Dara-VRd Leads to Sustained MRD Negativity in Newly Diagnosed Myeloma

Kathleen A. Dorritie, MD

Hematologist/Medical Oncologist

UPMC Hillman Cancer Center

Pittsburgh, PA

Targeted Oncology: What trial led to the use of quadruplet therapy in newly-diagnosed multiple myeloma?

Kathleen A. Dorritie, MD: One of the initial studies that led to the wide incorporation of quadruplet therapy was the GRIFFIN study [NCT02874742]. This study was looking at transplant preferred—some studies now are saying transplant preferred so you can include or not include patients on the preference of the physician and the patient, rather than just being eligible or not. These were transplant-preferred, newly-diagnosed patients with ECOG [performance status of] 0 to 2. Patients had to have adequate renal function, and there were some stratification factors.

This was a 1:1 randomization of VRd [bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone] vs daratumumab [Darzalex] plus VRd. Then patients went on to [autologous stem cell] transplant [ASCT]. They then had consolidation consistent with their initial randomization. Maintenance was also different in the 2 arms. In the quadruplet arm, it was daratumumab/lenalidomide maintenance. In the other arm, it was lenalidomide maintenance, and the primary end point was stringent complete response [CR] rate, because we know the depth of response seems to matter in multiple myeloma.

What were the final outcomes of the GRIFFIN trial?

In terms of the final analysis, there was a progression-free survival [PFS] benefit with the addition of the daratumumab [HR, 0.45; 95% CI, 0.21-0.95; P = .032].¹ There was not an overall survival benefit [HR, 0.90; 95% CI, 0.31-2.56; P = .84]. It is important to note that more and more like we are with a lot of our diseases in oncology, PFS is what we're trying to achieve, because in a cancer like multiple myeloma, patients are living longer. It can be very difficult to show overall survival benefit.

Then in terms of the response rates, one thing that was interesting that's come out across a bunch of studies is that the depth of response seemed to increase over time, and more so in the Dara-VRd group compared with the VRd group. There were very high rates of CR or better, of 83% at the final analysis vs 60% [respectively]. Lastly, with the GRIFFIN study, there was also improvement in MRD [minimal residual disease] negativity. There were higher rates of MRD negativity with the addition of daratumumab, which is a common theme throughout the studies that we look at.

How was Dara-VRd investigated in a larger patient population?

The PERSEUS study [NCT03710603], similarly, was looking at quadruplet vs triplet therapy; the randomizations were a little bit different. These were patients with intent for transplant, not preferred. It excluded patients who had neuropathy greater than or equal to grade 2. We found neuropathy can be a big barrier to enrollment of patients on trials, so a lot of studies are trying to relax this a little bit.

Essentially, after the initial Dara-VRd or VRd, patients had their ASCT, they then had consolidation of Dara-VRd or VRd. After that, the patients in the triplet arm went on to receive lenalidomide alone, and in the quadruplet arm, they then had daratumumab/lenalidomide maintenance, similar to the GRIFFIN study. Then, patients who had achieved MRD negativity for 12 months after their initial maintenance were then able to discontinue daratumumab and continue lenalidomide until progression vs continued daratumumab/lenalidomide if they were not MRD negative. It’s more of a complicated randomization at the second juncture, but similarly, PFS was statistically significantly improved with the addition of the daratumumab to the triplet [HR, 42; 95% CI, 0.30-0.59; P < .0001].²

MRD was also improved when adding daratumumab; sustained MRD negativity was higher with the quadruplet vs the triplet [64.8% vs 29.7%, respectively]. These look very similar to the GRIFFIN graphs. For response over time, it shows that in myeloma, there is a deepening of response over time. At the end of the daratumumab/lenalidomide maintenance, which would be at the 24-month time point, CR or better was achieved in 87.9% of patients in the quadruplet arm, and then in the triplet arm, it was 70%.

As I mentioned, part of the randomization was based on sustained MRD negativity. A good proportion of patients did maintain their MRD negativity for 12 months or longer in the quadruplet arm, certainly much higher numbers than in the VRd arm. There was a good proportion of patients who even sustained their MRD negativity for greater than or equal to 18 months [59.4% vs 25.1%, respectively]. This shows the benefit of adding a CD38 monoclonal antibody to upfront treatment.

What did the subgroup analyses and toxicity profile show in the PERSEUS trial?

I don't think this would be surprising, but the analysis showed that when you compare different risk groups of patients, when you're comparing Dara-VRd to in a standard-risk patient to VRd with standard-risk patient, Dara-VRd did better.³ When you look at high-risk patients, even though the high-risk patients did poorer than the standard-risk patients who received VRd, they still did better than high-risk patients who received the triplet.

In terms of adverse events, the main things we see with the quadruplets are higher rates of cytopenias, thrombocytopenia, neutropenia, and infection.⁴ This has been shown throughout these different studies of quadruplets.

DISCLOSURE: Dorritie previously disclosed research support from Kite Pharma-Gilead, Janssen, Bristol Myers Squibb, Genmab, Hoffman-LaRoche, and an advisory board member role for Janssen.

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. Rodríguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial. J Clin Oncol. 2024;42(suppl 16):7502. doi:10.1200/JCO.2024.42.16_suppl.7502

3. Dimopoulos MA, Sonneveld P, Rodríguez-Otero P, et al. Daratumumab (dara)/bortezomib/lenalidomide/dexamethasone (D-VRd) with D-R maintenance (maint) in transplant-eligible (TE) newly diagnosed myeloma (NDMM): analysis of PERSEUS based on cytogenetic risk. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P974.

4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054