IsKia trial: Isa-KRd vs KRd for pretransplant induction and posttransplant consolidation in NDMM

Therapy with carfilzomib-lenalidomide-dexamethasone (KRd) followed by posttransplant maintenance has been established as a favorable treatment choice for patients with newly diagnosed multiple myeloma (NDMM). While recent phase II single-arm trials have investigated the addition of daratumumab and isatuximab to this backbone treatment regimen, to date there have been no randomized trials evaluating the addition of a CD38 monoclonal antibody to the KRd backbone in patients with NDMM.

During the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, Gay presented a primary analysis from the randomized phase III IsKia trial (NCT04483739) investigating isatuximab-KRd (Isa-KRd) vs KRd as pretransplant induction and posttransplant consolidation in NDMM. Here, we summarize the key points.

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Study design

• The study took place across 42 clinical sites
• Patients were enrolled between October 7, 2020, and November 15, 2021
• Key eligibility criteria were:
  • Diagnosis of transplant-eligible NDMM
  • Age <70 years

The study design is shown in Figure 1.

ASCT, autologous stem cell transplant; Cy, cyclophosphamide; d, dexamethasone; G-CSF, granulocyte-colony stimulating factor; Isa, isatuximab; K, carfilzomib; MEL, melphalan; R, lenalidomide.
*Adapted from Gay.¹

• The primary endpoint was measurable residual disease (MRD) negativity after post-autologous stem cell transplantation consolidation
• Key secondary endpoints were:
  • MRD negativity after induction
  • Progression-free survival (PFS)

Results

Baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics*

HRCA, high-risk cytogenetic abnormality; Isa-KRd, isatuximab-carfilzomib-lenalidomide-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; R-ISS, Revised International Staging System; R2-ISS, second revision of the International Staging System. *Adapted from Gay.1
Characteristic, % (unless otherwise stated)	Isa-KRd (n = 151)	KRd (n = 151)
Median age, years	61	60
Sex
Male	52	56
Female	48	44
Cytogenetic risk
Standard	82	81
High	18	19
Number of HRCA
0	56	54
1	35	35
2+	9	11
R-ISS
I	35	34
II	58	59
III	7	7
R2-ISS
I	24	25
II	32	34
III	37	37
IV	6	4

• The median follow-up time was 21 months
• In total, 83% of patients on Isa-KRd completed both induction and consolidation compared with 90% treated with KRd
• Overall, 17% of patients in the Isa-KRd group discontinued treatment vs 10% of patients in the KRd group
• More patients achieved MRD negativity at 10⁻⁵ and 10⁻⁶ sensitivity in the Isa-KRd treatment group compared with the KRd group (Figure 2)

Isa-KRd, isatuximab-carfilzomib-lenalidomide-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; MRD, measurable residual disease.
*Adapted from Gay.¹

 Rates of MRD negativity at 10^-5 and 10^-6 sensitivity had a better improvement over time in patients treated with Isa-KRd vs patients treated with KRd (Figure 3)

ASCT, autologous stem cell transplant; Isa-KRd, isatuximab-carfilzomib-lenalidomide-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; MRD, measurable residual disease.
*Adapted from Gay.¹

 Patients with high-risk cytogenetic abnormalities also had higher rates of MRD negativity post-consolidation when treated with Isa-KRd compared with KRd (Figure 4)

HRCA, high-risk cytogenetic abnormalities; Isa-KRd, isatuximab-carfilzomib-lenalidomide-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; MRD, measurable residual disease.
*Adapted from Gay.¹

• Overall, 55% of patients had ≥1 hematologic toxicity of any grade when treated with Isa-KRd compared with 44% of patients treated with KRd.
• In contrast, 90% of patients had ≥1 non-hematologic toxicity of any grade when treated with Isa-KRd compared with 85% of patients treated with KRd.
• The most common hematologic and non-hematologic treatment-related adverse events of Grade 3–4 are shown in Figure 5.

GI, gastrointestinal; Isa-KRd, isatuximab-carfilzomib-lenalidomide-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; TRAE, treatment-related adverse event.
*Adapted from Gay.¹

 Conclusion

Results from the IsKia trial demonstrated that Isa-KRd significantly increased rates of MRD negativity after each treatment phase, post-consolidation, and in all patient subgroups compared with KRd therapy. The safety profile was tolerable and comparable with that of previous reports. A longer follow-up is warranted to analyze the correlation between depth of MRD negativity and progression-free/overall survival.