Relapsed or refractory multiple myeloma with renal insufficiency ushered in an effective treatment plan

Renal insufficiency (RI) is one of the common clinical manifestations of multiple myeloma (MM) patients, and it also affects the prognosis of newly diagnosed MM (NDMM) and relapsed or refractory MM (RRMM).

There are still many unmet clinical needs for RRMM with RI, and effective treatments are still needed.

Recently, a researcher analyzed the efficacy of Isatuximab combined with pomalidomide and dexamethasone (Isa-Pd) in RRMM patients with RI, and the results of the study were published in the journal Leukemia.

The editor organizes its main content as follows for the reference of readers.

Research background MM patients with RI account for about 50% of MM patients, most of which are caused by the deposition of free immunoglobulin light chains in the distal tubules, leading to tubular obstruction and cast nephropathy.

RI is an independent predictor of the poor prognosis of MM patients.
RI can shorten the median survival time of MM patients by nearly half.

At present, there is still an urgent need for anti-MM treatment programs that can improve renal function.

The International Myeloma Working Group (IMWG) currently recommends a bortezomib-based regimen as the preferred treatment for MM patients with RI.

The subgroup analysis of the ENDEAVOR study showed that in RRMM patients with RI who were treated with carfilzomib and dexamethasone, the complete renal response rate reached 15.
3%.
Compared with patients who did not achieve complete renal response, the rate of complete renal response was higher.
Long median progression-free survival (PFS) and overall survival (OS).

There are few data on monoclonal antibodies in MM patients with RI.

Isa is an IgG1 monoclonal antibody that targets a specific epitope on CD38 and has a variety of anti-MM mechanisms of action.

The ICARIA-MM study aims to evaluate the efficacy and safety of Isa-Pd vs Pd in ​​RRMM patients who have previously received ≥2 line therapy.

The preliminary results showed that Isa-Pd had a significant improvement in PFS compared with patients in the Pd group (11.
53 months vs 6.
47 months; hazard ratio [HR]: 0.
596; 95% confidence interval [CI]: 0.
436-0.
814; P=0.
001).

In addition, 36.
2% of patients in the ICARIA-MM study had RI (estimated glomerular filtration rate [eGFR]<60mL/min/1.
73m²).

Recently, a researcher reported a pre-specified subgroup analysis in the ICARIA-MM study, comparing the efficacy, renal response, and safety of Isa-Pd vs Pd in ​​RRMM patients with and without RI.

Research methods The ICARIA-MM trial is a prospective, randomized, open-label, and actively controlled multi-center phase III clinical study.

The study included RRMM patients with baseline eGFR ≥ 30 mL/min/1.
73 m² (moderate RI).

All patients received oral pomalidomide 4 mg on days 1-21 and oral or intravenous dexamethasone 40 mg on days 1, 8, 15 and 22 (20 mg for patients ≥75 years of age), one treatment on 28 days Cycle; and patients randomly assigned to the Isa-Pd treatment group received intravenous Isa 10 mg/kg on days 1, 8, 15, and 22 of cycle 1, and on days 1 and 15 of each subsequent cycle.

A complete renal response is defined as an improvement in eGFR from <50mL/min/1.
73m² at baseline to ≥60mL/min/1.
73m², with at least one post-baseline assessment (IMWG recommendation).

Results of the study A total of 307 patients were randomly assigned to the Isa-Pd group (n=154) and Pd group (n=153); in the two groups, the eGFR of 142 and 145 patients could be assessed.

Among them, there were 55 (38.
7%) and 49 (33.
8%) patients with RI at baseline in the two groups respectively.
Among them, there were 19 (13.
4%) and 19 patients with eGFR≥30 to <45mL/min/1.
73m².
16 cases (11.
0%). Baseline demographics and clinical characteristics were similar between the two treatment groups and between patients with or without RI at baseline.
Among them, patients with RI were older than those without RI, and the International Staging System (ISS) was stage III and There are more patients with light chain type (see Table 1 for details).

                                             Table 1: Baseline characteristics of patients in the ICARIA-MM trial.

Among patients with and without RI, the PFS benefit of the Isa-Pd group over Pd was consistent with that observed in the entire study population.

For patients with RI, the median PFS of the Isa-Pd treatment group (n=55) was 9.
5 months, and the median PFS of the Pd treatment group (n=49) was 3.
7 months (HR: 0.
50; 95% CI: 0.
30-0.
85) (Figure 1a).

For patients with eGFR<45mL/min/1.
73m², the median PFS of the Isa-Pd (n=20) and Pd (n=17) treatment groups were 7.
5 months and 2.
8 months, respectively (HR: 0.
50; 95% CI : 0.
22-1.
13) (Figure 1b).

Among patients without RI, the median PFS of the Isa-Pd treatment group (n=87) was 12.
7 months, and the median PFS of the Pd treatment group (n=96) was 7.
9 months (HR: 0.
58; 95%) CI: 0.
38-0.
88).

Figure 1: PFS in RRMM patients with or without RI in the ICARIA-MM trial.

The OS data of the entire ICARIA-MM study is not yet available for analysis, but it can be analyzed in a smaller number of RI subgroups.

The median OS of patients with RI in the Pd treatment group was 11.
6 months, while the median OS in the Isa-Pd treatment group had not yet reached (HR: 0.
53; 95% CI: 0.
30-0.
96; Figure 2a).

For patients with eGFR<45mL/min/1.
73m², the median OS of the Isa-Pd and Pd treatment groups was 10.
7 months vs.
6.
6 months (HR: 0.
62; 95% CI: 0.
26-1.
45; Figure 2b). In patients without RI, none of the treatment groups achieved a median OS (HR: 0.
62; 95% CI: 0.
33-1.
19; Figure 2c).

Figure 2: OS in RRMM patients with RI in the ICARIA-MM trial.

Regardless of whether the patient is associated with RI, Isa-Pd has a higher overall response rate (ORR) than the Pd treatment group (Figure 3).

The ORRs of patients with RI in the Isa-Pd and Pd treatment groups were 56.
4% and 24.
5% (odds ratio [OR]: 3.
98; 95% CI: 1.
60-10.
17); a very good part of the Isa-Pd and Pd treatment groups Remission or better (≥VGPR) rates were 32.
7% and 4.
1%, respectively.

Eight patients in the Isa-Pd group were minimal residual disease (MRD) negative (sensitivity 10-5), and 3 patients had baseline eGFR<60mL/min/1.
73m².

There were no MRD-negative patients in the Pd group.

The ORRs of patients with eGFR<45mL/min/1.
73m² in the Isa-Pd and Pd treatment groups were 35.
0% and 23.
5% (OR: 1.
75; 95% CI: 0.
34-10.
11).

For patients without RI, the ORR of the Isa-Pd and Pd treatment groups were 67.
8% and 42.
7% (OR: 2.
83; 95% CI: 1.
48-5.
42).

The ORR of patients with baseline eGFR≥45 to <60mL/min/1.
73m² in the Isa-Pd group was similar to that of patients without RI, which was 68.
6%.

Figure 3: The short-term efficacy of RRMM patients with or without RI in the ICARIA-MM trial.

The complete renal response rate of patients in the Isa-Pd group was 71.
9% (23/32 cases), while that of the Pd group was 38.
1% (8/21 cases) (OR: 4.
15; 95% CI: 1.
12-15.
78; Figure 4). The use of Isa-Pd treatment (31.
3% [10/32 cases]) was better than Pd treatment (19.
0% [4/21 cases]) to achieve a lasting complete renal response (OR: 1.
93; 95% CI: 0.
4-9.
82; Figure 4).

The median time of renal response in the Isa-Pd and Pd treatment groups were 3.
4 weeks and 7.
3 weeks, respectively.

Among patients with evaluable renal response (baseline eGFR<50mL/min/1.
73m²), patients with renal response in both Isa-Pd and Pd groups had a higher tumor response rate than patients without renal response (Isa-Pd group) 52% vs 44%; Pd group 38% vs 23%).

During the period of Isa-Pd and Pd treatment, fewer patients who received Isa-Pd treatment progressed to end-stage renal disease (ESRD; eGFR<15mL/min/1.
73m²) (2.
9% vs 7.
9%).

In patients with moderate RI at baseline, renal function deteriorated to severe RI or ESRD, 22.
6% (12/53 cases) in the Isa-Pd group and 34.
8% (16/46 cases) in the Pd group (OR: 0.
55; 95%) CI: 0.
20-1.
45).

In addition, the pharmacokinetics of Isa in RRMM patients with and without RI are comparable, suggesting that RI patients do not need to adjust the dose when using Isa.

Figure 4: Renal response of RRMM patients with RI in the ICARIA-MM trial.

Research conclusions The research shows that adding Isa to Pd can improve the ORR, complete renal response rate and PFS of RRMM patients with RI.

References Meletios A Dimopoulos, Xavier Leleu, Philippe Moreau, et al.
Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis.
Leukemia.
2021 Feb;35(2):562-572 .
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