Adding Bortezomib to Isa-Rd Elicits Durable Responses for Multiple Myeloma

Investigators of the phase 3 BENEFIT trial (NCT04751877) found that bortezomib (Velcade) plus isatuximab-irfc (Sarclisa), lenalidomide (Revlimid), and dexamethasone (Isa-VRd) elicited a more durable rate of minimal residual disease (MRD)–negative responses than Isa-Rd alone in patients with transplant-ineligible multiple myeloma, according to Thomas G. Martin, MD.

CancerNetwork® spoke with Martin, a clinical professor of Medicine at the Adult Leukemia and Bone Marrow Transplantation Program and associate director of the Myeloma Program at University of California San Francisco (UCSF); and co-leader of the Cancer Immunology & Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center, about developments in multiple myeloma that he believes have the potential to change clinical practice beyond the FDA approval for isatuximab plus VRd for patients with newly diagnosed multiple myeloma in September 2024.¹

Martin contextualized the BENEFIT trial by describing how bortezomib was being evaluated for its effect on multiple myeloma treatment. He explained that this trial was unique in that it left the anti-CD38 therapy, isatuximab, in and evaluated therapy with or without bortezomib instead.

The results were surprising to Martin in that the addition of bortezomib to Isa-Rd therapy resulted in more durable MRD-negative responses than the triplet therapy alone. Martin concluded by indicating that the progression-free survival (PFS) data were immature, although the median PFS with the addition of bortezomib was projected to surpass 60 months.

Efficacy data from the BENEFIT trial published in Nature Medicine showed an MRD negativity benefit in the quadruplet therapy group over triplet therapy, with 53% of the bortezomib arm (95% CI, 44%-61%) at 10-5 at 18 months vs 26% (95% CI, 19%-34%) in the Isa-Rd arm (odds ratio [OR], 3.16; 95% CI, 1.89-5.28; P < .0001).² Additionally, the estimated 24-month PFS rates were 85.2% (95% CI, 79.2%-91.7%) and 80.0% (95% CI, 73.3%-87.4%) in each respective arm.

Transcript:

One of the developments that I will talk about is in another isatuximab-based trial. It was called the BENEFIT trial, and the trial [compared] a quadruplet vs a triplet. That quadruplet was isatuximab, bortezomib, lenalidomide, and dexamethasone. It was Isa-VRd vs isatuximab, lenalidomide, and dexamethasone [Isa-Rd].

This [trial] was the first time we [assessed a] quadruplet vs triplet where the only drug that changed was bortezomib; [the trial left] bortezomib out, not anti-CD38 [therapy] out like all the [other trials evaluating] quadruplets vs triplets. The other advantage was that bortezomib was given in a weekly administration. It was given weekly [subcutaneously for 3 weeks] of 4 weeks for the first 12 cycles, and then it was every other week for the next 6 cycles. Bortezomib continued for 18 months.

This is also the first trial where bortezomib continued for this long as induction-based therapy. Usually, bortezomib is completed by the first 8 to 10 months, mostly because of neuropathy. This [trial assessed giving treatment] weekly to see [if this dosing was] better. In fact, I was anticipating that there would not be much difference between these 2, the quadruplet vs the triplet, but that is why we do the trials. The surprising result was that the quadruplet of Isa-VRd vs Isa-Rd showed a significant advantage [for] the primary endpoint, [which] was MRD negativity. There was a deeper and more durable response based on MRD negativity in the Isa-VRd arm vs the Isa-Rd arm.

The bortezomib, maybe even at weekly dosing with 3 of 4 weeks for the first 12 months, showed a significant advantage. That trial only has 24 months of follow up. We are not close to [determining the] median PFS just yet. The median PFS with these regimens may be over 60 months, which is amazing. We are going to need a couple more years––2 or 3 more years of follow up—to see what the difference in the PFS is in those 2 arms.

References

1. FDA approves istauximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. News release. September 20, 2024. Accessed September 20, 2024. https://shorturl.at/B8d3c
2. Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024;30:2235-2241 doi:10.1038/s41591-024-03050-2