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2024-02-06T21:13:36.000Z

KarMMa-3 trial: Updates from ASH 2023

Feb 6, 2024
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Learning objective: After reading this article, learners will be able to cite key updates from the KarMMa-3 trial presented at ASH 2023.

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Patients diagnosed with relapsed/refractory multiple myeloma (RRMM) who have been exposed to multiple prior lines of therapy have limited treatment options and a poor clinical prognosis. Idecabtagene vicleucel (ide-cel), a first-in-class chimeric antigen receptor T-cell therapy, has shown favorable responses and improved health-related quality of life (HRQoL) for the treatment of patients with triple-class exposed RRMM in the recent phase II KarMMa trial (NCT03361748).

During the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, updated results from the phase III KarMMa-3 trial (NCT03651128) investigating ide-cel compared with standard regimens in RRMM were presented. Updates focused on the final progression-free survival (PFS) analysis, real-world safety and efficacy, and HRQoL outcomes in patients who were diagnosed with triple-class exposed RRMM. We summarize key points below.

The full KarMMa-3 study design was previously reported by the Multiple Myeloma Hub.

Preplanned final PFS analysis from the KarMMa-3 trial1

  • An additional 12.3 month follow-up period
  • Primary endpoint was Independent Review Committee-assessed PFS in the intent-to-treat population
  • Secondary endpoints were Independent Review Committee-assessed overall survival (OS) and overall response rate (ORR)

Results

  • Median follow-up was 18.6 months
  • Ide-cel showed a significant improvement in median PFS compared with standard regimens (13.3 months vs 4.4 months)
    • 51% reduction in the risk of disease progression or death
  • Other key response rates are shown in Figure 1

Figure 1. Key response rates from the KarMMa-3 trial at additional follow-up* 

CR, complete response; ide-cel, idecabtagene vicleucel; MRD, measurable residual disease; ORR, overall response rate; PFS, progression-free survival.
*Adapted from Otero.1

  • The median duration of response was longer in ide-cel treated patients compared with standard regimens (16.6 months vs 9.7 months)
  • The median OS was also longer for ide-cel vs standard regimens in the intent-to-treat population (41.4 months vs 37.9 months)
  • PFS and ORR results were consistent with those from the interim analysis

Safety

  • No new safety signals were identified
  • Cytokine release syndrome (CRS) of any grade was experienced by 88% of patients treated with ide-cel
    • In total, 4% of patients experienced ≥Grade 3 CRS events
  • Any-grade neurotoxicity was experienced by 15% of patients treated with ide-cel
    • In total, 3% of patients experienced neurotoxic ≥Grade 3 events

Conclusion

  • Patients treated with ide-cel experienced significantly longer PFS vs standard regimens
  • The safety profile was manageable and consistent with previous analyses
  • Results support the continued use of ide-cel in patients with triple-class exposed RRMM

Real-world efficacy and safety of ide-cel2

An analysis of 821 patients who received a commercial infusion of ide-cel.

  • only 801 patients had PFS data
  • median follow-up was 11.6 months

Efficacy

Response rates for the overall patient cohort are shown in Table 1.

Table 1. Real-world response rates for ide-cel*

Type of response, %

Patients

ORR

73

≥VGPR

56

CR/sCR

25

VGPR

31

PR

17

CR, complete response; ide-cel, Idecabtagene vicleucel; ORR, overall response rate; PR, partial response; sCR, stringent CR; VGPR,
very good PR.
*Adapted from Sidana.2

  • median PFS was 9 months
  • median OS was not reached
    • the 1-year OS estimate was 67%
  • PFS for ide-cel in patient subgroups are shown in Table 2

Table 2. PFS for ide-cel in patient subgroups*

Patient subgroup, months

PFS

Cytogenetic risk

              High

7.6

              Standard

9.74

Prior BCMA therapy

              <6 months

4.9

              ≥6 months

5.89

              None

9.67

Lymphodepletion type

              Bendamustine

3.85

              Fludarabine/cytarabine

9.14

BCMA, B-cell maturation antigen; ide-cel, Idecabtagene vicleucel; PFS, progression-free survival.
*Adapted from Sidana.2

  • OS was found to be inferior in patients treated with standard regimens compared with ide-cel in all subgroups (p = 0.019; p < 0.001; and p < 0.001, respectively)

Safety

  • The real-world safety profile was as expected
  • CRS of any grade was experienced by 80% of patients treated with ide-cel
    • 3% of patients experienced a ≥Grade 3 CRS events
  • Any-grade immune effector cell-associated neurotoxicity syndrome was experienced by 28% of patients treated with ide-cel
    • Overall, 5% of patients experienced a Grade ≥3 immune effector cell-associated neurotoxicity syndrome event
  • Infections were experienced by 45% of patients treated with ide-cel
  • Prolonged cytopenia was experienced by 28% of patients treated with ide-cel

Conclusion

  • This was the longest real-world study of ide-cel in patients with RRMM
  • Efficacy and safety were both favorable, with an ORR of 73% and median PFS of 9 months
  • This data supports the use of ide-cel in the heavily pretreated, real-world patient population.

HRQoL analysis from the KarMMa-3 trial3

  • This analysis of HRQoL outcomes from the KarMMa-3 trial included an extended follow-up of patient-reported outcomes data.
  • The primary outcome of this analysis was health status in several domains specified by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire, including:
    • physical and cognitive function;
    • fatigue;
    • pain;
    • quality of life; and
    • disease symptoms and side effects, as defined by the European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Questionnaire

Results

  • The baseline patient-reported outcomes were comparable between the ide-cel group and standard regimen group
  • Patients treated with ide-cel experienced significant and clinically meaningful improvements vs standard regimens in all the included domains
  • Overall, the least square mean change from baseline to Month 25 showed significant improvements in patients treated with ide-cel vs standard regimen in 18 of 21 health domains
    • The differences in these changes exceeded the threshold for the minimally important difference
  • Time to confirmed deterioration was significantly longer for patients treated with ide-cel vs standard regimens in the following health domains:
    • emotional;
    • cognitive and social functioning;
    • dyspnea; and
    • constipation.

Conclusion

  • Ide-cel significantly and meaningfully improved disease-associated symptoms compared with standard regimens
  • Overall, 18 of 21 health domains showed statistical improvement, and 13 of 21 showed clinically meaningful improvement
  • QoL-based improvements were experienced sooner with ide-cel treatment vs standard regimens and were sustained for >2 years
  • Results showed extended HRQoL benefits with ide-cel vs standard regimens in patients with triple-class exposed RRMM

Overall conclusion

Collectively, the updated results from the phase III KarMMa-3 trial demonstrate ide-cel can significantly extend PFS compared with standard regimens, with a manageable safety profile in both clinical trials and real-world settings. Disease-associated symptoms and HRQoL were also significantly improved, supporting the continued use of ide-cel in heavily pretreated patient populations.

  1. Rodríguez Otero P. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class exposed (TCE) relapsed and refractory multiple myeloma (RRMM): Updated analysis from KarMMa-3. Oral abstract #1028. 65th American Society of Hematology Annual Meeting and Exposition; Dec 11, 2023; San Diego, US.
  2. Sidana S. Real world outcomes with idecabtagene vicleucel (ide-cel) CAR-T cell therapy for relapsed/refractory multiple myeloma. Oral abstract #1027. 65th American Society of Hematology Annual Meeting and Exposition; Dec 11, 2023; San Diego, US.
  3. Delforge M. Effects of idecabtagene vicleucel (ide-cel) versus standard regimens on health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma (RRMM) who had received 2–4 prior regimens: Updated results from the phase 3 KarMMa-3 trial. Oral abstract #96. 65th American Society of Hematology Annual Meeting and Exposition; Dec 9, 2023; San Diego, US.

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