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Letters to the Editor
Isatuximab plus pomalidomide and dexamethasone in elderly patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis
Multiple myeloma (MM) typically affects elderly patients, with a median age at diagnosis of 69 years.1 Treatment of elderly patients is challenging due to frailty, comorbidities, and decreased resilience to treatment- related toxicity.2 Furthermore, advanced age has a nega- tive impact on the prognosis of patients with MM.3,4 Considering these challenges, new, well-tolerated treat- ment options for this age group are needed.
Isatuximab is a monoclonal antibody that targets a spe- cific epitope on CD38 and triggers MM cell death via multiple mechanisms.5-7 Isatuximab-irfc is approved in the USA for use in combination with pomalidomide and dex- amethasone (Pd) to treat patients with relapsed/refracto- ry MM (RRMM) patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.8
ICARIA-MM (ClinicalTrials.gov, number NCT02990338) was a randomized, open-label, multicen- ter phase III study of isatuximab in combination with Pd (Isa-Pd) that showed significantly improved progression- free survival in heavily treated patients with RRMM with a manageable safety profile compared with that of Pd alone.9,10 Due to its prognostic relevance, age (<75 versus ≥75 years) was one of the stratification factors in ICARIA-MM. As the population <75 years was very large, it was further divided into 65-74 and <65 years subpopulations in this pre-specified subgroup analysis of ICARIA-MM, comparing efficacy and safety in these three age groups.
The baseline characteristics of the patients, divided by age group, are shown in Table 1, and were generally bal- anced across arms.
The median progression-free survival was significantly prolonged with Isa-Pd and was similar in all three age subgroups (Figure 1A-C). In the age group ≥75 years old it was 11.40 months (Isa-Pd; n=32) versus 4.47 months (Pd; n=29), hazard ratio (HR)=0.479; 95% confidence interval (95% CI): 0.242-0.946. In the age group 65-74 years old it was 11.57 months (Isa-Pd; n=68) versus 8.58 months (Pd; n=54), HR=0.638; 95% CI: 0.385-1.059. In the age group <65 years old it was 11.53 months (Isa-Pd; n=54) versus 5.03 months (Pd; n=70), HR=0.656; 95% CI: 0.401-1.074.
The overall response rate was also improved with Isa- Pd versus Pd in all three age subgroups (Figure 1D). In the age group ≥75 years old the overall response rate was 53.1% versus 31.0%, respectively (odds ratio [OR] 2.52; 95% CI: 0.79-8.26). In the subgroup 65-74 years old it was 64.7% versus 38.9% (OR 2.88; 95% CI: 1.29-6.46). In the age group <65 years old it was 59.3% versus 34.3% (OR 2.79; 95% CI: 1.26–6.20). Across age groups, the proportion of patients who achieved a very good partial response (VGPR) or better rate was consistently higher with Isa-Pd than with Pd (Figure 1D): ≥75 years, 31.2% versus 0% (OR not calculable); 65-74 years, 32.3% versus 13.0% (OR 3.21; 95% CI: 1.17-9.70); and <65 years 31.5% versus 8.6% (OR 4.90; 95% CI: 1.64-16.35).
arm died versus 15 of 29 (51.7%) in the Pd arm. The median overall survival in these patients was not reached in the Isa-Pd arm and was 10.3 months in the Pd arm with a CI for the HR that does not cross 1 (HR=0.40; 95% CI: 0.17-0.96). Among patients 65-74 years old, the median overall survival was not reached in the Isa-Pd arm and was 14.5 months in the Pd arm (HR 0.75; 95% CI: 0.38-1.45). The median overall survival was not reached in either treatment arm in patients <65 years old (HR 0.85; 95% CI: 0.46-1.59).
Multivariate analyses adjusting progression-free sur- vival and overall survival for International Staging System stage at study entry in the three age groups were performed and suggest that the imbalance in the International Staging System stage at study entry did not influence the treatment effect in favor of Isa-Pd for pro- gression-free or overall survival outcomes (Online Supplementary Table 1).
Health-related quality of life parameters were better maintained in the Isa-Pd arm among patients aged ≥75 years, versus 65-74 years and <65 years (Online Supplementary Figures S1, S2 and S3, respectively), as demonstrated by the results of Global Health Status/Quality of Life, Physical Functioning and Role Functioning scores and no worsening of Fatigue, C30 Pain, and MY20 Disease Symptoms. The maintenance of quality of life in elderly MM patients is important because (i) while younger patients with MM are usually more concerned with achieving a complete response or minimal residual disease negativity, older patients want to have their disease controlled while maintaining their quality of life;11 and (ii) MM-related complications tend to be more severe and debilitating in older patients, and therefore treatments that preserve quality of life are par- ticularly desired in this group of patients.2
As indicated in Online Supplementary Table S2, the treat- ment duration was longer with Isa-Pd than with Pd, inde- pendently of age. In the Isa-Pd arm, treatment exposure was longer and higher numbers of cycles were started in patients ≥75 years old compared with the other two age groups. Additionally, a tendency towards lower relative dose intensity was observed for patients ≥75 years old, followed by patients aged 65-74 years and <65 years in both treatment arms.
Eight patients in the Isa-Pd arm have minimal residual disease negativity rate (at a sensitivity level of 10-5 assessed by next-generation sequencing): two were ≥75 years old, two were 65-74 years old and four were <65 years. No patients in the Pd arm achieved minimal resid- ual disease negativity.
The number of patients with any treatment-emergent adverse event (TEAE) was similar in the Isa-Pd and Pd arms (Table 2). The incidences of grade ≥3 TEAE, serious TEAE, and discontinuations due to TEAE were higher in patients ≥75 years old than in younger patients with both Isa-Pd and Pd, but there was no increase in fatal TEAE in the Isa-Pd arm or impact on median treatment duration (Online Supplementary Table 2). The most common any- grade non-hematologic TEAE with Isa-Pd were infusion reactions, regardless of age group (Table 2). Infusion reac- tions were mostly grade 1-2, reversible, and occurred with the first infusion. Interestingly, fewer infusion reac- tions were observed in patients ≥75 years (28.1%) than in those 65-74 years (36.4%) or <65 years (42.6%). The underlying mechanism of anti-CD38 infusion reactions is not currently understood; it is possible that cytokine release by involved immune cell subset(s) is less pro- nounced in elderly patients due to their impaired immune function.
In patients ≥75 years, eight of 32 (25.0%) in the Isa-Pd
The most common grade ≥3 non-hematologic TEAE was pneumonia, regardless of patients’ age or treatment group (Table 2). In the Isa-Pd arm, the incidence of pneu- monia was lower in patients ≥75 years (12.5%), followed by those <65 (16.7%) and 65-74 years (27.3%). This might be explained by a higher percentage of older
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haematologica | 2021; 106(4)