The landscape of multiple myeloma treatment is evolving with the emergence of monoclonal antibodies for newly-diagnosed patients, with DARZALEX maintaining a strong market position compared to its competitors. DARZALEX has become a standard of therapy in frontline clinical studies for multiple myeloma, exceeding expectations in both efficacy and safety, poised to dominate the market.

SARCLISA, a second CD38 antibody, has gained approval for multiple myeloma treatment and is rapidly gaining acceptance in key markets. However, DARZALEX holds a competitive advantage over SARCLISA of over four years. Both antibodies compete in quadruplet regimens for both transplant-eligible and ineligible patients, with ongoing comparisons in those ineligible for transplant based on recent studies involving CD38-RVd combinations.

IMROZ study sought to determine the efficacy of CD38 targeting immunotherapy using twice weekly in combination with VRD, where, Dara-Rd has also become a new standard of care. It was shown that in transplant-ineligible (Ti) newly diagnosed multiple myeloma (NDMM) patients, including in the context of the combination of bortezomib plus lenalidomide and dexamethasone, a weekly schedule demonstrated less peripheral neuropathy and has been adopted in clinical practice. To further enhance the safety profile of treatments for Ti patients, a fixed duration of dexamethasone was evaluated and proved beneficial in various studies.

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At a median follow-up of 5-year, Isa-VRd demonstrated a 40.4% reduction in the risk of progression or death compared to VRd alone (HR 0.596, 98.5% CI [0.406, 0.876]). Median progression-free survival was not reached with Isa-VRd versus 54.34 months with VRd. The 60-month PFS rate was 63.2% for Isa-VRd and 45.2% for VRd alone.

Patients treated with Isa-VRd also showed significant improvements in response rates. The complete response rate or better was 74.7% with Isa-VRd versus 64.1% with VRd alone (p = .008). Very good partial response or better was achieved in 89.1% of patients with Isa-VRd compared to 82.9% with VRd alone (overall response [OR] 1.729, 95% CI [0.994, 3.008]).

Since Oncologic Drugs Advisory Committee (ODAC) approval in April 2024, achieving minimal residual disease (MRD) negativity has become a critical endpoint in multiple myeloma. In the intent-to-treat population, the MRD-negative rate was 58.1% with Isa-VRd versus 43.6% with VRd alone. Among patients achieving a complete response, MRD negativity rates were 55.5% with Isa-VRd versus 40.9% with VRd alone. 

Additionally, Isa-VRd showed higher rates of sustained MRD negativity for 12 months or longer than VRd alone (46.8% vs 24.3%; OR 2.729, 95% CI [1.799, 4.141]).

As far as safety is concerned, Isa-VRd was well-tolerated. Grade 3 or worse TEAEs occurred in the majority of patients in the Isa-VRd (91.6%) and VRd (84.0%) arms. Numerical differences in TEAEs are largely explained by longer exposure to Isa-VRd than VRd.

Grade 5 TEAEs occurred in 11.0% of patients assigned to Isa-VRd and 5.5% of patients assigned to VRd, but the treatment period for Isa-VRd included 7 deaths from COVID-19 pneumonia and 1 death from COVID-19 pneumonia/multiorgan failure.

KOL insights

“It is important to be able to say to patients that you can add this antibody and gain a lot of efficacy and benefits with no negative QOL impact.” – MD, United States

“Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation.”- MD, United States

Conclusion 

IMROZ, the first global Phase III trial of an anti-CD38 monoclonal antibody alongside VRd in non-transplant eligible newly diagnosed multiple myeloma patients, demonstrated a significant decrease in progression risk, highlighting substantial progression-free survival benefits. Isa-VRd showed favorable tolerability, maintaining consistent safety profiles for each component. The enhanced effectiveness of Isa-VRd followed by Isa-Rd, alongside its reliable safety profile, presents a significant treatment advancement for managing initial disease stages, establishing Isa-VRd as a new standard of care for patients up to 80 years old with non-transplant eligible newly diagnosed multiple myeloma.

A possible new usage for isatuximab is being reviewed by the US Food and Drug Administration (FDA) in light of the IMROZ findings. On May 27, 2024, the US FDA accepted for Priority Review the supplemental Biologics License Application (sBLA) for the investigational use of isatuximab-VRd for treating patients with TI NDMM. Isatuximab, if authorized, would be the first anti-CD38 medication used in this patient population in combination with standard-of-care VRd. The FDA is expected to make a decision by September 27, 2024. The European Union (EU) is now reviewing a similar application.

SARCLISA is being evaluated in transplant-eligible newly diagnosed multiple myeloma. The drug is expected to face stiff competition from DARZALEX in both settings. In TI NDMM, DARZALEX can be added to VMP as a backbone therapy (D-VMP) or to Rd (DRd). For first-line, transplant-eligible myeloma patients, Janssen is also seeking FDA approval for DARZALEX -VRd combo.