An important treatment option for patients with 1q21+ relapsed/refractory multiple myeloma – isatuximab-based combination therapy

1q21+, defined as 1q21 acquisition (gain[1q21], 3 copies of number) and 1q21 amplification (amp[1q21], ≥4 copy numbers), is one of the most common chromosomal abnormalities in multiple myeloma (MM) and is detectable
in approximately 40% of patients at diagnosis.
The number of MM cells and copy number of 1q21+ increases
with disease progression.
Its negative effect on prognosis suggests that 1q21+ is associated with
disease progression and the pathophysiology of resistance to MM therapy.
In addition, the coexistence of certain high-risk chromosomal abnormalities is common, which further worsens the prognosis
of patients with 1q21+.

The addition of the anti-CD38 monoclonal antibody isatuximab (Isa) to pomalidomide-dexamethasone (Pd) or carfilzomib-dexamethasone (Kd) in phase III ICARIA-MM and IKEMA studies improved progression-free survival (PFS) in patients with relapsed/refractory (R/R) MM, and subgroup analysis suggested benefit
in 1q21+ patients 。 Therefore, the researchers analyzed 4 patient subgroups studied by ICARIA-MM and IKEMA (1q21+ [≥ 3 copies with or without high-risk chromosomal abnormalities], isolated 1q21+ [≥ 3 copies without high-risk chromosomal abnormalities], 1q21 acquisition [3 copies with or without high-risk chromosomal abnormalities], 1q21 amplification [≥ 4 copies with or without high-risk chromosomal abnormalities]
).

The randomized, open-label, phase III ICARIA-MM and IKEMA studies are described earlier
.
The primary endpoint of two studies was PFS
.
Secondary endpoints were overall survival (OS) and overall response rate
as assessed according to the International Myeloma Working Group's efficacy criteria.
For each study (Isa-Pd versus Pd or Isa-Kd versus Kd), efficacy was assessed within and between treatment groups in the following populations: with and without 1q21+ patients; Patients with and without isolation 1q21+; Patients with and without 1q21 acquisition; Patients
with and without 1q21 amplification.
Assess the presence of 1q21+ using CD138⁺
plasma cells and a 30% cut-off value.
The cut-off values for high-risk chromosomal abnormalities were 50% del(17p), 30% t(4;14) and t(14;16).

Of the 307 and 302 randomized patients studied by ICARIA-MM and IKEMA, cytogenetic risk
was assessed in 241 (78.
5%) and 265 (87.
7%) patients, respectively 。 In the intention-to-treat population, 49.
4% (n=76/154; Isa-Pd) and 34.
0% (n=52/153; Pd) of patients in the ICARIA-MM study had 1q21+, and 41.
9% (n=75/179; Isa-Kd) and 42.
3% (n=52/123; Kd) in the IKEMA study had 1q21+
.
Regardless of the treatment group, patient-related and clinical features were balanced between treatment groups at baseline in terms of 1q21+
.
The baseline characteristics of the 1q21+ patient subgroup are shown
in Table 1.

Table 1

Patients in the Isa-Pd group had superior PFS and OS compared to the Pd group (Figure 1).

The median PFS of 1q21+ patients in the Isa-Pd group and the Pd group were 9.
5 months and 3.
8 months (Figure 1A), and the median OS was 21.
3 and 13.
9 months, respectively (Figure 1B).

The median PFS of patients with and without 1q21+ in the Isa-Pd group were 9.
5 and 11.
6 months (Figure 1C) and median OS of 21.
3 and 21.
2 months, respectively (Figure 1D).

In contrast, the median PFS of patients with and without 1q21+ in the Pd group was 3.
8 months and 9.
8 months (Figure 1E), and the median OS was 13.
9 months and 28.
3 months, respectively (Figure 1F).

The PFS and OS curves of patients with 1q21+ in the Isa-Pd group overlapped with curves from patients without 1q21+ (Figures 1C, D).

In contrast, the PFS and OS curves of patients with 1q21+ in the Pd group were significantly separated from those of patients without 1q21+, and PFS and OS were shorter in patients with 1q21+ (Figure 1E, F).

In addition, the investigators performed outcome analyses
for other subgroups of patients with isolated 1q21+, 1q21 gain, and 1q21 amplification in the ICARIA-MM study.
The results showed that significant benefit
was observed in all patient subgroups for patients who added ISA, regardless of the concomitant high-risk chromosomal abnormalities.

Figure 1

In patients with 1q21+, PFS was superior in the Isa+Kd group compared to the Kd group (Figure 2).

Among patients with 1q21+, median PFS was not achieved in the Isa-Kd group and 16.
2 months in the Kd group (Figure 2A).

Median PFS was not achieved in patients in the Isa-Kd group with and without 1q21+, and the curves overlapped until approximately 11 months (Figure 2B).

The median PFS of patients in the Kd group with and without 1q21+ was 16.
2 months and 20.
3 months, respectively, and the curves were separated early after initiation of treatment (Figure 2C).

Figure 2D shows forest plots
of PFS in two studies.
Risk ratios for all subgroups associated with 1q21+ showed that Isa-Pd was superior to Pd (range, 0.
32–0.
50) and Isa-Kd was superior to Kd (range, 0.
46–0.
69).

With the exception of Isa-Kd with 1q21 amplification with the Kd subgroup, the upper limit of 95% CI for the different subgroups associated with 1q21+ was not cross-aligned
.

Figure 2

In the ICARIA-MM study, Pd in combination with Isa improved depth of response in subgroups of patients with 1q21+, isolated 1q21+, 1q21 gain, and 1q21 amplification (Figure 3A
).
In the IKEMA study, patients with 1q21+, isolated 1q21+, 1q21 gained, and 1q21 amplification in the Isa-Kd group had a better depth of response than the Kd group: higher response rates, very ≥ partial response rates, and minimal residual disease negative rates (Figure 3B).

Safety data between subgroups were consistent
with the overall treatment populations of the ICARIA-MM and IKEMA studies.

Figure 3

Two separate phase III studies have now shown the same degree of improvement in PFS in combination with Isa in addition to standard care (Pd or Kd) in patients with 1q21+, 1q21 gain, and 1q21 amplification
.
In the ICARIA-MM study, the PFS curves of patients with and without 1q21+ appeared to overlap
in the Isa group.
In the IKEMA study, PFS curves in the Isa group overlapped
over the first 11 months.
The depth of remission was always similar
in patients with and without 1q21+.
In two studies, the PFS curve of patients with 1q21+ was inferior in the standard treatment group to patients
without 1q21+.
This was especially pronounced in patients receiving Pd, but less pronounced in patients receiving Kd; This also confirms a recent study that carfilzomib-based therapy (carfilzomib-lenalidomide-dexamethasone with or without stem cell transplantation) is beneficial
in patients with 1q21+.

The beneficial outcomes of Isa-based combination therapy observed in ICARIA-MM and IKEMA studies in 1q21+ patients suggest that this treatment can mitigate the adverse prognostic effects
of 1q21+ in patients with R/R MM.
In summary, Isa-Pd and Isa-Kd are important treatment options
for the subgroup of patients with R/R MM and 1q21+ refractory patients.

References:

Martin T, Richardson P G, Facon T, et al.
Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: subgroup analyses from ICARIA-MM and IKEMA[J].
Haematologica, 2022, 107(10):2485-2491.