Isatuximab Quadruplet Therapy Appears Well Tolerated in Multiple Myeloma

CancerNetwork® spoke with Thomas G. Martin, MD, a clinical professor of Medicine at the Adult Leukemia and Bone Marrow Transplantation Program and associate director of the Myeloma Program at University of California San Francisco (UCSF); and co-leader of the Cancer Immunology & Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center, about how isatuximab-irfc (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Isa-VRd) may be implemented into clinical practice for patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM).

Martin began by explaining that the addition of isatuximab to VRd triplet therapy did not significantly increase toxicities in patients with NDMM. Additionally, he stated that the increased anti-myeloma effect observed with the isatuximab quadruplet therapy makes it easy for implementation into clinical practice. Martin emphasized high tolerability among most patient subgroups apart from those with severe frailty, for whom he suggested starting with a doublet or triplet therapy before working up to quadruplet therapy.

Safety data from the phase 3 IMROZ trial (NCT03319667) presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the New England Journal of Medicine showed that any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.6% of patients receiving quadruplet therapy and 98.3% of patients undergoing triplet therapy without isatuximab (VRd).^1,2 Grade 3 TEAE rates were 91.6% and 84.0% in each respective arm, with grade 5 and serious TEAEs occurring in 11.0% and 70.7% of the isatuximab arm and 5.5% and 67.4% of the comparator arm, respectively.

Common any-grade AEs in the quadruplet and triplet arms included neutropenia (87.5% vs 80.1%); infections (91.3% vs 96.7%), including pneumonia (30.0% vs 19.3%) and upper respiratory infections (34.2% vs 33.7%); diarrhea (54.8% vs 48.6%); and peripheral sensory neuropathy (54.4% vs 60.8%).

Based on data from the phase 3 IMROZ trial, the FDA approved Isa-VRd for the treatment of patients with transplant-ineligible NDMM in September 2024.³

Transcript:

These data stand out and speak for themselves, especially in the safety component of the data. The addition of isatuximab to VRd does not add a significant amount of toxicity, which is great. That means that adding in this CD38 antibody to what many people use as their induction regimen for transplant–ineligible [population], VRd, is easy, in my mind. It is very well tolerated. It is not going to enhance significant cytopenias or other [adverse] effects that need to be mitigated. [It may] provide a more beneficial anti-myeloma effect.

People will see the safety data as well as the response data and say there is no reason why I should not give this particular patient a quadruplet over a triplet. We just had [the 21st Annual International Myeloma Society Meeting and Exposition] in Brazil, and there was much discussion of who can tolerate a triplet [vs] a quadruplet. Many myeloma physicians like myself [are] supporting the fact that these quadruplet regimens are so well tolerated that, essentially, there are few frail patients that we would start with perhaps a doublet or a triplet and try to get to the quadruplet. Most patients––and this involved patients up to the age of 80––certainly can tolerate this. In my personal practice, I actually use it in patients who are over the age over the age of 80, especially if they are in good shape.

References

1. Facon T, Dimopoulos MA, Leleu XP, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol. 2024;42(suppl 16):7500. doi:10.1200/JCO.2024.42.16_suppl.7500.
2. Facon T, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. Published online June 3, 2024. doi:10.1056/NEJMoa2400712
3. FDA approves istauximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. News release. September 20, 2024. Accessed September 20, 2024. https://shorturl.at/B8d3c