Dr Gay on Efficacy Findings From the IsKia Trial in Multiple Myeloma

Francesca Gay, MD, PhD, associate professor, Department of Molecular Biotechnology and Health Sciences, the University of Torino, hematologist, the Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, discusses the safety and efficacy findings derivedfrom the phase 3 IsKia trial (NCT04483739) in patients with newly diagnosed multiple myeloma.

The IsKia trial, findings from which were presented at the 2023 ASH Annual Meeting, revealed that the combination of isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd) significantly increased minimal residual disease (MRD) negativity rates at the 10-5 and 10-6 cutoffs post-consolidation compared with carfilzomib, lenalidomide, and dexamethasone (KRd) in newly diagnosed patients. At a median follow-up of 21 months, MRD negativity rates at the 10-5 cutoff post-consolidation were 77% in the Isa-KRd arm (n = 151) vs 67% in the KRd arm (n = 151; OR, 1.67; 

 = .049). At the 10-6 cutoff, the MRD negativity rates were 67% and 48%, respectively (OR, 2.29; 

As such the trial’s primary end point, MRD negativity by next-generation sequencing after autologous stem cell transplant consolidation, was significantly higher with Isa-KRd vs KRd. Adverse effects (AEs), primarily hematological, were well managed in both arms. Subgroup analyses demonstrated consistent MRD negativity benefits with Isa-KRd vs KRd across risk groups.

Gay states that in the trial, Isa-KRD elicited a significantly higher rate of MRD negativity compared with KRd. This difference was evident at both the 10-5 and the 10-6 cutoffs, indicating a deep level of MRD negativity with Isa-KRd, she explains. Gay goes on to say that a key secondary end point of the study was the rate of MRD negativity after induction, which again favored Isa-KRd over KRd. At the 10-5 cutoff, the MRD negativity rates post-induction were 45% vs 26% in the Isa-KRd and KRd arms, respectively (OR, 2.34; 

 < .001), and at the 10-6 cutoff, these rates were 27% vs 14%, respectively (OR, 2.36; 

 = .004). MRD negativity rates improved over time after transplant and consolidation, Gay continues.

Approximately 40% of patients in the Isa-KRd arm and 30% of those in the KRd arm experienced grade 3/4 hematologic AEs, primarily neutropenia (36% vs 22%, respectively), she states. However, the infection rates were comparable between the 2 arms, Gay explains. Notably, there were no grade 3/4 neuropathy events, and the rate of cardiovascular toxicity was low, she concludes.

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Francesca Gay, MD, PhD, discusses the safety and efficacy findings derived from the phase 3 IsKia trial in patients with newly diagnosed multiple myeloma.

Francesca Gay, MD, PhD, presents results from the phase III randomized IsKia trial investigating isatuximab-carfilzomib-lenalidomide-dexamethasone in MM.

Results of the Phase III Randomized IsKia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone as Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients

The current standard treatment for transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of quadruplet induction with proteasome inhibitors, immunomodulatory agents, dexamethasone and anti-CD38 monoclonal antibody followed by high-dose melphalan and autologous stem-cell transplant (MEL200-ASCT), with subsequent consolidation.

The phase III IsKia trial assessed efficacy and safety of isatuximab-carfilzomib-lenalidomide-dexamethasone (IsaKRd) as pre-ASCT induction and post-ASCT consolidation vs KRd.

TE NDMM pts aged <70 years were enrolled and randomized.

IsaKRd pts received 4 28-day cycles of Isa: 10 mg/kg IV days 1, 8, 15, 22 cycle 1, followed by 10 mg/kg days 1, 15 cycles 2–4; K: 20 mg/m2 IV day 1 cycle 1, followed by 56 mg/m2 IV days 8, 15 cycle 1 and days 1, 8, 15 cycles 2–4; R: 25 mg PO daily days 1–21; d: 40 mg PO days 1, 8, 15, 22; MEL200-ASCT and 4 consolidation cycles with IsaKRd at the same schedule.

KRd pts received 4 KRd induction cycles; MEL200-ASCT and 4 KRd consolidation cycles (K, R and d at the same schedule as in the IsaKRd arm).

The primary endpoint was the rate of minimal residual disease (MRD) negativity by next-generation sequencing (NGS; 10-5) after consolidation in the intention-to-treat (ITT) population. MRD was tested in all pts who achieved at least a very good partial response (≥VGPR).

Key secondary endpoints were the rate of NGS MRD negativity (10-5) after induction and PFS. MRD rates were evaluated in an ITT analysis (pts with missing MRD data or who achieved ≤PR were considered as MRD positive).

The data cut-off for the analysis was May 22, 2023.

302 pts were enrolled and randomized (151 in both the IsaKRd and KRd arms). Pt characteristics were well balanced between the two arms: median age was 61 vs 60 years, respectively; 18% vs 19% of pts had high-risk (HiR) cytogenetic abnormalities (CA) [del(17p) and/or t(4;14) and/or t(14;16)]; 9% vs 8% had ≥2 HiR CA [double hit; including del(17p), t(4;14), t(14;16) and gain/amp(1q)].

In ITT analysis, the rates of MRD negativity at the 10-5 cut-off after consolidation (primary endpoint) were 77% vs 67% (OR 1.67; p=0.049) with IsaKRd vs KRd

The respective rates of MRD negativity at the 10-6 cut-off were 67% vs 48% (OR 2.29; p<0.001); consistent MRD results were detected by next-generation flow. ≥VGPR after consolidation was 94% in both arms; ≥CR 74% vs 72% and sCR 64% vs 67% in the IsaKRd vs KRd arms.

The MRD negativity advantage, both at 10-5 and 10-6, was retained in all subgroups analyzed, with similar benefit in pts with standard-risk (SR) and HiR features. In particular, the 10-5 MRD negativity rates with IsaKRd were 76% in HiR and 77% in double-hit pts, comparable to the one in SR pts (79%).

In the KRd arm, the 10-5 MRD negativity rates were 58% in HiR and 53% in double-hit pts, inferior to the one in SR pts (70%). The 10-6 MRD negativity rates with IsaKRd were 72% in HiR, 77% in double-hit pts and 67% in SR pts. The MRD negativity rate after induction (first key secondary endpoint) was also significantly higher with IsaKRd vs KRd (10-5: 45% vs 26%, OR 2.34, p<0.001; 10-6: 27% vs 14%, OR 2.36, p=0.004), with a consistent benefit in all subgroups.

After induction, the MRD negativity rates in HiR and double-hit pts treated with IsaKRd were: 10-5, HiR 60%, double-hit 54%; 10-6, HiR 40%, double-hit 31%. The MRD negativity rates after ASCT were also significantly better with IsaKRd vs KRd (10-5: 64% vs 49%, OR 1.93, p=0.006; 10-6: 52% vs 27%, OR 3.01, p<0.001), with a consistent advantage in all subgroups.

At the current follow-up (median, 20 months, IQR 18–23), there was no difference in PFS (95% at 1 year in both arms).

55% of pts had ≥1 hematologic adverse events (AEs) with IsaKRd vs 43% with KRd; main grade 3–4 hematologic AEs in IsaKRd vs KRd were neutropenia (37% vs 22%) and thrombocytopenia (15% vs 17%). 41% of pts had ≥1 non-hematologic AEs with IsaKRd vs 37% with KRd, including infections (16% vs 12%), gastrointestinal (7% vs 5%), vascular (2% vs 7%) and cardiac events (1% vs 4%).

Discontinuation for toxicity was 6% in IsaKRd vs 5% in KRd arms; treatment-related deaths were 4 with IsaKRd (2 COVID, 1 pneumonia, 1 pulmonary embolism) and 1 with KRd (septic shock).

In TE NDMM pts, the addition of isatuximab to KRd induction and consolidation significantly increased MRD negativity rates in every treatment phase as compared to KRd, with no new safety concerns. This benefit was retained in HiR pts.

Gay F, Roeloffzen W, Dimopoulos M et al. Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients. Presented at: 65th ASH Annual Meeting and Exposition, December 9-12, 2023. San Diego, California.

Francesca Gay, MD, PhD, presents results from the phase III randomized IsKia trial investigating isatuximab-carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in patients with newly diagnosed multiple myeloma.

Francesca Gay, MD, PhD, hematologist, Myeloma Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, discusses the updated efficacy data from the FORTE trial of patients with newly-diagnosed multiple myeloma.

In the study of 474 patients, 315 were treated with carfilzomib (Kyprolis), lenalidomide (Revlimid) and dexamethasone (KRd), and 159 were treated with carfilzomib, cyclophosphamide and dexamethasone (KCd). The rate of partial response (PR) after induction was very high in both arms, Gay says, with a 97% PR in patients treated with KRd, and a 91% PR in patients treated with KCd. However, the depth of response was higher in patients treated with KRd who received a very good PR or a stringent complete response.

A subset of patients were also evaluated for minimum residual disease (MRD) negativity. The rate of MRD negativity for patients treated with KRd was 56%, and for patients treated with KCd, MRD negativity was 29% (

= 0.008). Additionally, treatment in both arms was well tolerated.

Francesca Gay, MD, PhD

Articles

Dr Gay on Efficacy Findings From the IsKia Trial in Multiple Myeloma

Results of the Phase III Randomized IsKia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone as Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients

Dr. Gay Discusses the Efficacy Data from the FORTE Trial in Myeloma