Isa-KRd Yields Significant MRD Negativity in High-Risk NDMM Cytogenetic Subgroups

MRD-negative remission was achieved in 74.8% of all patients with newly diagnosed multiple myeloma treated with isatuximab, carfilzomib, lenalidomide, and dexamethasone.

Isatuximab-irfc (Sarclisa) plus carfilzomib, lenalidomide, and dexamethasone (KRd) induced high rates of minimal residual disease (MRD) negativity across various cytogenetic subgroups of patients with high-risk newly diagnosed multiple myeloma, according to results from cytogenetic subgroup analyses of the phase 2 GMMG-CONCEPT trial (NCT03104842) presented at the 22nd Annual International Myeloma Society Meeting and Exposition.

As of the April 28, 2025, data cut-off date, in the intention-to-treat (ITT) population (n = 219), the rate of MRD negativity, defined as next-generation flow with a sensitivity of 10^-5, at the end of consolidation was 74.8%.

Notably, of the patients with 2 high-risk cytogenetic aberrations (HRCA) combinations, MRD was achieved in 54.2% of patients with 17p deletions and at least 3 copies of 1q21, in 46.7% of patients who had 17p deletions and t(4;14), and 37.5% of patients with 17p deletions and t(14;16). MRD negativity was also achieved in 70.6% of those with t(4;14) and at least 3 copies of 1q21, and in 80.0% of those with t(14;16) and at least 3 copies of 1q21.

In the patients with only 1 HRCA, MRD negativity was achieved in 77.1% of patients with 17p deletions, in 82.8% with t(4;14), in 73.3% with t(14;16), and in 78.9% with at least 3 copies of 1q21.

Additionally, patients who had 17p deletions demonstrated MRD-negative remission at later time points in the study, most commonly in the post-consolidation and maintenance phases; it was noted that this underlines the importance of intensification, consolidation, and continuous combination treatment.

A high proportion of patients with high-risk disease achieved MRD-negative remission while receiving isatuximab plus KRd induction therapy.

“The full GMMG-CONCEPT cohort represents the largest prospective trial cohort of purely [patients with high-risk newly diagnosed multiple myeloma], including [patients with ultra high-risk disease], reported so far,” said presenting study author Lisa B. Leypoldt, MD, an assistant physician in the Department of Internal Medicine at University Cancer Center Hamburg – Eppendorf in Hamburg, Germany, during the presentation. “These CONCEPT data underline the high potency of [isatuximab plus KRd] to induce high rates of MRD negativity and the importance of multi-agent maintenance to sustain MRD-negative remissions across different cytogenetic subgroups in [patients with high-risk newly diagnosed multiple myeloma].”

A total of 245 patients with high-risk newly diagnosed multiple myeloma were enrolled in the trial and split into 2 groups: arm A enrolled patients who were transplant-eligible and 70 years or younger (n = 219), and arm B enrolled patients who were transplant-ineligible or older than 70 years (n = 26).

High-risk multiple myeloma was defined as International Staging System stage II or III plus at least 1 aberration of 17p deletion, t(4;14), t(14;16), and/or at least 3 copies of 1q21.

Regarding HRCAs, 22.9% of patients only had 17p deletions, 14.7% only had t(4;14), 6.5% had only t(14;16), and 19.2% had at least 3 copies of 1q21. At least 2 HRCAs were noted in 35.6% of the transplant-eligible patient population and 26.9% of the transplant-ineligible patients.

Further, 10.6% of patients had 17p deletions and at least 3 copies of 1q21, 14.7% had t(4;14) and at least 3 copies of 1q21, 7.3% had 17p deletions and t(4;14), 3.3% had 17p deletions and t(14;16), 6.5% had t(14;16) and at least 3 copies of 1q21; and 0.4% had t(4;14) and t(14;16).

Treatment in arm A consisted of 6 cycles of isatuximab plus KRd, with stem cell mobilization after cycle 3, for induction therapy, followed by high-dose therapy and autologous stem cell transplantation, then isatuximab plus KRd for 4 cycles of consolidation therapy, and finally 26 cycles of isatuximab plus KRd maintenance. In arm B, patients received 8 cycles of isatuximab plus KRd for induction therapy, followed by 4 cycles of consolidation therapy, and finally 26 cycles of maintenance. Notably, arm A maintenance began approximately 15 to 18 months after inclusion, and arm B maintenance began 12 months after inclusion.

Isatuximab was administered at 10 mg/kg on days 1, 8, 15, and 22 in cycle 1, then days 1 and 15 from cycle 2 onward; carfilzomib was administered at 20 mg/m² on days 1 and 2 of cycle 1, then 36 mg/m² on days 8, 9, 15, and 16 of cycle 1 and days 1, 2, 8, 9, 15, and 16 from cycle 2 onwards; lenalidomide was administered at 25 mg on days 1 to 21 of all cycles; and dexamethasone was administered at 40 mg, or 20 mg in patients older than 75 years, on days 1, 8, 15, and 22 for all cycles.

From 2021 onwards, carfilzomib dosage was altered to be 56 mg/m² on days 1, 8, and 15, and 70 mg/m² on days 1 and 15 in maintenance.

The primary end point of the trial was MRD negativity after consolidation, defined as next-generation flow with a sensitivity of 10^-5. Secondary end points included progression-free survival, overall response rate, and overall survival.

“An unmet need still remains for patients with double-hit HRCA, including [17p deletions] whereas e.g., patients with at least 3 copies of 1q21 seem to be adequately addressed by this isatuximab-containing regimen,” concluded Leypoldt.

Disclosures: Dr. Leypoldt reported advisory roles for GSK, Janssen, and Pfizer; Honoraria for Adaptive, Amgen, AbbVie, Janssen, BMS/Celgene, Pfizer, GSK, Takeda, and AstraZeneca; research funding from AbbVie, GSK (both to the institution), and Amgen; and travel from Sanofi, Oncopeptides, and Johnson and Johnson.

References

Leypoldt LB, Ginde VR, Besemer B, et al. Insights from cytogenetic subgroup analyses in the GMMG-CONCEPT trial with Isa-KRd in high-risk newly diagnosed multiple myeloma. Presented at the 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-49.