was continued and the patients who were not on the dara-RVd arm were just on lenalidomide.

The 2 groups were equally balanced, in terms of International Staging System staging and cytogenetic risk profile. Most of them were standard risk; there was about 14% of the patients who had high-risk cytogenetic abnormalities, and it breaks it down there of whether they had deletion 17p, translocation 4;14, or translocation 14;16. The revised set of generic abnormal risk profiles include gain of 1q21 and translocation 4;14, 14;16, or 14;20.¹

What were the final efficacy and safety findings from the GRIFFIN trial?

The final analysis for GRIFFIN clearly showed there was a progression-free survival [PFS] benefit at 3 and 4 years [89.0% with dara-RVd vs 80.7% with RVd at 3 years and 87.2% vs 70.0% at 4 years, respectively].¹ There was some long-lasting benefit for the patients who were treated with daratumumab vs those that were treated without daratumumab. But the overall survival [OS] rate was similar in both arms: approximately 92% to 93% at 3 and 4 years.

There is more detailed information on how these patients did in terms of depth of response. At the end of induction, it was pretty low at 19% for dara-RVd vs 13% for RVd. If you received RVd for complete response [CR] or better, this significantly deepened at the end of consolidation. After transplant and consolidation, CR or better was about half the patients with dara-RVd vs 42% with RVd alone. Then at the final analysis, after maintenance the response again deepened some more, there was a CR [or better] of 83% for the dara-RVd vs 60% for patients who were on the RVd arm.

RVd sets a high bar. We're already seeing over 90% overall response rates [ORR] with just a triplet. It does have to surpass that significantly to make an impact and change our practice patterns. But the ORR with dara-RVd is 99% vs 92% with RVd. The thing to note with dara-RVd is we're seeing deeper responses overall. With dara-RVd, there was [more minimal residual disease (MRD) negativity]. [The study measured] 10^-5 threshold and…10^-6. This is making a distinction of the sensitivity whether you're dealing with, for example, clonoSEQ or by flow [cytometry]. But by the definition, 10^-5 is still MRD negativity.

The adverse events [AEs] you might see with the quadruplet therapy are mainly cytopenias, anemia, thrombocytopenia, leukopenia—things that we are very comfortable with managing—and some electrolyte abnormalities. But it wasn't significantly different from RVd. The AE profile seems pretty equivalent between the 2 arms.

What other studies looked at quadruplet therapy in NDMM?

The MASTER study [NCT03224507] is dara-KRd [daratumumab, carfilzomib (Kyprolis), lenalidomide, and dexamethasone] for 4 cycles, [followed by] transplant, and then they got another 4 cycles after that for consolidation, and another 4 cycles. At each point, after induction, transplant, and every 4 cycles, they checked for MRD negativity and when they achieved 2 or more points of MRD negativity, they were able to come off of treatment.²

For PFS, the patients who had 0 or 1 high-risk cytogenetic abnormality did a lot better than the patients who had 2 high-risk cytogenetic abnormalities.³ For OS, again, [there was a] difference in the curves of the patients who had one or fewer high-risk cytogenetic abnormalities vs those who had more.

[Looking at] the patients who were MRD positive vs MRD negative, the PFS looks about the same [HR, 1.06; 95% CI, 0.50-2.12; log-rank P = .94]. The OS look like it was there is a separation of the curves of those who are MRD negative vs MRD positive [HR, 0.33; 95% CI, 0.07-1.49; log-rank P = .11].

The PERSEUS trial [NCT03710603] is the phase 3 version of GRIFFIN. This is the study that's going to put dara-RVd in the front line and establish that as the new standard of care.

[It led to] great separation in terms of PFS [84.3% with dara-RVd vs 67.7% with RVd at 48 months] and deepening of response with dara-RVd [87.9% with at least a CR vs 70.1% with RVd].⁴ The subset analysis shows that there's a benefit in pretty much all the subgroups [favoring dara-RVd].

_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. 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}

_{3. 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}

_{4. 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}