Results from the KarMMa trial on ide-cel in patients with relapsed/refractory MM

Idecabtagene vicleucel (ide-cel) is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with relapsed/refractory (R/R) multiple myeloma (MM) following four or more previous lines of therapy. Ide-cel is the first CAR T-cell therapy approved for MM.

The first-in-human phase I CRB-401 study (NCT02658929) recruited patients who had received three or more prior lines of therapy (including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody) and who were refractory to their last line of therapy. The latest report shows that ide-cel is effective and safe at target doses ≥150 × 10⁶ CAR+ T cells, achieving deep responses that lasted for a median of 10.3 months regardless of patient age, presence of extramedullary disease, and need of bridging therapy. After a median follow-up of 18.1 months, patients treated with ide-cel had a median progression-free survival (PFS) of 8.8 months and a remarkable median overall survival (OS) of 34.2 months.¹

These promising results led to the initiation of a pivotal phase II study, the KarMMa trial (NCT03361748), evaluating the safety and efficacy of ide-cel in patients with triple-class-exposed R/R MM.² The FDA approval was based on results from this study.

Study design²

Eligible patients were ≥18 years, had received ≥3 previous regimens for MM (including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), had measurable disease refractory to the last treatment regimen, and adequate organ function.

After lymphodepletion with fludarabine and cyclophosphamide, patients received target doses of 150 × 10⁶, 300 × 10⁶, or 450 × 10⁶ CAR+ T cells. The study design is shown in Figure 1.

The primary endpoint of the study was the overall response (partial response or better). The key secondary endpoint was complete response (CR) or better, and additional secondary endpoints were time to response and duration of response, PFS and OS, minimal residual disease (MRD), safety, pharmacokinetics, and immunogenicity.

Figure 1. Study design* 

CAR, chimeric antigen receptor; CY, cyclophosphamide; FLU, fludarabine; ide-cel, idecabtagene vicleucel.
*Data from Munshi et al.²

Patient characteristics

Of the 140 patients enrolled in the study, 128 received ide-cel infusions. Baseline characteristics of the patients are reported in Table 1.

Table 1. Baseline characteristics of patients who received ide-cel infusions*

Results

Efficacy

The tumor response in the 128 treated patients is shown in Figure 2. At a median follow-up of 13.3 months (range, 0.2─21.2 months), the overall response rate was 50%, 69%, and 81% at the 150 × 10⁶, 300 × 10⁶, and 450 × 10⁶ target doses, respectively. Efficacy in all enrolled patients (N = 140) and in the 28 patients retreated with ide-cel after disease progression is reported in Table 2. Out of 42 patients with a CR or stringent CR (sCR), 33 also had MRD-negative status (evaluated in bone marrow aspirates by next-generation sequencing at a sensitivity level of 10⁻⁵ nucleated cells); 9 patients could not be evaluated for MRD.

Figure 2. Response rates with ide-cel* 

CR, complete response; ide-cel, idecabtagene vicleucel; MRD, measurable residual disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Munshi et al.²

Table 2. Efficacy in all enrolled and retreated patients*

In the treated population:

• Median time to first response was 1.0 month (range, 0.5─8.8 months)
• Median time to CR or better was 2.8 months (range, 1─11.8 months)
• Median duration of response was 10.7 months (95% confidence interval [CI], 9.0─11.3) overall and 11.3 months (95% CI, 10.3─11.4) at the dose of 450 × 10⁶ CAR+ T cells
• The duration of response increased with the depth of response; the median response duration was:
  • 4.5 months (95% CI, 2.9─6.7) in patients having a best response of partial response
  • 10.4 months (95% CI, 5.1─11.3) in patients having a very good partial response
  • 19.0 months (95% CI, 11.3─not estimated) in patients having a CR or sCR
• Median PFS was:
  • 8.8 months (95% CI, 5.6─11.6) overall
  • 12.1 months (95% CI, 8.8─12.3) at the 450 × 10⁶ dose
  • 20.2 months (95% CI, 12.3─not estimated) in patients having a CR or sCR
• Median OS was 19.4 months (95% CI, 18.2─not estimated), with an OS of 78% at 12 months

A subgroup analysis showed an overall response in ≥50% of patients and a CR or sCR in ≥10% of patients in most subgroups examined, including older patients, those who received bridging therapy, patients with high-risk cytogenetics, and those with triple- or penta-refractory disease, a high tumor burden, or extramedullary disease.

Of the 28 patients retreated with ide-cel (at a dose higher than their initial dose) after disease progression, six had a second response, with durations of response ranging between 1.9 months and 6.8 months.

Safety

Adverse events of any grade occurred in all the treated patients and are reported in Table 3. Most of the adverse events occurred within the first 8 weeks after infusion.

Table 3. Hematologic adverse events, cytokine release syndrome, and neurotoxic effects*

The median time to the onset of cytokine release syndrome (CRS) was 1 day (range, 1─12 days) and the median duration was 5 days (range, 1─63 days). The median time to any neurotoxic effect was 2 days (range, 1─10 days) and the median duration was 3 days (range, 1─26 days). The management of both CRS and neurotoxic effects included tocilizumab and glucocorticoids; their use increased with higher doses of ide-cel.

Of the 128 treated patients, 44 (34%) died during the study; 27 deaths were attributed to complications of disease progression.

Pharmacokinetic and biomarkers

The data cutoff date for the pharmacokinetic analysis was April 19, 2019. Among 127 treated patients, maximum CAR+ T-cell expansion occurred at a median of 11 days, with higher exposures in responders versus nonresponders. Higher exposure was associated with deeper responses and longer PFS. At 6 months and 12 months after infusion, CAR+ T cells were detected in 29 of 49 patients (59%) and 4 of 11 patients (36%), respectively.

Early after ide-cel infusion, an increase in levels of proinflammatory markers (including cytokines, ferritin, and C-reactive protein) was observed, with higher peak levels in patients developing Grade ≥3 CRS. These levels decreased by Month 1.

Elevated levels of soluble BCMA (sBCMA), a marker of MM burden, observed in treated patients, decreased rapidly after infusion in responders. Undetectable levels of sBCMA were observed in 63% of patients with a partial response, 81% with a very good partial response, and 95% with a CR or sCR. The duration of undetectable sBCMA correlated with duration of response, and clearance of sBCMA at Month 2 was associated with longer PFS.

Conclusions

• Ide-cel treatment showed deep responses in patients with triple-class-exposed R/R MM, with higher CAR+ T-cell doses associated with greater depth of response.
• Efficacy was encouraging, with a PFS and an OS of 8.8 months and 19.4 months, respectively.
• CRS and neurotoxic effects of Grade ≥3 were observed in 5% and 3% of patients, respectively.
• The most common but transient adverse events were hematologic events.

Future perspectives

Other ongoing clinical trials are investigating ide-cel, including the following¹:

• KarMMa-2 (NCT03601078): a phase II study of ide-cel in triple-class-exposed patients and patients with high-risk MM.
• KarMMa-3 (NCT03651128): a phase III study of ide-cel vs standard regimens in triple-class-exposed patients with two to four prior lines of therapy.
• KarMMa-4 (NCT04196491): a phase I study of ide-cel in patients with high-risk newly diagnosed MM.

A CAR T-cell therapy (bb21217) using the same CAR molecule as ide-cel, but with the addition of the phosphoinositide 3-kinase inhibitor bb007 during ex vivo culture to enrich for memory-like T cells, is under investigation in the CRB-402 (NCT03274219) phase I trial in patients with R/R MM who received ≥3 prior regimens, including proteasome inhibitor, immunomodulatory agent, and a CD38 antibody. Preliminary results showed a safety profile consistent with that of CAR T-cell therapies and encouraging efficacy.³