Latest updates on idecabtagene vicleucel: Results from the KarMMa-2 and KarMMa-3 trials

Relapse remains common in multiple myeloma (MM), despite several recent clinical advances.^1,2 Many patients experience triple-class exposure early in their treatment regimens and are left with limited options.^1,2

Standard therapy approaches remain poorly defined, with suboptimal response rates and poor median survival outcomes.¹ Chimeric antigen receptor (CAR) T-cell therapy was recently approved for the treatment of heavily pretreated patients with relapsed/refractory (R/R) MM and now represents a significant clinical option for improving outcomes in these patients.^1,2

The KarMMa-3 trial evaluated idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed CAR T-cell therapy, with standard regimens for the treatment of MM patients who had received 2–4 lines of previous therapy and were refractory on the last regimen. We are pleased to summarize the key findings of the trials below.

Ide-cel versus standard care regimens^1,2

The KarMMa-3 trial study design has been illustrated in this previous Multiple Myeloma Hub article. Here, we summarize results published in The New England Journal of Medicine by Rodriguez-Otero et al.¹ and presented by Rodriguez-Otero² at the 5th European CAR T-Cell Meeting.

Results

Patients were enrolled from May 2019 to April 2022 at 49 sites across 12 countries. A total of 254 patients were randomized to the ide-cel treatment arm and 132 to the standard care (SC) arm. Baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics*

ECOG, Eastern Cooperative Oncology Group; HSCT, hematopoietic stem-cell transplantation; R‑ISS, revised International Staging System. *Adapted from Rodriguez‑Otero, et al.1
Characteristic, % (unless otherwise stated)	Ide-cel (n = 254)	Standard care (n = 132)
Age, median	63.0	63.0
<65 years	59.0	59.0
≥65 years	41.0	41.0
≥75 years	5.0	7.0
Median time from initial diagnosis to screening, years	4.1	4.0
Median time to progression during last previous antimyeloma therapy, months	7.1	6.9
Extramedullary disease	24.0	24.0
High tumor burden	28.0	26.0
ECOG performance status score
0	47.0	50.0
1	52.0	47.0
≥2	<1.0	3.0
R-ISS disease stage
I	20.0	20.0
II	59.0	62.0
III	12.0	11.0
Unknown	9.0	8.0
Median number of previous regimens	3.0	3.0
Previous autologous HSCT	84.0	86.0
Previous radiation therapy	35.0	35.0
Double-class-refractory disease	67.0	69.0
Triple-class-refractory disease	65.0	67.0
Penta-refractory disease	6.0	4.0

The median follow-up time was 18.6 months. Progression-free survival (PFS) was significantly longer in the ide-cel group at 13.3 months (95% confidence interval [CI], 11.8–16.1) compared with 4.4 months (95% CI, 3.4–5.9) in the SC group (hazard ratio, 0.49; 95% CI, 0.38–0.65; p < 0.001). The rates of PFS at the 6‑ and 12‑month timepoints are shown in Figure 1.

Ide-cel, idecabtagene vicleucel; SC, standard care.
*Adapted from Rodriguez‑Otero, et al.¹

Response rates were also significantly higher for ide-cel treatment, with 71% of patients achieving an overall response rate compared with 42% in the SC group (95% CI, 2.24–5.39; p < 0.0001). Moreover, the complete response (CR) rate was 39% for ide-cel as compared with 5% for the SC group. The median time to response was similar in both treatment groups whilst the median duration of response was longer in the ide-cel group (Figure 2).

Ide-cel, idecabtagene vicleucel; SC, standard care.
*Adapted from Rodriguez‑Otero, et al.¹

The proportion of patients who achieved negative measurable residual disease status within 3 months prior to the occurrence of CR was 20% (95% CI, 15.2–25.0) in the ide-cel group and 1% (95% CI, 0–2.2) in the SC group.

Safety

Safety outcomes from the ide-cel group and SC group are shown in Table 2.

Table 2. Adverse events that occurred in ≥20% of patients*

AE, adverse event; CRS, cytokine release syndrome: SC, standard care; TRAE, treatment-related adverse event. *Adapted from Rodriguez‑Otero, et al.1
Safety outcome, %	Ide-cel (n = 250)	SC (n = 126)
AE of any grade	99	98
Grade 3 or 4 AE	93	75
Grade 5 AE	14	6
Serious AE	52	38
Grade 5 TRAE	3	1
Sepsis	2	1
Most common hematologic AE of any grade
Neutropenia	78	44
Anemia	66	36
Thrombocytopenia	54	29
Infection
Any grade	58	54
Grade 3 or 4	24	18
Grade 5	4	2
CRS
Any grade	88	0
Grade 3 or 4	4	0
Grade 5	1	0
Neurotoxic event
Any grade	15	0
Grade 3 or 4	3	0

Secondary primary malignancy was recorded in 6% of patients in the ide-cel group and 4% in the SC group. The mortality rate for the ide-cel group was 30% compared with 26% in the SC group. Death was most commonly due to disease progression and infection in both treatment groups.

Ide-cel in earlier lines of treatment³

During the KarMMa-2 trial, ide-cel therapy was also investigated for use in earlier lines of treatment.

Here, we summarize results from a subgroup analysis of cohort 2a presented by Patel³ at the 64th American Society of Hematology Annual Meeting and Exposition. The analysis included a total of 37 patients, with a primary efficacy endpoint of CR. The key eligibility criteria were as follows:

• R/R MM
• Early relapse <18 months
• Measurable disease
• One prior anti-myeloma treatment
• Eastern Cooperative Oncology Group status ≤1

Results

The median follow-up was 21.5 months and 15 patients discontinued ide-cel treatment. Efficacy outcomes are shown in Table 3.

Table 3. Efficacy outcomes*

CI, confidence interval; CIa, Clopper-Pearson confidence interval; CR, complete response; CRR, CR rate; MR, minimal response; NE, not evaluable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; sCR, stringent CR; SD, stable disease; VGPR, very good partial response. *Adapted from Patel3 and Usmani, et al.4
Efficacy outcome, % (unless otherwise stated)	N = 37	p value
ORR (95% CIa)	83.8 (68.0–93.8)	<0.0001
CRR (95% CIa)	45.9 (29.5–63.1)	—
CR	8.1	—
sCR	37.8	—
VGPR	21.6	—
PR	16.2	—
MR	5.4	—
SD	10.8	—
Median PFS (95% CI), months	11.4 (5.6–19.6)	—
Median duration of response in patients who achieved ≥CR (95% CI), months	23.5 (10.2–NE)	—
Median duration of response in patients who responded (95% CI), months	15.7 (7.6–19.8)	—
Median OS, months	Not reached	—

Measurable residual disease data were available for 34 patients and showed a negative rate of 85% after 6 months and 70% after 12 months in patients who achieved a CR.

The most common hematologic adverse event was neutropenia, with 94.6% of patients experiencing a Grade 3/4 event. The most common non-hematologic adverse event was infection/infestation, with 21.6% of patients experiencing a Grade 3/4 event and 5.4% experiencing a Grade 5 event. Grade 1/2 cytokine release syndrome was recorded in 81.1% of patients and Grade 1/2 neurotoxicity in 21.6% of patients.

Conclusion

Overall, ide-cel treatment has shown durable responses in very difficult-to-treat patient populations. In comparison with SC regimens, ide-cel was associated with longer PFS, deeper responses, and attained clinical benefits from only a single infusion. The safety profile was consistent with previous studies. The use of ide-cel as an earlier line of therapy resulted in both frequent and encouraging responses, with expansion and persistence data consistent with other heavily pretreated cohorts. As a result, the clinical risk-benefit profile combined with the high-risk patient population highlights the possibility of use in earlier lines of treatment.