A New Era in Multiple Myeloma Treatment: Isatuximab with VRd Improves Outcomes in Newly Diagnosed Patients

Multiple myeloma (MM) is a type of blood cancer originating in the plasma cells of the bone marrow, leading to an overproduction of abnormal plasma cells. This accumulation disrupts normal blood cell production and results in a range of complications, such as bone pain, anemia, kidney issues, and increased infection risk. Historically, treatment options for MM have evolved from chemotherapy to more advanced targeted therapies, proteasome inhibitors, immunomodulatory drugs, and now, monoclonal antibodies. Despite these advancements, multiple myeloma remains incurable yet treatable with durable remissions long term measured in years. This can particularly challenging in older adults who are ineligible for intensive treatments like stem cell transplants. These results were recently published in NEJM October 2024.

The Role of CD38 in Myeloma and the Mechanism of Action of Isatuximab

The recent addition of isatuximab, a CD38-targeting monoclonal antibody, offers a promising option in the treatment of multiple myeloma, especially for patients who cannot undergo transplant. CD38 is a cell surface protein abundantly expressed on myeloma cells and is involved in cell adhesion, signal transduction, and the suppression of immune responses. Targeting CD38 disrupts these pathways, promoting immune-mediated destruction of myeloma cells.

Isatuximab, an IgG1 monoclonal antibody, binds specifically to a unique CD38 epitope, inducing cell death through several mechanisms:

1. Antibody-Dependent Cellular Cytotoxicity (ADCC): Isatuximab binds to CD38 on myeloma cells, attracting immune cells (like NK cells) that release cytotoxic compounds, leading to the direct killing of cancer cells.
2. Antibody-Dependent Cellular Phagocytosis (ADCP): Isatuximab also engages macrophages, which engulf and digest the tagged cancer cells.
3. Complement-Dependent Cytotoxicity (CDC): The drug activates the complement system, a part of the immune response, creating a cascade that leads to myeloma cell lysis.
4. Direct Apoptotic Signaling: By binding CD38, isatuximab also directly signals the cancer cells to undergo programmed cell death (apoptosis).

These mechanisms of action enhance the immune system’s ability to recognize and destroy myeloma cells, making isatuximab a valuable addition to existing myeloma therapies.

The IMROZ Trial: Assessing Isatuximab with VRd in Newly Diagnosed Multiple Myeloma

The IMROZ trial aimed to investigate whether adding isatuximab to the standard VRd regimen (bortezomib, lenalidomide, and dexamethasone) would improve outcomes in newly diagnosed multiple myeloma patients who were ineligible for transplantation. Here’s a breakdown of the study design and findings.

Study Design

• Type: Phase 3, randomized, open-label trial.
• Participants: 446 patients, aged 18-80, with newly diagnosed, symptomatic multiple myeloma who could not undergo transplant due to age or other health conditions.
• Randomization: Patients were randomized in a 3:2 ratio to receive either isatuximab-VRd or VRd alone.
• Endpoints:
  • Primary Endpoint: Progression-free survival (PFS).
  • Secondary Endpoints: Complete response (CR) rate, minimal residual disease (MRD)-negative status, overall survival, and quality of life.

Results: Improved Progression-Free Survival and Depth of Response

1. Progression-Free Survival (PFS):
   • Outcome: At a median follow-up of 59.7 months, the isatuximab-VRd group achieved a significant improvement in PFS.
   • Statistics: The 5-year PFS rate was 63.2% for isatuximab-VRd, compared to 45.2% for VRd alone, marking a 40% reduction in risk of progression or death (HR: 0.60; P<0.001).
2. Complete Response and MRD-Negativity:
   • Depth of Response: The isatuximab-VRd group had a higher percentage of patients achieving complete response or better, at 74.7%, compared to 64.1% in the VRd group alone.
   • MRD-Negative Status: More patients in the isatuximab-VRd group reached MRD-negative status (55.5% vs. 40.9% in the VRd group). MRD-negativity is a key indicator of deep response, associated with longer PFS and potentially prolonged survival.
3. Sustained MRD-Negative Status:
   • A remarkable finding was the high rate of sustained MRD negativity, with 46.8% of patients in the isatuximab-VRd group maintaining MRD negativity for at least 12 months, compared to 24.3% in the VRd group. This long-term MRD negativity strongly correlates with durable disease control.
4. Overall Survival (OS):
   • Although OS data were not yet mature at this interim analysis, early trends indicated a favorable outcome for the isatuximab-VRd group, showing a lower incidence of death due to disease progression (4.9% vs. 12.2% in the VRd group).

Safety Profile and Side Effects

Isatuximab-VRd showed an acceptable safety profile, consistent with previous studies, with no new safety signals observed. Adverse events were similar between the two groups, though some differences were noted:

• Infections: Higher rates of severe infections (grade 3 or higher) were observed in the isatuximab-VRd group (44.9%) compared to VRd alone (38.1%). COVID-19–related infections accounted for some of this difference.
• Infusion Reactions: Infusion-related reactions, generally mild and manageable, occurred more frequently in the isatuximab-VRd group.
• Hematologic Toxicities: Grade 3 or higher neutropenia was more common in the isatuximab-VRd group (54.4% vs. 37.0%).

These side effects were mostly manageable, with recommended prophylactic measures (e.g., antibiotics) effectively reducing infection risk.

Implications for Clinical Practice

The IMROZ trial results support the use of isatuximab-VRd as a new standard for transplant-ineligible, newly diagnosed multiple myeloma patients. The addition of isatuximab offers significant benefits in progression-free survival and depth of response, particularly in achieving sustained MRD negativity, which is predictive of longer-term disease control.

For clinicians, this combination provides a potent treatment option that can deliver deep, lasting responses without markedly increasing toxicity. Importantly, it offers a valuable alternative for older patients who may be unable to tolerate more intensive therapies.

The IMROZ trial marks a step forward in the treatment of multiple myeloma, with isatuximab showing promising results as an addition to the VRd regimen. By enhancing progression-free survival and achieving high rates of MRD negativity, isatuximab-VRd holds the potential to improve quality of life and overall outcomes for transplant-ineligible multiple myeloma patients. As this and other CD38-targeting therapies continue to evolve, the future looks increasingly hopeful for patients battling this challenging disease.

About the author

Dr. Daniel Landau is a distinguished board-certified hematologist/oncologist renowned for his exceptional contributions in the field. With an illustrious career spanning across esteemed institutions like the Orlando Health Cancer Institute and the Medical University of South Carolina, Dr. Landau’s expertise shines in both genitourinary oncology and hematology. .