Efficacy of Isatuximab with Pomalidomide and Dexamethasone in Elderly Patients with Relapsed/Refractory Multiple Myeloma: Icaria-MM Subgroup Analysis
Authors: Schjesvold Fredrik H. , Richardson Paul G. , Attal Michel , Facon Thierry , Alegre Adrián , Spencer Andrew , Jurczyszyn Artur , Sunami Kazutaka , Frenzel Laurent , Min Chang-Ki , Le-Guennec Solenn , Campana Frank , van de Velde Helgi , Bensfia Samira , Bringhen Sara 
Published: November 2019

INTRODUCTION: Multiple myeloma (MM) is most frequently diagnosed among people aged 65-74, and approximately one-third of patients (pts) are aged ≥75 years. Advanced age has a negative effect on the prognosis of pts with MM. The randomized, open-label, active-controlled, multicenter phase 3 ICARIA-MM study (NCT02990338) compared treatment with the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) with Pd. Pts had relapsed/refractory MM (RRMM) after ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. This subgroup analysis of ICARIA-MM examined efficacy and safety in elderly pts (≥75 years) compared with younger pts.
METHODS: Pts were randomized (1:1) to receive Isa-Pd or Pd. Isa (10 mg/kg IV) was given on days 1, 8, 15, and 22 (cycle 1), and days 1 and 15 in subsequent 28-day cycles. All pts received pomalidomide 4 mg on days 1-21 of each cycle and dexamethasone 40 mg (20 mg for pts ≥75 years old) on days 1, 8, 15, and 22 of each cycle. The primary endpoint was progression-free survival (PFS), assessed by an independent response committee. Subgroup analyses were conducted for pts aged <65, 65-74, and ≥75 years of age.
RESULTS: Overall, 307 pts were randomized to Isa-Pd (n=154) or Pd (n=153) and included in the intent-to-treat population. The median age of pts was 68.0 years in the Isa-Pd arm and 66.0 years in the Pd arm. In the Isa-Pd and Pd arms, there were 54 (35%) and 70 (46%) pts <65 years of age, 68 (44%) and 54 (35%) pts 65-74 years of age, and 32 (21%) and 29 (19%) pts ≥75 years of age, respectively.
In the overall population, PFS was significantly improved with Isa-Pd versus Pd (median 11.53 vs 6.47 months; hazard ratio [HR] 0.596; 95% confidence interval [CI] 0.436-0.814; p=0.001). Consistent with this, pts ≥75 years of age had a median PFS of 11.40 with Isa-Pd vs 4.47 months with Pd (HR 0.479; 95% CI 0.242-0.946). Similarly, in the Isa-Pd and Pd groups, pts 65-74 years of age had a PFS of 11.57 and 8.58 months (HR 0.638; 95% CI 0.385-1.059); in pts <65 years of age, PFS was 11.53 vs 5.03 months, respectively (HR 0.656; 95% CI 0.401-1.074).
Overall response rate (ORR) for all pts was 60.4% with Isa-Pd and 35.3% with Pd with an odds ratio (OR) of 2.80 (95% CI 1.72-4.56). ORR by age group in pts receiving Isa-Pd vs Pd was: 53.1% and 31.0% in the ≥75 years group (OR 2.52; 95% CI 0.79-8.26); 64.7% and 38.9% in the 65-74 years group (OR 2.88; 95% CI 1.29-6.46); and 59.3% and 34.3% in the <65 years group (OR 2.79; 95% CI 1.26-6.20).
At least a very good partial response (≥VGPR) was achieved by 31.8% of pts with Isa-Pd and 8.5% with Pd, with an OR of 5.03 (95% CI 2.51-10.59). Rates of ≥VGPR by age in pts receiving Isa-Pd vs Pd was: 31.3% and 0% in the ≥75 years group (OR not calculated); 32.4% vs 13.0% in the 65-74 group (OR 3.21; 95% CI 1.17-9.70); and 31.5% and 8.6% in the <65 years group (OR 4.90; 95% CI 1.64-16.35). Of 8 pts with negative minimal residual disease at 10−5, 2 were ≥75 years old.
At the time of analysis, overall survival (OS) data are not yet mature. However, in the elderly population, 8/32 (25%) pts in the Isa-Pd arm had died with median OS not reached, and in the Pd arm, 15/29 (51.7%) had died with a median OS of 10.25 months (HR 0.404; 95% CI 0.171- 0.956).
In the Isa-Pd arm, the incidence of all-grade treatment-emergent adverse events (TEAEs) across age groups was: <65 years, 98.1%; 65-74 years, 100%; and ≥75 years, 100%. There were more Grade ≥3 TEAEs with Isa-Pd in pts aged ≥75 years (93.8%) compared with pts <65 years of age (85.2%), with a similar trend observed in the Pd arm (75.0% and 64.7%, respectively). There were also more treatment discontinuations because of TEAEs in pts ≥75 vs <65 years of age in the Isa-Pd arm (15.6% and 7.4%, respectively) and in the Pd arm (14.3% and 10.3%). There was a higher incidence of serious TEAEs (SAEs) in pts ≥75 vs <65 years of age in both arms (Isa-Pd, 68.8% and 57.4%; Pd, 57.1% and 47.1%, respectively). The incidence of TEAEs with fatal outcome was lower in pts aged ≥75 years in the Isa-Pd arm (6.3%) than in pts <65 years (11.1%), while the opposite trend was observed with Pd (14.3% vs 5.9%).
CONCLUSION: The addition of Isa to Pd improved PFS, ORR, ≥VGPR, and OS in elderly pts, consistent with the benefit observed in the overall study population. There was a consistent trend toward higher rates of SAE and discontinuation due to TEAEs in elderly pts in both the Isa-Pd and Pd arms, but with no increase in fatal AEs in the Isa-Pd arm.

Disclosures
Schjesvold: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; SkyliteDX: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Facon:Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Spencer:Janssen Oncology: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Amgen: Other: Consulting/advisory role, Research Funding; AbbVie: Other: Consulting/advisory role, Research Funding; Servier: Other: Consulting/advisory role; Takeda: Other: Consulting/advisory role, Research Funding; Secura Bio: Other: Consulting/advisory role; Haemalogix: Other: Consulting/advisory role; Celgene: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Sanofi: Other: Consulting/advisory role; Specialised Therapeutics Australia: Consultancy, Honoraria. Sunami:Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Alexion-pharma: Research Funding; GSK: Research Funding; Janssen: Research Funding; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Le-Guennec:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Bensfia:Sanofi: Employment. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy.