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2023-03-08T15:50:40.000Z

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

Mar 8, 2023
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Learning objective: After reading this article, learners will be able to cite a new clinical development in relapsed/refractory MM

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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 regimens1,2

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*

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

ECOG, Eastern Cooperative Oncology Group; HSCT, hematopoietic stem-cell transplantation;
R‑ISS, revised International Staging System.
*Adapted from RodriguezOtero, et al.1

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.

Figure 1. Progression-free survival at 6 and 12 months* 

Ide-cel, idecabtagene vicleucel; SC, standard care.
*Adapted from RodriguezOtero, 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).

Figure 2. Median time to response and median duration of response* 

Ide-cel, idecabtagene vicleucel; SC, standard care.
*Adapted from RodriguezOtero, 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*

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

AE, adverse event; CRS, cytokine release syndrome: SC, standard care;
TRAE, treatment-related adverse event.
*Adapted from RodriguezOtero, et al.1

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*

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

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

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.

  1. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023. Online ahead of print. DOI: 1056/NEJMoa2213614
  2. Rodríguez-Otero P. Idecabtagene vicleucel (ide-cel; bb2121) versus standard regimens in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM): Phase III randomized controlled trial (RCT) KarMMa-3. Oral abstract #BA02-7. 5th European CAR T-Cell Meeting. February 10, 2023; Rotterdam, NL.
  3. Patel K. KarMMa-2 Cohort 2a: Efficacy and safety of idecabtagene vicleucel in clinical high-risk multiple myeloma patients with early relapse after frontline autologous stem cell transplantation. Oral abstract #361. 64th American Society of Hematology Annual Meeting and Exposition; Dec 10, 2022; New Orleans, US.
  4. Usmani S, Patel K, Hari P, et al. KarMMa-2 Cohort 2a: Efficacy and safety of idecabtagene vicleucel in clinical high-risk multiple myeloma patients with early relapse after frontline autologous stem cell transplantation. Abstract #361. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; Dec 10, 2022; New Orleans, US.

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