Final OS Analysis of ICARIA-MM Study Shows Continued Survival Benefit of Isatuximab Triplet in R/R Multiple Myeloma

Paul G. Richardson, MD

Isatuximab-irfc (Sarclisa) plus pomalidomide (Pomalyst) and low-dose dexamethasone (Isa-Pd) continues to show clinically meaningful benefit for patients with relapsed or refractory multiple myeloma (RRMM) demonstrating an improved overall survival (OS) over Pd alone, according to results of a final OS analysis of the ICARIA-MM study (NCT02990338).¹

The OS analysis of the randomized, multicenter, open-label, phase 3 study found that there was a 6.9-month improvement in median OS (HR, 0.77; 95% CI, 0.59-1.10; log rank P = .0319) for patients on Isa-Pd (n = 154) compared with Pd (n = 153).

At a median follow up of 35.3 months (interquartile range [IQR], 33.5-37.4) at data cut off, median OS was 24.6 months (95% CI, 20.3-31.3) in the isatuximab group vs 17.7 months (95% CI, 14.4-26.2) in the Pd group (HR, 0.77; 95% CI, 0.59-1.02). Overall, there were 220 OS events with 106 (68.8%) in the Isa-Pd arm and 114 (74.5%) in the Pd arm.

The final analysis also looked to examine the impact of the Isa-PD treatment in the real world by observing deaths due to COVID-19, according to Paul G. Richardson, MD. This sensitivity analysis was presented along with the final OS analysis at the 19th International Myeloma Society (IMS) Annual Meeting and Exposition, where researchers found that COVID-19 negatively impacted the OS of the Isa-Pd arm. In the isatuximab arm, 4 patients died due to COVID-19 compared with no patients in the Pd arm. Onset of COVID-19 in these 4 patients was at 37.6, 40.5, 54.2, and 56.1 months from randomization.

In the OS sensitivity analysis censoring COVID-19, investigators counted 102 deaths in the Isa-Pd arm and 114 in the Pd arm and found a slightly adjusted hazard ratio for death of 0.76 (95% CI, 0.58-0.99; log-rank P = .0223). Median OS for the isatuximab arm in sensitivity analysis was also slightly adjusted at 24.57 months (95% CI, 20.3-31.31) compared with 17.71 months in the Pd arm (95% CI, 14.39-26.22).

It was important to note the difference in median treatment of both arms was 47.57 weeks (range, 1.3-245.6) in the isatuximab arm and 24 weeks (range, 1-241.6) in the Pd arm, Richardson added. He highlighted that the high relative dose intensity for all drugs increased the dose reductions see in the Isa-Pd arm compared with the control arm at 46.1% vs 26.8% reductions of pomalidomide and 40.8% vs 30.2% reductions of dexamethasone, respectively. He also added that the main reason for dose reductions in the isatuximab arm was due to neutropenia and infection, yet there were no new safety signals observed in the final analysis.

“The takeaway for time to next treatment was quite striking, if you look at [the median] time to next therapy it was [15.51 months] with the triplet therapy vs [8.87 months] with the doublet therapy,” explained Richardson, clinical program leader of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute. “The conclusion there is that time to next treatment was clearly longer for the 3 drugs than the 2.”

Secondary end points of the analysis also included progression-free survival 2 (PFS2) to assess if treatment benefit continued after the first subsequent therapy. In a previous interim analysis of the study, researchers found a hazard ratio of 0.76 (95% CI, 0.58-0.99). In the final analysis, median PFS2 in the isatuximab arm was longer than in the Pd arm at 17.51 months (95% CI, 14.88-19.22) vs 12.88 months (95% CI, 10.09-16.62) with a hazard ratio of 0.74 (95% CI, 0.57-0.95; log-rank P = .0091).

In the primary analysis of the ICARIA-MM trial,³ at a median follow-up of 11.6 months (IQR, 10.1-13.9), the median PFS was 11.5 months (95% CI, 8.9-13.9) in the triplet arm vs 6.5 months (95% CI, 4.5-8.3) in the doublet arm (HR, 0.60; 95% CI, 0.44-0.81; P = .001). In the intent-to-treat population of the study, the primary analysis showed that PFS benefit with isatuximab occurred in all subgroups of the analysis, including patients who were refractory to lenalidomide (Revlimid) (HR, 0.59; 95% CI, 0.43-0.82; P = .30), a proteasome inhibitor (HR, 0.58; 95% CI, 0.41-0.82; P = .87), or both (HR, 0.58; 95% CI, 0.40-0.84; P = .24).

“Now, one interesting aspect of survival data now in the myeloma spaces, things are going so well with subsequent treatments that sometimes it’s important to dissect what the impact of subsequent therapies may be on your outcome,” Richardson said. “And in this regard, we did a sensitivity analysis to estimate the impact of subsequent CD38-targeted therapy on outcome. [We used] a statistical tool called RPSFT, which stands for rank-preserving structural failure time.”

Results of the sensitivity analysis discussed at the IMS session showed a survival time increase of 1.62 between the 2 arms from the main OS analysis with a hazard ratio of 0.71 (95% CI, 0.54-0.93).¹ Richardson added that the more frequent use of daratumumab (Darzalex) in subsequent lines of therapy in the triplet arm at 59.7% vs 22.5% in the doublet arm could have impacted the power to detect statistically significant OS when looking at the sample size.

Median PFS on the first line of subsequent daratumumab vs those on non-daratumumab treatment remained similar in both arms at 4.2 months (95% CI, 2.8-4.8) in the isatuximab arm compared with 5 months (95% CI, 3.8-6.6) in the Pd arm.² When looking at just daratumumab, median PFS was lower in the isatuximab group at 2.2 months (95% CI, 3.8-10.5) compared with 5.1 months (95% CI 3.8–10.5).

Richardson also explained that the use of further CD38 therapies can lead to frequent pneumonias and infections, but that no new patients experienced a second primary malignancy since the last interim analysis. Moreover, the most frequent grade 3 or worse treatment-emergent adverse events (TEAEs) found in the isatuximab group vs the Pd group were neutropenia (50% vs 35%), pneumonia (23% vs 21%), and thrombocytopenia (13% vs 12%), respectively.

Grade 1/2 upper respiratory tract infection was seen in 36% of patients in the isatuximab group compared with 1% in the Pd group. More grade 1/2 diarrhea (30% vs 22%, respectively), bronchitis (24% vs 11%), and peripheral oedema (19% vs 12%) were observed in the triplet group vs the doublet group, but more grade 1/2 fatigue was seen in the Pd group at 22% vs 18%. However, grade 3 fatigue was seen in 4% of patients in the study arm compared with no patients in the control arm.

While 136 patients discontinued from treatment in the Isa-Pd arm, 19 were due to AEs compared with 101 discontinuing due to disease progression. In comparison, 117 patients in the Pd arm who discontinued due to disease progression and 22 due to AEs. Although no new safety signals were noted, Richardson considered febrile neutropenia to be an AE of special interest with 18 patients experiencing grade 3 or higher febrile neutropenia vs 5 in the Pd arm.

“I think it’s fair to say that [Isa-Pd] has been confirmed in this final analysis to maintain its efficacy, to show no new tolerability issues, and therefore constitutes an important regimen in relapsed/refractory disease,” he concluded.

_References

_{1. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide/low-dose dexamethasone versus pomalidomide/low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (ICARIA-MM): final overall survival analysis. Poster presented at: 19th Annual International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-52.}

_{2. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23(3):416-427. doi:10.1016/S1470-2045(22)00019-5}

_{3. Attal M, Richardson PG, Rajkumar SV, ICARIA-MM study group, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096-2107. doi:10.1016/S0140-6736(19)32556-5}