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Adding isatuximab to pomalidomide/dexamethasone significantly prolongs progression-free survival of patients with relapsed/refractory multiple myeloma

The randomized phase III ICARIA-MM trial demonstrated that adding isatuximab to a backbone of pomalidomide and low-dose dexamethasone results in a significantly longer PFS in a population of relapsed/refractory multiple myeloma patients who received at least 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. Importantly, this PFS benefit was seen in all investigated subgroups, including patients with high-risk cytogenetic features, patients with renal impairment and patients who was refractory to lenalidomide.

Background

Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. The ICARIA-MM study is the first randomized, phase III trial evaluating a combination of the anti-CD38 antibody isatuximab (Isa) in combination with pomalidomide (P) and dexamethasone (d) in patients with relapsed/refractory (RR)MM.

Study design

In this trial, 307 patients with RRMM who received at least 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor (PI), were randomized (1:1) to a treatment with Isa-Pd (Isa: 10 mg/kg on day 1, 8, 15 and 22 of cycle 1 and on days 1 and 15 in subsequent cycles; P: 4 mg on days 1-21 of 28 day cycles; d: 40 mg [20 mg for patients aged 75 or older] on day 1, 8, 15 and 22) or Pd alone (P and d in similar schedule as in the experimental arm). Patients were treated until disease progression, or unacceptable adverse events (AEs). The primary endpoint of the trial was progression-free survival (PFS) by independent review, with objective response rate (ORR) and overall survival (OS) as key secondary objectives.

Results

The patient population in the trial was representative for the patients that are seen in clinical practice. The median age of patients was 67 years, but patients up to age of 86 years were enrolled in the trial (19.9% was 75 years or older). A substantial proportion of patients in the trial suffered from renal impairment with 36.2% and 19.9% of patients having an eGFR of <60 and <50 mL/min/1.73m2, respectively. About one in five patients in the trial had high-risk cytogenetic features at baseline. The median number of prior treatment lines was 4, but some patients had received up to 11 prior therapies before enrollment in the study. Per protocol, all patients were PI and lenalidomide exposed. Importantly, 93.5% of patients in the Isa-Pd arm was lenalidomide refractory and 73.4% was refractory to both lenalidomide and a PI.

After a median follow-up of 11.6 months, the PFS was found to be significantly better with Isa-Pd than with Pd alone. In Isa-Pd treated patients, the median PFS was 11.53 months, which was 5 months longer than the 6.47 months median seen with Pd alone (HR 0.596 [95% CI 0.436-0.814]; p=0.001). This benefit in PFS from adding Isa to Pd was seen in all investigated subgroups, irrespective of baseline eGFR, cytogenetic risk and lenalidomide refractoriness. The PFS was also consistently improved across treatment lines. In patients who received 2-3 prior lines of therapy, the median PFS was improved from 7.8 months with Pd to 12.3 months with Isa-Pd (HR 0.59 [95% CI 0.40-0.88]; p=0.0084). Similarly, patients who received more than 3 prior therapies had a median PFS of 9.4 months under Isa-Pd as compared to 4.3 months with Pd alone (HR 0.59 [95% CI 0.36-0.98]; p=0.0375).

Also with respect to ORR Isa-Pd outperformed Pd with an ORR of 60.4% and 35.3%, respectively (p<0.0001). The percentage of patients who achieved a very good partial response or better was 31.8% with Isa-Pd as compared to 8.5% with Pd alone. Responses also occurred earlier with Isa-Pd where the median time to a first response was 35 days as compared to 58 days with Pd alone. At the time of the analysis, the OS data were not yet mature but already suggest a trend for a better OS with Isa-Pd compared to Pd (HR 0.687 [95% CI 0.461-1.023]; p=0.0631). At 12 months, 72% of patients in the Isa-Pd arm were still alive as compared to 63% with Pd alone. Finally, the addition of Isa to Pd also led to a significant delay in the need for a next treatment line. In fact, the median time to next therapy was not reached for Isa-Pd, while this was reported to be 9.1 months with Pd alone (HR 0.538 [95% CI 0.382-0.758]).

The incidence of grade 3-5 AEs was higher with Isa-Pd than with Pd alone (86.8% vs 70.5%) and this was also the case for the rate of serious AEs (61.8% vs 53.7%). However this did not lead to a higher rate of AE induced treatment discontinuation (7.2% vs 12.8%) or a higher incidence of fatal AEs (7.9% vs 9.4%) with Isa-Pd versus Pd alone. Overall, Isa-Pd had a tolerable safety profile with upper respiratory tract infection (28.3%), diarrhea (25.7%), bronchitis (23.7%), and pneumonia (20.4%) as the most common adverse events. Apart from pneumonia (15% grade 3/4), these AEs rarely reached grade 3 or 4 in severity. The incidence of anemia and thrombocytopenia was similar for Isa-Pd and Pd, but adding Isa to Pd did lead to a higher rate of grade 4 neutropenia. Importantly, the quality of life of patients was not compromised from the addition of Isa to Pd.

Conclusions

Isa in combination with Pd significantly improved the PFS and ORR compared to Pd alone, with a manageable safety profile. This clinical benefit was seen in all investigated subgroups, including patients with lenalidomide-refractory MM. As such, Isa in combination with Pd represents an important new treatment option for the management of patients with RRMM.

Reference

Advani R, Bartlett N, Smith S, et al. The first-in-class anti-CD47 antibody HU5F9-G4 with rituximab induces durable responses in relapsed/refractory DLBCL and indolent lymphoma: interim phase 1B/2 results. Presented at EHA 2019; abstract S867.

Speaker Paul Richardson

richardson

Paul Richardson, MD, PhD, Dana Farber Cancer Institute, Boston, MA, USA

 

See: Keyslides

 

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