Positive Isa-VRd Trials in Transplant-Ineligible Myeloma Show New Approach

Andrzej Jakubowiak, MD, PhD

Professor of Medicine

Director, Myeloma Program

UChicago Medicine

Chicago, IL

Targeted Oncology: Could you discuss the recent data presented on the use of the Isa-VRd combination (isatuximab [Sarclisa] bortezomib [Velcade], lenalidomide [Revlimid] and dexamethasone) in patients with newly diagnosed transplant-ineligible multiple myeloma?

Andrzej Jakubowiak, MD, PhD: There are ongoing studies for new indications in transplant-ineligible [multiple myeloma] that have been presented at key meetings recently…and published. The IMROZ trial [NCT03319667] is similar to PERSEUS [NCT03710603] to some extent but using isatuximab instead of daratumumab [Darzalex] as the anti-CD38 antibody with VRd vs VRd in transplant-ineligible patients, but it was designed with a 3:2 randomization. The patients received induction for 4 cycles with either quadruplet or triplet and then continued triplet with isatuximab plus Rd or doublet with Rd, and there was crossover allowed.

The study was presented at an oral session at the American Society of Clinical Oncology Annual Meeting this year….¹ The primary end point was progression-free survival [PFS] and it was met. The difference between PFS for Isa-VRd vs VRd was quite significant, [63.2% vs 45.2%, respectively, at 60 months]. [PFS] was decent for VRd, but the HR was high, and its statistical significance quite high as well [HR, 0.596 (98.5% CI, 0.406-0.876; log-rank P = .0005]. The CR [(complete response) or better] rate was 74.7% vs 64.1%, respectively.

Minimal residual disease [MRD] was also superior for this study…. The differences are mostly in the depth of response for quadruplet, and that has been consistent over and over again. But importantly in this study, which I think is more important of the 2 studies that were presented for Isa-VRd, is that here we have clear PFS superiority, which is a more established primary end point. This was highly statistically superior; at 60 months, [the median PFS] was not reached [for Isa-VRd vs 54.34 months for VRd].

As far as toxicities go, it was as expected. In some categories, they were higher [with Isa-VRd] than VRd as expected. But as they have looked further in this study, they were mostly related to a longer treatment plan, because on Isa-VRd, patients received 53.2 months compared with 31.3 months, mostly related to progression on VRd, so ultimately, more toxicity is generated, but if they calculated toxicities per year, they were almost identical in those arms [13.39 vs 12.6 any-grade adverse event rate and 1.17 vs 0.99 grade 3 or higher rate per patient-year, respectively]. So I want to make it a point that we see higher toxicities, but [if] they are adjusted for time of treatment, [it was] quite concurrent between those 2 arms.

What other approach was there to investigating this combination vs a triplet?

There was a second study [presented] in the same session.² This was a study from French investigators called BENEFIT/IFM2020-05 [NCT04751877], which was interestingly also Isa-VRd in an experimental arm with [some] different details of postinduction treatment and was also for nontransplant candidates, but the control arm was Isa-Rd, so it's to some extent, it was [investigating] Isa-Rd with or without bortezomib, so it's a different [way] to look at it, but the study was also designed a little bit differently. It was looking for MRD as the primary end point at 18 months…. What they showed us after almost 2 years of follow up was that at 18 months, you see highly superior MRD for Isa-VRd compared with Isa-Rd [53% vs 26% at 10^-5 sensitivity; OR, 3.16; 95% CI, 1.89-5.28; P < .0001].

One can look at this as the MAIA trial [NCT02252172] but [instead of Rd, the comparator is] a triplet with an anti-CD38 antibody. So we see that with the quadruplet, in nontransplant candidates up to age 80, it performed very well. Not only [does VRd perform well], which we expected it to, but also triplet without bortezomib but with anti-CD38 antibody [does well].

[In terms of] responses, the difference in the rate of very good partial response or better is obvious [82% with Isa-VRd vs 70% with Isa-Rd], but also for CR, between the 2 arms, 58% and 31% [respectively]. So 2 studies with quadruplet Isa-VRd in the nontransplant candidates showed up when we were looking for [more data].

The toxicities are quite similar. I would say there is less difference in toxicity in the 2 arms because there was longer treatment in both arms with quadruplets. This was also time adjusted [showing] difference between the 2 arms [12.53 vs 5.57 any-grade adverse event rate and 0.96 vs 0.88 grade 3 or higher rate per patient-year, respectively].

REFERENCES:

1. Facon T, Dimopoulos MA, Leleu XP, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol. 2024;42(suppl 16):7500 doi:10.1200/JCO.2024.42.16_suppl.7500

2. Leleu XP, Hulin C, Lambert J, et al. Phase 3 randomized study of isatuximab (Isa) plus lenalidomide and dexamethasone (Rd) with bortezomib versus IsaRd in patients with newly diagnosed transplant ineligible multiple myeloma (NDMM TI). J Clin Oncol. 2024;42(suppl 16):7501 doi:10.1200/JCO.2024.42.16_suppl.7501