Adding Isatuximab to Carfilzomib-Based Combo for Those Newly Diagnosed With Multiple Myeloma Boosts MRD Negativity Rates

Patients who were newly diagnosed with multiple myeloma and eligible for transplant achieved greater rates of minimal residual disease (MRD) negativity when isatuximab (Sarclisa) was added to a regimen of carfilzomib (Krypolis), lenalidomide (Revlimid), and dexamethasone (KRd), according to trial results presented Sunday.

The findings from the phase 3 IsKia trial, which compared MRD rates in patients treated with isatuximab and KRd and those treated with KRd alone, were unveiled during the plenary session of the 65th American Society of Hematology Annual Meeting and Exposition, taking place in San Diego, California.

Francesca Gay, MD, PhD, University of Torino

Francesca Gay, MD, PhD, a hematologist and associate professor at the University of Torino, Italy, explained that current standard of care for patients with multiple myeloma who are eligible for a bone marrow transplant consists of induction with proteasome inhibitors, immunomodulatory agents, dexamethasone and an anti-CD38 monoclonal antibody, followed by high-dose melphalan and autologous stem-cell transplant (ASCT). IsKia was designed to use MRD to assess the efficacy and safety of isatuximab plus KRd as a pre-transplant induction and a post-plant consolidation regimen, compared with KRd.

Use of isatuximab with KRd in this patient group is investigational, Sanofi officials, the makers of isatuximab, said in a statement.

MRD as a Surrogate Endpoint

MRD negativity is defined as the absence of myeloma cells in the bone marrow following treatment, as measured by a validated diagnostic test that must have a sensitivity of at least 1 in 100,000 cells. The IsKia trial measured MRD negativity with a sensitivity of 10-5, which means no cancer cells were detected within 100,000 bone marrow cells, and also 10-6, which means no cancer cells were detected within 1,000,000 bone marrow cells.

FDA does not currently accept MRD as a surrogate endpoint to compare drug combinations in multiple myeloma, but as plenary commenter Peter Voorhees, MD, of Atrium Health Levine Cancer Institute explained, advances in the field and the use of 4 different classes of agents to treat relapsed disease call for one. “Increasingly, it’s become difficult to discern overall survival differences,” he said.

Voorhees was the lead author for recent final results of the GRIFFIN trial involving the monoclonal daratumumab, lenalidomide, bortezomib, and dexamethasone in multiple myeloma. He commented, “How do you improve upon on a 4-year progression-free survival of 87%?” Then, he posited a hypothetical phase 3 study would require enrollment of more than 1700 patients, take more than 4.5 years to accrue patients, and last more than 9 years to determine PFS.

“Clearly, we need a surrogate endpoint for longitudinal outcomes,” he said.

Study Design and Methods

To be eligible for IsKia, patients with newly diagnosed multiple myeloma had to be younger than 70 years of age. Gay explained that patients in the trial went through 4 phases of treatment: induction, ASCT, consolidation, and light consolidation; MRD was measured at the end of each phase. Patients in both arms received the same dosing schedules of KRd in each cycle, but patients in the isatuximab arm were treated with the monoclonal antobody intravenously on days 1, 8, 15, and 22 of the first cycle; followed by days 1 and 15 on cycles 2-4.

The primary end point was the rate of MRD negativity as measured by next-generation sequencing (10-5) after consolidation in the intent-to-treat (ITT) population. MRD was tested in all patients who achieved at least a very good partial response. Key secondary end points are rates of MRD negative (10-5) after induction and PFS.

Results

The trial enrolled 302 patients who were randomized 1:1 and well-balanced between the 2 arms. Of note, median age was 61 for the isatuximab-KRd arm and 60 for the KRd-only arm; 18% and 19% of patients high-risk clinical features, respectively; these included 17p deletion, t(4;14), t(4;16), and gain/amp(1q).

Gay explained during the session that MRD negativity levels increased after each phase of treatment. Results of the ITT analysis showed:

• For the primary end point, rates of MRD negativity at the 10-5 cutoff following consolidation were 77% for the isatuximab-KRd arm and 67% for the KRd-only arm (OR 1.67, P = .049). Rates of MRD negativity at the 10-6 cutoff were 67% vs 48%, respectively (OR 2.29, P < .001).
• The MRD negativity advantage at both cutoff levels was retained across subgroups, with similar benefits seen in patients with standard risk and high-risk patients.
• The MRD negativity rate after induction, the first secondary end point, was also significantly greater in the isatixumab-KRd group than it was in KRd patients. At 10-5, the comparison was 45% vs 26%, for OR 2.34, P < .001. At 10-6 it was 27% vs 14%, OR 2.36, P = .004).
• MRD rates after transplant were significantly better for the isatuximab group: at 10-5, they were 64% vs 49%, OR 1.93, P = .006. At 10-6, they were 52% vs 27%, OR 3.01, P < .001. Investigators reported advantages were consisted across subgroups.
• At the current follow-up median of 20 months, there is not yet any difference in PFS. Gay said the data are not mature and will be reported at a later date.

Among adverse events (AEs), 55% of patients in the isatuximab arm reported 1 hematological event, compared with 43% of patients in the KRd-only arm. The major grade 3-4 AEs in both arms were neutropenia (37% vs 22%, respectively), and thrombocytopenia (15% vs 17%). Non-hematological AEs were seen in 41% of the isatuximab patients vs 37% of the KRd-only patients; infections and gastrointestinal events were slightly higher in the isatuximab group but cardiac and vascular events were higher in the KRd-only group.

Four deaths were reported in the isatuximab group: 2 from COVID-19, 1 from pneumonia, and 1 pulmonary embolism; 1 death from septic shock occurred in the KRd-only group.

In her concluding remarks, Gay noted that the combination with isatuximab produced particularly good MRD negativity rates among patients with high-risk clinical features, relative to the KRd-only group.

Overall, she said, the increase in MRD negativity “was evident already after induction, and the rate of response progressively increased with treatment. The advantage for the isatuximab [group] we're seeing in our subgroups of patients includes the high risk group,” she said. “Treatment was tolerable with a toxicity profile that was similar to that in previous records.”

Use of MRD, she said, “may be more informative,” than other potential surrogate endpoints in multiple myeloma.

Peter C. Abramson, global development head of oncology for Sanofi, said in a statement, “The statistically significant rates of MRD negativity observed with [isatuximab] combination therapy further support our belief in [isatuximab] as a potential best-in-class therapy. Effective front-line treatment is critical for newly diagnosed patients, because achieving undetectable levels of disease early in the treatment journey may lead to better long-term outcomes.”

Reference

Gay F, Roeoffzen W, Dimopoulous MA, et al. Results of the phase III randomized IsKia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone. Presented at: 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California; Paper No. 0004. https://doi.org/10.1182/blood-2023-177546