In newly diagnosed, transplant-ineligible patients with multiple myeloma, treatment with the anti-CD38 monoclonal antibody isatuximab plus bortezomib, lenalidomide, and dexamethasone (VRd) led to a 40% reduction in the risk of disease progression or death and “deep and sustained responses,” almost doubling the achievement of sustained undetectable measurable residual disease (MRD) at 12 months, according to Thierry Facon, MD, Head, Haematology Division, and Professor of Hematology, Lille University Hospital, France.1
Thierry Facon, MD
Dr. Facon said the findings, which he reported at the 2024 ASCO Annual Meeting, “highlight an outstanding progression-free survival benefit.” IMROZ is the first global phase III study of this type of agent in combination with this standard-of-care regimen in this patient population.
Another study presented at the 2024 ASCO Annual Meeting, the phase III BENEFIT trial (IFM 2020-5), evaluated the benefit of adding weekly bortezomib to isatuximab, lenalidomide, and dexamethasone. It showed a significant improvement in undetectable MRD status for isatuximab plus VRd vs isatuximab plus lenalidomide and dexamethasone.2
“We showed that isatuximab plus VRd led to a statistically significant improvement in MRD negativity at 12 and 18 months, deep responses (including MRD at 10–6), and a statistically significant improvement in the MRD-negative complete response rate,” said Xavier P. Leleu, MD, PhD, Professor and Head, Department of Haematology, Hôpital La Mileterie, Centre Hospitalier Universitaire, Poitiers, France.3 The results of IMROZ were simultaneously published in The New England Journal of Medicine,3 and the results of BENEFIT were published in Nature Medicine.4
Xavier P. Leleu, MD, PhD
Multiple Positive Outcomes in IMROZ
As Dr. Facon pointed out, the first line of treatment is important for patients with newly diagnosed multiple myeloma, as many will not have a chance for subsequent therapy. Isatuximab is approved in combination with pomalidomide and dexamethasone after two or more prior therapies that included lenalidomide and a proteasome inhibitor, as well as in combination with carfilzomib and dexamethasone after one to three prior lines.
The IMROZ study evaluated isatuximab plus VRd, vs VRd alone, in transplant-ineligible, newly diagnosed patients. It was a global, prospective, open-label trial conducted at 102 study sites in 21 countries with 446 patients (< age 80) with newly diagnosed myeloma not considered for transplant because of age or comorbidities. Patients were randomly assigned 3:2 to receive isatuximab plus VRd (n = 265) or VRd alone (n = 181). Isatuximab plus VRd was given as induction, with treatment continued with isatuximab plus lenalidomide and dexamethasone; the control arm received VRd induction, with continuation of lenalidomide and dexamethasone.
At a median follow-up of 59.7 months, median progression-free survival was not reached with isatuximab plus VRd and was 54.3 months with VRd alone (hazard ratio [HR] = 0.596; P = .0005). The 5-year progression-free survival rate was 63.2% vs 45.2%, respectively. “The progression-free survival benefit was consistent across most subgroups,” Dr. Facon reported.
At a median follow-up of 5 years, overall survival is still immature. However, “a favorable trend” was observed for the isatuximab-plus-VRd arm, with a 22.4% risk reduction, based on a 5-year survival rate of 72.3% vs 66.3%, respectively.
Dr. Facon further reported: “Isatuximab plus VRd resulted in deep responses vs VRd alone, with a statistically significant improvement in MRD negativity (10–5), complete responses, as well as higher rates of MRD negativity and almost double the rate of MRD negativity sustained for at least 12 months.”
Objective responses were seen in about 92% of both arms; they were complete responses or better in 74.7% given isatuximab plus VRd and in 64.1% given VRd alone and very good responses or better in 89.1% and 82.9%, respectively. Undetectable MRD at 10–5 was achieved by 58.1% and 43.4%, respectively, and complete responses with undetectable MRD at 10–6 were reported in 55.5% vs 40.9%. Undetectable MRD status was sustained for at least 12 months in 46.8% vs 24.3%.
Quality-of-life measures remained stable over time in both arms, with no negative impact from adding isatuximab. The safety profile was consistent with known profiles for the agents, and the numerical differences in treatment-emergent adverse events may be largely explained by longer exposure to isatuximab plus VRd, he said. There were eight grade 5 events related to COVID-19 in the group given isatuximab plus VRd vs two in the group given VRd alone.
“These results support isatuximab plus VRd as a potential new standard of care in patients not intended for transplant,” Dr. Facon said.
Key Findings From BENEFIT
Dr. Leleu reported the following key findings from the BENEFIT trial of isatuximab plus VRd vs isatuximab plus lenalidomide and dexamethasone, respectively:
- At 12 months, undetectable MRD rates of 51% vs 21% at 10–5 (odds ratio [OR] = 3.88; P < .0001) and 32% vs 13% at 10–6 (OR = 2.97; P = .0005);
- At 18 months, undetectable MRD rates of 53% vs 26% at 10–5 (OR = 3.16; P < .0001) and 36% and 17% at 10–6 (OR = 2.74; P = .0006);
- At 18 months, the undetectable-MRD complete response rate was 27% vs 12% at 10–6 (OR = 2.85; P = .002);
- The benefit of undetectable MRD with isatuximab plus VRd was consistent across most subgroups, with hazard ratios ranging from 1.82 to 3.52;
- Estimated 24-month progression-free survival rate was 85.2% vs 80.0%; estimated overall survival rate was 91% in each arm.
“The study provides evidence that a weekly bortezomib regimen with isatuximab plus VRd can be an effective and feasible option in newly diagnosed, transplant-ineligible myeloma,” Dr. Leleu commented.
Expert Point of View
In his discussion of both IMROZ and BENEFIT, C. Ola Landgren, MD, PhD, Professor of Medicine and Director of the Sylvester Myeloma Institute at the University of Miami Miller School of Medicine, shared these comments regarding transplant-ineligible patients up to age 80: IMROZ “establishes isatuximab plus VRd [bortezomib, lenalidomide, and dexamethasone] followed by isatuximab plus lenalidomide and dexamethasone as a new standard of care.” BENEFIT “further supports” this regimen as a new standard. However, he argued, the second-generation proteasome inhibitor carfilzomib might be a better addition to isatuximab and lenalidomide plus dexamethasone. Studies evaluating this combination are underway. “Quadruplet therapies deliver higher rates of MRD [measurable residual disease] negativity and longer progression-free survival, compared with triplet therapies, regardless of age and transplant eligibility, establishing them as a new standard of care in newly diagnosed multiple myeloma,” he added.
C. Ola Landgren, MD, PhD
Dr. Landgren noted that a subanalysis of the PERSEUS trial, also presented at the 2024 ASCO Annual Meeting, showed a high rate of undetectable MRD at 10–6 (47%) sustained after 12 months. The significant improvements seen in undetectable MRD status in these three trials, he added, “are well in line with the recent ODAC [Oncology Drugs Advisory Committee] ruling in favor of MRD as an early endpoint for accelerated approval in multiple myeloma.”
Dr. Landgren shared these closing thoughts: “Immunotherapy added to an existing backbone can improve outcomes independent of transplant status…. This raises an important question: Why are we still talking about transplant-eligible and transplant-ineligible patients in the modern era? Immunotherapy narrows the gap between younger, fit, transplant-eligible and older, less-fit, transplant-ineligible patients with newly diagnosed multiple myeloma…. We need to better personalize treatment approaches to limit over- and undertreatment.”
DISCLOSURE: Dr. Facon reported no conflicts of interest. Dr. Leleu has received honoraria from Sanofi, Janssen, Novartis, Pfizer, Takeda, GSK, BMS, AbbVie, and Roche. Dr. Landgren has received research funding from NCI/NIH, FDA, LLS, Rising Tide Foundation, MMRF, IMF, Paul and Rodger Riney Foundation, Tow Foundation, Myeloma Solutions Fund, Cannon Guzy Family Fund, Amgen, Celgene, Janssen, AbbVie, and Pfizer; honoraria from AbbVie, Adaptive, Amgen, Binding Site, BMS, Celgene, GSK, Janssen, Juno, and Pfizer; served as an advisor to AbbVie, Adaptive, Amgen, Binding Site, BMS, Celgene, GSK, Janssen, Juno, and Pfizer; and served on independent data monitoring committees for trials by Takeda, Merck, Janssen, and Novartis outside the presented work.
REFERENCES
1. Facon T, et al: 2024 ASCO Annual Meeting. Abstract 7500. Presented June 2, 2024.
2. Leleu X, et al: 2024 ASCO Annual Meeting. Abstract 7501. Presented June 2, 2024.
3. Facon T, et al: N Engl J Med. June 3, 2024 (early release online).
4. Leleu X, et al: Nat Med. June 3, 2024 (early release online).
