Page 231 - Haematologica Vol. 109 - July 2024

ARTICLE - ICARIA-MM final overall survival analysis P.G. Richardson et al.
Figure 4. Exploratory analysis of response rate on first subsequent therapy,* intention-to-treat population. *Median washout period between therapies was 13 (range, 2-100) days for the isatuximab group and 22 (range, 1-822) days for the control group. Isa-Pd: isatuximab-pomalidomide-dexamethasone; ORR: overall response rate; Pd: pomalidomide-dexamethasone; VGPR: very good partial response or better.
data not shown), whereas all others were reported in the first three infusions. Grade 3/4 IR were reported in four (3%) of 152 patients. Hematologic laboratory abnormalities are shown in Online Supplementary Table S8. SPM occurred in ten (7%) of 152 patients in the Isa-Pd group and three (2%) of 149 in the Pd group (Online Supplementary Appen- dix page 21). Of these, three (Isa-Pd) occurred during the post-treatment period.
Treatment-emergent serious AE (SAE) occurred in 112 (74%) of 152 patients in the Isa-Pd group and 91 (61%) of 149 in the Pd group (Online Supplementary Table S9). Pneumonia was the most frequent SAE (all grades, both groups), re- ported in 35 (23%) of 152 patients in the Isa-Pd group and 31 (21%) of 149 in the Pd group. TEAE with a fatal outcome were reported in 23 (15%) of 152 patients in the Isa-Pd group and 19 (13%) of 149 in the Pd group. There were two (1%) treatment-related deaths in the Isa-Pd group (sepsis, 1; cerebellar infarction, 1) and two (1%) in the Pd group (pneumonia, 1; urinary tract infection, 1; data not shown). Overall, 108 (71%) patients in the Isa-Pd group and 113 (76%) in the Pd group died during the on- or post-treatment period due to disease progression (Isa-Pd: 76 [50%]; Pd: 81 [54%]), AE (7 [5%] vs. 8 [5%]), or other causes (25 [16%] vs. 24 [16%]; data not shown).
Dose reductions for pomalidomide and dexamethasone due to TEAE were more frequent in the Isa-Pd arm versus the Pd arm (pomalidomide reductions in 115/152 [76%] patients vs. 70/149 [47%] patients; dexamethasone reductions in 104 [68%] patients vs. 76 [51%] patients) and were primarily due to infections and neutropenia (data not shown). Definitive
treatment discontinuation due to TEAE was infrequent and occurred at similar rates in both treatment arms (19/152 [13%] patients in the Isa-Pd group vs. 22/149 [15%] patients in the Pd group; Online Supplementary Table S10).
Discussion
This final OS analysis of ICARIA-MM showed a clinically meaningful benefit with a 6.9-month improvement in me- dian OS with the addition of isatuximab to Pd (HR=0.78; log-rank 1-sided P=0.0319). Because the 1-sided P value for statistical significance was set to 0.02 due to α level spent at previous interim analyses, the current analysis did not cross the level of significance; however, early separation was observed in the OS curves between arms. The more frequent use of subsequent daratumumab in the control group (59.7% vs. 22.5% [isatuximab group]) may have led to a diminished treatment effect between the two arms after daratumumab use and affected the power to detect statis- tically significant OS in the ITT analysis, given the planned number of events and sample size, which was supported by sensitivity analyses to estimate the OS treatment effect in the absence of daratumumab therapy using the RPSFT model that demonstrated a better estimate versus the ITT estimate, with overall similar results (HR=0.706, 95% CI: 0.538-0.926) in favor of the Isa-Pd arm (described in the Online Supplementary Appendix, page 17).
The RPSFT analysis estimated a counterfactual factor and indicated there was a gain in survival time of the patients
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