Quadruplet Therapy With Isatuximab Improves MRD Negativity in Newly Diagnosed Multiple Myeloma

Emerging data from the randomized phase 3 IsKia trial (NCT04483739) reveal that adding isatuximab (Sarclisa; Sanofi) to the standard KRd therapy (carfilzomib [Kyprolis; Onyx Pharmaceuticals, Inc], lenalidomide [Revlimid; Celgene Corporation], and dexamethasone) had a significant improvement in measurable residual disease (MRD) negativity in patients with newly diagnosed multiple myeloma (NDMM). Patients treated with the quadruplet therapy achieved more durable responses than those who received standard therapy alone. These findings suggest that adding a CD38-targeting antibody can potentially further improve outcomes in transplant-eligible patients.¹

MM is a rare and incurable form of blood cancer that originates in bone marrow and is defined by recurrent relapse in spite of treatment, progressively decreasing quality of life.³ In patients eligible for transplant, the standard treatment is KRd, which can be administered orally or intravenously. Each agent in this triplet combination plays a critical role in the selective targeting of myeloma cells and in initiating apoptosis (cell death).

Carfilzomib disrupts the protein disposal system in cancer cells; lenalidomide reinforces the immune system; and dexamethasone reduces inflammation in the bone marrow and supports cancer cell death. Researchers are investigating the addition of isatuximab (a monoclonal antibody targeting CD38 on myeloma cells) to KRd and have found that the combination yields higher MRD negativity rates than KRd monotherapy. This can aid in positive advancement for patients with Multiple Myeloma who are transplant eligible.

A total of 302 patients were randomly assigned in the phase 3 EMN24 IsKia trial (NCT04483739) to receive either the quadruplet therapy (Isa-KRd) or KRd monotherapy as induction and posttransplant consolidation therapy. Patients receiving the quadruplet therapy were more likely to have no detectable cancer cells in their bone marrow using sensitive MRD testing. The study data revealed that 77% of patients on the quadruplet therapy reached this level of response, compared with 67% on KRd alone.¹

The adverse effects (AEs) reported in the Isa-KRd arm were deemed manageable overall, with the most significant AE being a low white blood cell count. These findings suggest that adding isatuximab improves treatment response without substantially increasing overall toxicity.

These data are especially relevant for pharmacists as MM treatment continues to evolve with the growing use of combination and antibody-based therapies. Pharmacists should be considerate of AEs associated with this combination therapy. It is crucial to monitor for infusion reactions, hematologic toxicities (such as neutropenia), and any risk of infection.

Pharmacists are responsible for ensuring that proper premedication procedures are followed, verifying dosing schedules, monitoring kidney function, and regularly reviewing a patient’s blood test to measure treatment response and reduce the risk of AEs.

With KRd-based therapies, including Isa-KRd, the combination of intravenous (carfilzomib and isatuximab, if included) and oral therapies (lenalidomide and dexamethasone) requires careful attention to oral medication adherence and infusion visit attendance. Counseling patients about treatment expectations and emphasizing the importance of adhering to dosing schedules can help reduce the risk of treatment interruptions.

Pharmacists should have a thorough understanding of the value of MRD negativity and its correlation with long-term outcomes to better inform treatment decisions. MRD negativity is highly associated with improved outcomes in MM.³ The current recommendations from the National Comprehensive Cancer Network emphasize combination therapy and individualized treatment approaches, further reinforcing the pharmacist’s role in optimizing therapy selection, monitoring safety, and improving patient outcomes in MM.⁴

REFERENCES

1. Gay F, Roeloffzen W, Dimopoulos MA, et al. Isatuximab, carfilzomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma: a randomized phase 3 trial. Nat Med. Published online April 6, 2026. doi:10.1038/s41591-026-04282-0

2. Caravita di Toritto T, Rago A. MRD in multiple myeloma: the clinical perspective. Front Oncol. 2026;15:1740112. doi:10.3389/fonc.2025.1740112

3. Munshi NC, Avet‑Loiseau H, Anderson KC, et al. A large meta‑analysis establishes the role of MRD negativity in long‑term survival outcomes in patients with multiple myeloma. Blood Adv. 2020;4(23):5988‑5999. doi:10.1182/bloodadvances.2020002827

4. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2026. Accessed April 13, 2026. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf