At data cut-off (January 14, 2022), the median follow-up was 44 months; 49 (27.4%) patients in the Isa-Kd arm and 11 (8.9%) in the Kd arm were still on treatment (Fig. 1). The most frequent reason for discontinuation in both arms was progressive disease, although it was less frequent in Isa-Kd vs Kd (43.0% vs 52.0%). Twenty-two patients in each arm discontinued due to an AE (12.3% in Isa-Kd and 17.9% in Kd).
Patient demographic and baseline characteristics were balanced between treatment arms (Table 1). Median age was 65 years in Isa-Kd (range, 37–86) and 63 years in Kd (range, 33–90). ECOG performance status was 0 in 53.1% and 59.3% of patients in Isa-Kd and Kd, respectively. In either treatment arm, at baseline, 24–25% of patients had high-risk cytogenetic status (23.5% in Isa-Kd and 25.2% in Kd) and 42% had 1q21 + (by gain or amplification; 41.9% of patients in Isa-Kd and 42.3% in Kd). The number of prior treatment lines was comparable between study arms, with a median of 2 (range, 1–4) and with 44.1% vs 44.7% of patients with 1 prior treatment line in Isa-Kd vs Kd. A similar incidence of patients had received prior IMiD (76.0% in Isa-Kd and 81.3% in Kd) and/or prior PI therapy (92.7% and 85.4%, respectively). The incidence of lenalidomide-refractory patients was 31.8% in Isa-Kd and 34.1% in Kd.
Consistent with the interim analysis results , the PFS updated analysis, with median follow-up of 44 months, favored Isa-Kd with a HR of 0.58 (95.4% CI: 0.42–0.79), which corresponds to a 42% reduction in the risk of progression or death in the Isa-Kd vs Kd arm. Median PFS (mPFS) reached by Isa-Kd patients was 35.7 (95% CI: 25.8–44.0) months vs 19.2 (95% CI: 15.8–25.0) months in Kd (Fig. 2).
To evaluate the robustness of the primary analysis, PFS sensitivity analyses using different censoring rules, as per IRC and per investigator assessment, were also updated (Supplementary Table S1). All PFS sensitivity analyses showed consistent benefit with Isa-Kd vs Kd, with HRs ranging from 0.57 to 0.64. A further analysis using censoring rules requested and considered by the United States Food and Drug Administration (FDA) as the primary PFS analysis (censoring PFS events occurring >8 weeks from the last valid disease assessment), showed results consistent with the main PFS analysis, with a HR of 0.59 (95.4% CI: 0.42–0.83) and a mPFS of 41.7 months (95% CI: 27.1–not calculable [NC]) with Isa-Kd vs 20.8 months (95% CI: 16.2–28.2) with Kd (Supplementary Table S1, Supplementary Fig. S1).
As presented in Fig. 3, PFS subgroup analyses, by patient main baseline characteristics and prognostic factors, showed consistent PFS benefit with Isa-Kd vs Kd across all subgroups, including patients with poor prognosis: e.g., elderly patients, patients with renal function impairment, high-risk cytogenetics [del17p, t(4;14) t(14;16)], or 1q21+ status, as well as lenalidomide-refractory patients (PFS subgroup analyses by FDA censoring rules are shown in Supplementary Fig. S2).
Although the overall response rates were comparable between treatment arms (86.6% vs 83.7%), deeper responses were seen with Isa-Kd vs Kd in the ITT population: the sCR/CR rate was 44.1% with Isa-Kd vs 28.5% with Kd (odds ratio Isa-Kd vs Kd: 2.09, 95% CI: 1.26–3.48) (Fig. 4A), with additional CRs compared with the interim analysis, 8 in Isa-Kd and 1 in Kd. Half of these 8 additional CRs in the Isa-Kd arm were linked to the availability and use of the Hydrashift 2/4 Isa immunofixation assay (which could detect endogenous IgG M-protein without Isa interference), at time points prior to the interim analysis cut-off (07Feb22).
As shown in Fig. 4B, the addition of Isa to Kd improved the MRD negativity rate to 33.5% vs 15.4% with Kd (odds ratio 2.78, 95% CI: 1.55–4.99 for Isa-Kd vs Kd). The MRD negativity and CR rate with Isa-Kd was 26.3% vs 12.2% with Kd (odds ratio 2.57, 95% CI: 1.35–4.88 for Isa-Kd vs Kd). The MRD negativity rates were consistently higher with Isa-Kd vs Kd across subgroups of patients with poor prognostic characteristics, including older age, renal function impairment, higher ISS stage at study entry, 1q21+ status, more lines of prior therapy, and refractoriness to lenalidomide (Supplementary Fig. S3). Further, exploratory analysis of PFS by MRD status showed that the Kaplan-Meier curves of the MRD-negative patients were largely above those of the MRD-positive patients (Supplementary Fig. S4), with a HR for MRD-negative versus MRD-positive patients of 0.29 (95% CI: 0.17–0.48) in the Isa-Kd arm and 0.19 (95% CI: 0.08–0.47) in the Kd arm (Supplementary Table S2). The medians in MRD-negative patients were not reached in either study arm.
The addition of Isa to Kd also delayed time to the next treatment (TTNT) vs Kd with a HR of 0.55 (95% CI: 0.40–0.76); the median TTNT in the Isa-Kd arm was 44.9 months (95% CI: 31.6–NC) vs 25.0 months (95% CI: 17.9–31.3) in the Kd arm (Fig. 5A). Fewer patients initiated further anti-myeloma therapy in Isa-Kd than in Kd (44.1% vs 64.2%) and among them, 25.3% in Isa-Kd and 60.8% in Kd received anti-CD38 agents: 25.3% vs 54.4%, 1.3% vs 11.4%, and none vs 1.3% of patients in Isa-Kd vs Kd subsequently received daratumumab, Isa, and/or another anti-CD38 agent, respectively (Supplementary Table S3).
Despite the high percentage of patients in Kd who received anti-CD38 in further anti-myeloma therapy, benefit with Isa-Kd over Kd was maintained late through PFS2 with a HR of 0.68 (95% CI: 0.50–0.94) (Fig. 5B). PFS2 was defined as the time from randomization to disease progression on next line of treatment or death, whichever occurred first. Median PFS2 with Isa-Kd was 47.2 (95% CI: 38.1–NC) months vs 35.6 (95% CI: 24.1–40.5) months with Kd. Analysis of overall survival (OS) is planned for 2023, 3 years after the interim PFS analysis that showed significant improvement in PFS. Nonetheless, in the current updated analysis, descriptive OS showed a trend in favor of Isa-Kd vs Kd with HR of 0.78 (95% CI: 0.54–1.12) (Supplementary Table S4).
Duration of treatment was longer in the Isa-Kd arm with a median treatment duration of 94.0 (range, 1–215) weeks vs 61.9 (range, 1–208) weeks with Kd (Supplementary Table S5). The median relative dose intensity for Isa was 93.2% (range, 66.7–108.2%) and for carfilzomib it was similar between study arms, despite longer treatment in the Isa-Kd arm: 89.5% (range, 18.2–108.7%) vs 90.8% (range, 41.5–108.6%) in the Kd arm. The median relative dose intensity for dexamethasone was lower in Isa-Kd vs Kd, although it remained above 80% in both arms, at 82.6% (range, 19.3–101.1%) vs 88.1% (range, 23.1–101.6%), respectively. A total of 4405 treatment cycles were administered to Isa-Kd patients and 2181 to Kd patients (Supplementary Table S5).
The safety findings, summarized in Table 2, were consistent with previous findings of the interim analysis ; the addition of Isa to Kd did not increase the incidence of TEAEs with fatal outcome during study treatment (5.6% vs 4.9%) or of TEAEs leading to definitive discontinuation of all study treatment (12.4% vs 18.0%).
At interim analysis , there was no difference in the incidence of all-causality serious TEAEs, whereas a 10% difference was observed in this updated analysis between the Isa-Kd and Kd arms (70.1% vs 59.8%, respectively). However, this difference was related to the longer treatment exposure in Isa-Kd, since evaluation of the event rate per patient year showed a similar incidence of serious TEAEs in the 2 treatment arms (0.58 in Isa-Kd vs 0.62 in Kd) (Supplementary Table S6). Keeping in consideration duration of treatment exposure, the results also showed that grade ≥3 TEAEs remained more frequent in Isa-Kd vs Kd at the final analysis with an event rate per patient year of 1.08 in Isa-Kd vs 0.97 in Kd, although the difference between the 2 arms decreased (1.26 in Isa-Kd vs 1.05 Kd at the interim analysis). With 2 additional years of follow-up, the incidence of treatment-emergent fatal events remained similar between study arms (5.6% vs 4.9%) and the event rate per patient year remained identical to the one reported at interim analysis (0.03 vs 0.03), despite longer exposure in the Isa-Kd arm and the Covid-19 pandemic (Supplementary Table S6).
As listed in Table 3, the most common, non-hematologic TEAEs were infusion reactions (45.8% vs 3.3%) (all grades 1–2, except for a grade 3 reported as related to carfilzomib), diarrhea (39.5% vs 32.0%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27.0%), and fatigue (31.6% vs 20.5%), similar to those reported at interim analysis . Pneumonia occurred in 48 (27.1%) patients in Isa-Kd and 26 (21.3%) patients in Kd (grade ≥3 in 18.6% vs 12.3%). Grade ≥3 fatigue was reported in 5.6% of patients in the Isa-Kd arm and 0.8% in the Kd arm. The incidence of cardiac failure events remained similar in both study arms (8.5% vs 7.4%) . The incidence of second primary malignancies during all study periods (study treatment and post study treatment) was similar between the 2 arms (9.0% vs 7.4%). By type of cancer, the incidence of skin cancer was slightly higher in the Isa-Kd arm (6.2%) than in Kd (3.3%). None led to study treatment discontinuation.
Evaluation of hematologic laboratory abnormalities showed grade 3 anemia in 24.3% vs 21.3% of patients in the Isa-Kd vs Kd arm (with no grade 4 events), grade 3–4 neutropenia in 20.4% vs 7.4% (mainly grade 3, 18.1% vs 6.6%), and grade 3–4 thrombocytopenia in 30% vs 23.8% of patients, respectively (Supplementary Table S7; incidences of anemia, neutropenia, and thrombocytopenia reported as hematologic TEAEs are listed in Supplementary Table S8).