KarMMa-3 trial: Updates from ASH 2023

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

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*

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
Type of response, %	Patients
ORR	73
≥VGPR	56
CR/sCR	25
VGPR	31
PR	17

• 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*

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

• 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.