The interim analysis results of the phase III IKEMA trial | Isatuximab + Kd for the treatment of relapsed and refractory multiple myeloma

IKEMA (NCT03275285) is an ongoing phase III study on the efficacy and safety of isatuximab (Isa) in combination with carfilzomib (K) and dexamethasone (d) versus carfilzomib and dexamethasone alone in patients with relapsed and refractory multiple myeloma (RRMM) previously treated with 1–3 lines of therapy. The objective of the study is to demonstrate the benefit in the prolongation of progression-free survival (PFS)¹; and a prespecified interim analysis was conducted when 65% of expected PFS events (103) were observed. In May 2020, it was announced that IKEMA met its primary endpoint.

Philippe Moreau, Steering Committee member of the MM Hub, and colleagues reported the results of Isa + Kd in RRMM at the 25th European Hematology Association (EHA) Virtual Congress, and this article provides a summary of the presentation.

Isatuximab is an IgG1 monoclonal antibody targeting a CD38 transmembrane glycoprotein expressed in plasma cells. Its efficacy in MM is explained by multiple modes of action including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, direct apoptosis, immunomodulation, and inhibition of ectoenzyme activity².

The combination of isatuximab with pomalidomide and dexamethasone was approved recently for the treatment of RRMM after at least two prior therapies².

The MM Hub has been focusing on the ongoing potential of monoclonal antibodies in MM as an editorial theme, find more information on the agents discussed here.

Study design²

Patient characteristics

• Patients received no prior carfilzomib neither anti-CD38 therapy
• About 10% of patients were older than 75 years
• Patient characteristics were well balanced between treatment arms (see Table 1)

Table 1. Patient demographics and baseline characteristics²

CrCl, creatinine clearance; d, dexamethasone; IMiD, immunomodulatory drug; Isa, isatuximab; ISS, International Staging System; ITT, intent to treat; K, carfilzomib; MDRD, modification of diet in renal disease; PI, proteasome inhibitor *cut-off 50% for del(17p), 30% for t(4;14) and t(14;16)
ITT population	Isa-Kd (n = 179)	Kd (n = 123)
Median age, years (range)	65.0 (37–86)	63.0 (33–90)
Age by category, n (%) < 65 65 – < 75 ≥ 75	88 (49.2) 74 (41.3) 17 (9.5)	66 (53.7) 47 (38.2) 10 (8.1)
CrCl < 60 mL/min/1.73m2 (MDRD), n (%)	43 (26.1)	18 (16.2)
ISS stage at baseline, n (%) Stage I Stage II Stage III	89 (48.7) 63 (35.2) 26 (14.5)	71 (57.7) 31 (25.2) 20 (16.3)
High-risk cytogenetics at baseline*, n (%)	42 (23.5)	31 (25.2)
Prior lines of therapy, median (range) 1, n (%) 2, n (%) ≥ 3, n (%)	2 (1–4) 79 (44.1) 64 (35.8) 36 (20.1)	2 (1–4) 55 (44.7) 36 (29.3) 32 (26)
Prior PI, n (%)	166 (92.7)	105 (85.4)
Prior IMiDs®, n (%)	136 (76.0)	100 (81.3)
Patients refractory to, n (%) IMiD Lenalidomide PI Last regimen	78 (43.6) 57 (31.8) 56 (31.3) 89 (49.7)	58 (47.2) 42 (34.1) 44 (35.8) 73 (59.3)

 

Randomization

Patients were stratified based on the number of prior lines (1 vs > 1) and MM stage according to the Revised International Staging System (R-ISS) (I or II vs III vs not classified)

Patients were randomized in a ratio of 3:2 to receive either:

• Isa-Kd arm (28-day cycles):

Isatuximab intravenous (IV) infusion: 10 mg/kg at Days 1, 8, 15, and 22 during the first cycle, every 2 weeks (Q2W) thereafter

Carfilzomib (IV): 20 mg/m² at Days 1–2; 56 mg/m² at Days 8–9 and Days 15–16 during the first cycle; 56 mg/m² at Days 1–2, 8–9, and 15–16 for all subsequent cycles

Dexamethasone (IV or oral): 20 mg at Days 1–2, 8–9, 15–16, and 22–23 each cycle

• Kd arm (28-day cycles):

Carfilzomib (IV): 20 mg/m² at Days 1–2; 56 mg/m² at Days 8–9 and Days 15–16 during the first cycle; 56 mg/m² at Days 1–2, 8–9, and 15–16 for all subsequent cycles

Dexamethasone (IV or oral): 20 mg at Days 1–2, 8–9, 15–16, and 22–23 each cycle

The treatment continued until progression, unacceptable toxicities, or at the discretion of patients. The percentage of patients who were still receiving treatment by the time of this analysis was higher in the Isa-Kd group compared with Kd (52.0% vs 30.9%). The discontinuation rates due to progression or adverse events in the Isa-Kd arm and Kd arm were 37.4% and 53.7%, respectively.

Results²

Efficacy analysis after a median follow-up of 20.7 months

• Isa-Kd combination achieved a risk reduction of 47% in progression or death compared with Kd (HR 0.531 [99% CI, 0.318–0.889]; p = 0.0007)
• PFS subgroup analyses showed consistent treatment effects for the Isa-Kd combination, including in patients ≥ 65 years old and treated with > 1 prior line
• Time to next treatment was estimated to be longer with the Isa-Kd combination (HR: 0.566 [95% CI, 0.380–0.841])
• The overall survival data was immature but to date, it showed no significant difference between the two arms (death rate: 17.3% in Isa-Kd, and 20.3% in Kd)

A summary of efficacy outcomes is provided in Table 2.

Table 2. Efficacy outcomes²

CR, complete response; d, dexamethasone; Isa, isatuximab; ITT, intent to treat; K, carfilzomib; MRD, minimal residual disease; NR, not reached; ORR, overall response rate; PFS, progression-free survival; VGPR, very good partial response
Outcome	Isa-Kd (n = 179)	Kd (n = 123)	p value
ORR, %	86.6	82.9	0.1930
≥ VGPR, %	72.6	56.1	0.0011
≥ CR, %	39.7	27.6	—
MRD negativity rate (10-5), % ITT population Patients with ≥ VGPR	29.6 41.4	13.0 22.9	0.0004 —
Median PFS, months	NR	19.15	0.0007
Mortality rate, %	17.3	20.3	—

 

Exposure

Estimated exposure was obtained from the patients included in the safety analysis, i.e. Isa-Kd arm and Kd arm, 177 patients and 122 patients, respectively. The high relative dose intensity of Isa and K in the Isa-Kd arm showed the feasibility of combination (see Table 3).

Table 3. Exposure to treatments²

Safety population	Isa-Kd (n = 177)	Kd (n = 122)
Median treatment duration, weeks (range)	80.0 (1–111)	61.4 (1–114)
Relative dose intensity, median % (range) Isatuximab (Isa) Carfilzomib (K) Dexamethasone (d)	94.27 (66.7–108.2) 91.18 (18.2–108.7) 84.78 (24.5–101.1)	— 91.35 (41.8–108.6) 88.37 (27.4–101.6)

 Safety analysis

The results obtained from the safety population are presented in Table 4.

• Despite more Grade ≥ 3 treatment-emergent adverse events (TEAEs) with isatuximab, there were no differences in serious or fatal TEAEs between the two arms
• The rate of definitive discontinuation of treatment due to TEAEs was lower with the triplet combination
• Infusion-related reactions were observed in almost 45% of patients in the Isa-Kd arm, but only 0.6% were Grade ≥ 3
• 32.2% of patients in the Isa-Kd arm, and 23.8% of patients in the Kd arm experienced Grade ≥ 3 respiratory infections

Table 4. Safety outcomes²

AEs, adverse events; d, dexamethasone; Isa, isatuximab; K, carfilzomib; TEAE, treatment-emergent adverse events; URTI, upper respiratory tract infection *Grouping based on MedDRA SMQ cardiac failure narrow terms
Safety population	Isa-Kd (n = 177)	Kd (n = 122)
Grade ≥ 3 TEAEs, n (%)	136 (76.8)	82 (67.2)
Drug-related Grade ≥3 TEAEs, n (%)	87 (49.2)	58 (47.5)
Serious TEAEs, n (%)	105 (59.3)	70 (57.4)
Serious drug related TEAEs, n (%)	44 (24.8)	31 (25.4)
Main reasons for treatment discontinuation, n (%) Disease progression AEs	52 (29.4) 15 (8.5)	49 (40.2) 17 (13.9)
Fatal TEAEs, n (%)	6 (3.4)	4 (3.3)
Infusion-related reactions, n (%) All grades Grade ≥ 3	79 (44.6) 1 (0.6)	4 (3.3) —
Grade ≥ 3 TEAEs, n (%) Thrombocytopenia Anemia Hypertension Neutropenia Pneumonia Dyspnea Cardiac failure* URTI Fatigue Diarrhea Bronchitis	53 (29.9) 39 (22.0) 36 (20.3) 34 (19.2) 29 (16.4) 9 (5.1) 7 (4.0) 6 (3.4) 6 (3.4) 5 (2.8) 4 (2.3)	29 (23.8) 24 (19.7) 24 (19.7) 9 (7.4) 15 (12.3) 1 (0.8) 5 (4.1) 2 (1.6) 1 (0.8) 3 (2.5) 1 (0.8)

 Conclusion

Based on the results of the interim analysis, isatuximab combination with a proteasome inhibitor showed a statistically significant improvement in PFS and clinically meaningful improvement in the depth of response.

Adding isatuximab to carfilzomib and dexamethasone did not cause any additional toxicities than the ones described previously for Kd. The safety profile is manageable with a good level of tolerability and the risk/benefit is favorable. Overall, the triple combination of isatuximab, carfilzomib, and dexamethasone provides an effective and safe treatment option in patients with RRMM.

Review here the results from the primary analysis of the phase III CANDOR study comparing daratumumab plus Kd vs Kd in patients with RRMM, presented in 2019 at the 61st American Society of Hematology (ASH) meeting.