Adding Isatuximab to Standard Backbone Improves Outcomes in Multiple Myeloma

CHICAGO — Combining the anti-CD38 monoclonal antibody isatuximab (Sarclisa) with the standard backbone of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) significantly improved outcomes in patients with transplant-ineligible, newly diagnosed multiple myeloma, according to two phase III trials.

In the IMROZ trial, the estimated progression-free survival (PFS) rate at 60 months was 63.2% among patients treated with isatuximab-VRd compared with 45.2% for those treated with VRd alone (HR 0.60, 98.5% CI 0.41-0.88, P<0.001), reported Thierry Facon, MD, of the Centre Hospitalier Universitaire de Lille in France.

This difference “highlights an outstanding PFS benefit in patients with transplant-ineligible, newly diagnosed multiple myeloma,” Facon said at the American Society of Clinical Oncology (ASCO) annual meeting.

Meanwhile, the BENEFIT trial showed that the isatuximab-VRd combination significantly improved minimal residual disease (MRD) negativity rates at 10-5 at 18 months compared with isatuximab, lenalidomide, and dexamethasone (53% vs 26%; OR 3.16, 95% CI 1.89-5.28, P<0.0001), reported Xavier Leleu, MD, PhD, of Centre Hospitalier Universitaire in Poitiers, France.

The higher MRD negativity rates with isatuximab-VRd were also observed at 12 months at both 10-5 and 10-6.

Facon and Leleu agreed that the results from IMROZ and BENEFIT, which were published in the New England Journal of Medicine and Nature Medicine, respectively, supported isatuximab-VRd as a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma.

ASCO-invited discussant Ola Landgren, MD, PhD, of the Sylvester Comprehensive Cancer Center in Miami, Florida, said that these two studies — along with the phase III PERSEUS trial, which demonstrated a benefit with add-on daratumumab (Darzalex) to VRd in patients with transplant-eligible newly diagnosed multiple myeloma — showed that “quadruplet therapies deliver higher rates of MRD negativity and longer progression-free survival compared to triplet therapies, and this is regardless of age and transplant eligibility.”

It is clear that CD38-targeted monoclonal antibodies narrow the gap between younger, fit, transplant-eligible patients and older, less fit, transplant-ineligible patients, he added.

“We have seen how immunotherapy added to existing backbones can improve outcomes in multiple myeloma, independent of transplant status,” Landgren said. “It is logical to ask the question: Is it time to retire the 40-year-old terminology ‘transplant eligible’ and ‘transplant ineligible?’ In my opinion, the answer is yes.”

IMROZ Trial

IMROZ was an open-label trial conducted at 93 sites in 21 countries that included 446 patients with newly diagnosed multiple myeloma who were ineligible for transplantation. Median age was 72 years, 51.9% to 54% were men, and 72% to 73% were white. They were assigned in a 3:2 ratio to receive isatuximab-VRd or VRd alone.

As of data cutoff, 47.2% of patients in the isatuximab-VRd group and 24.3% of those in the VRd group were still on treatment.

A PFS benefit was observed in most of the study’s subgroups, with the exception of those with high-risk cytogenetic features (HR 0.97, 95% CI 0.48-1.96).

The percentage of patients who achieved an overall response was similar between the isatuximab-VRd and VRd groups (91.3% and 92.3%). However, Facon reported that a significantly higher percentage of patients had a complete or better response with isatuximab-VRd (74.7% vs 64.1%, P=0.01).

A significant improvement in MRD negativity was observed among patients with a complete response at any time (55.5% with isatuximab-VRd vs 40.9% with VRd alone, P=0.003). The percentage of patients with MRD-negative status was higher in the isatuximab-VRd group than in the VRd group (58.1% vs 43.6%), and 46.8% and 24.3%, respectively, had a sustained MRD-negative status lasting at least 12 months.

At a median follow-up of 5 years, overall survival data were not mature, but did demonstrate a trend in favor of isatuximab-VRd (HR 0.78, 95% CI 0.41-1.48).

Adverse events (AEs) leading to discontinuation of therapy occurred in 22.8% of patients in the isatuximab-VRd arm and 26% in the VRd arm. Serious AEs were reported in 70.7% and 67.4% of the two arms, respectively.

The incidence of grade 3 or higher infection was 44.9% with isatuximab-VRd and 38.1% with VRd, with lower rates among patients who received antibiotic prophylaxis.

Grade 5 AEs during the treatment period were reported in 11% of patients in the isatuximab-VRd group and 5.5% in the VRd group. Four deaths in the isatuximab-VRd group and one death in the VRd group occurred within 60 days after receipt of the first dose.

BENEFIT Trial

This multicenter trial included 270 patients who were randomized to either isatuximab-VRd or isatuximab, lenalidomide, and dexamethasone. Median age was 73 to 74 years, and 53% to 55% were men.

The overall rates of complete response or better were 58% with isatuximab-VRd versus 31% with the triplet (OR 2.97, 95% CI 2.0-5.0, P<0.0001).

The time to the first occurrence of a confirmed partial response or better (≥PR) and very good partial response or better (≥VGPR) were significantly shorter with the triplet versus isatuximab-VRd (≥PR: 0.99 months vs 0.95 months, HR 1.30, 95% CI 1.01-1.67, P=0.040; ≥VGPR: 3.7 months vs 2.1 months, HR 1.65, 95% CI 1.27-2.14, P=0.0002).

PFS and OS data were immature at the time of data cutoff.

Leleu reported that isatuximab-VRd was well tolerated, but as expected, thrombocytopenia and peripheral neuropathy were more common with the quadruplet versus the triplet.

  • Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

IMROZ and BENEFIT were supported by Sanofi.

Facon disclosed no relationships with industry.

Leleu disclosed relationships with Sanofi, Janssen-Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptides, AbbVie, GSK, and Bristol Myers Squibb.

Co-authors for both studies reported multiple relationships with industry.

Landgren reported honoraria from Amgen, Bristol Myers Squibb, Celgene, GSK, Janssen, Karyopharm Therapeutics, and Medscape; consulting or advisory roles with Bristol Myers Squibb, Celgene, GSK, and Janssen; and research funding from Amgen, Janssen, Menarini Silicon Biosystems, Pfizer, and Sebia.

Primary Source

New England Journal of Medicine

Source Reference: Facon T, et al “Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma” N Engl J Med 2024; DOI: 10.1056/NEJMoa2400712.

Secondary Source

Nature Medicine

Source Reference: Leleu X, et al “Isatuximab, lenalidomide, dexamethasone, and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial” Nat Med 2024; DOI: 10.1038/s41591-024-03050-2.

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