SUMMARY

• CARVYKTI is not approved by the regulatory agencies for treatment of patients with high-risk smoldering multiple myeloma (SMM). Janssen does not recommend the use of CARVYKTI in a manner that is inconsistent with the approved labeling.
• CAR-PRISM (PRecision Intervention Smoldering Myeloma) is a phase 2, interventional study investigating the safety and efficacy of CARVYKTI in patients with high-risk SMM.¹
• The initial safety and efficacy results for the first 6 patients enrolled in the safety run-in cohort of CAR-PRISM were presented at a median follow-up of 10.5 months.²
  • No dose-limiting toxicities (DLTs) were observed in the safety run-in cohort.
  • All 6 patients experienced cytokine release syndrome (CRS), with 4 patients having grade 1 CRS and 2 patients having grade 2 CRS. No patients experienced grade 3 or higher CRS.
  • The overall response rate (ORR) was 100% and all 6 patients achieved a complete response (CR) as their best response. All 6 patients achieved minimal residual disease (MRD)-negativity at the 10^-6 threshold.

CLINICAL DATA

CAR-PRISM (clinicaltrials.gov identifier NCT05767359) is a phase 2, interventional study investigating the safety and efficacy of CARVYKTI in patients with high-risk SMM.¹

Study Design/Methods

• The study design is shown in Figure: CAR-PRISM: Study Design.
• Key eligibility criteria:
  • High-risk SMM with ≤40% plasma cells in the bone marrow and with high-risk criteria defined as having any 1 of the following criteria^1,2:
    • International Myeloma Working Group (IMWG) high risk per “20-2-20” criteria, defined as the presence of any 2 of the following^1,2:
      • Serum M-protein spike of ≥2 g/dL, involved-to-uninvolved free light chain (FLC) ratio of ≥20, and bone marrow plasma cell (BMPC)% of ≥20%
    • Having an IMWG total score of 9, computed using the following scoring system^1,2:
      • FLC ratios: >10-25=2, >25-40=3, and >40=5
      • Serum M-protein (g/dL): >1.5-3=3 and >3=4
      • BMPC%: >15-20=2, >20-30=3, >30-40=5, and >40=6
      • Fluorescence in situ hybridization (FISH) abnormality (t(4;14), t(14;16), 1q gain, or del13q)=2
    • Presence of ≥10% BMPC and at least 1 of the following^1,2:
      • Evolving pattern: evolving monoclonal protein (≥10% increase in serum M-protein over a 6-month period) or evolving change in hemoglobin (≥0.5 g/dL decrease in hemoglobin over a 12-month period) or progressive increase of >10% in involved light chain over a 6-month period along with a light chain ratio of >8.
      • Abnormal plasma cell immunophenotype: ≥95% of BMPCs are clonal and reduction of ≥1 uninvolved immunoglobulin (Ig) isotype (only IgG; IgA and IgM will be considered).
      • High-risk cytogenetics: defined as the presence of t(4;14), t(14;16), t(14;20), 17p deletion, TP53 mutation, or 1q21 gain.
• Exclusion criteria: presence of SLIM-CRAB criteria for active multiple myeloma; BMPC of >40%; diagnosis of or treatment for another malignancy within 2 years of enrollment; receipt of prior SMM-directed therapy within 6 months of beginning treatment in the study; occurrence of stroke or seizure within 6 months; presence of uncontrolled intercurrent illnesses including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social circumstances that would limit compliance with study requirements.^1,2
• Safety run-in: Patients were enrolled into either of the 2 safety run-in phases in a standard 3+3 design.^1,2
  • The first 3 patients were treated at a lower target dose of 0.5×10⁶ chimeric antigen receptor-positive (CAR+) viable T cells/kg, with Food and Drug Administration (FDA) review of safety prior to dose escalation.
  • The next 3 patients were treated at a target dose of 0.75×10⁶ CAR+ viable T cells/kg.
  • Enrollment was staggered, with 1 patient dosed every 60 days.

Results

Patient Characteristics

• Baseline patient characteristics are presented in Table: CAR-PRISM: Patient Characteristics.

Safety

• No DLTs were observed in the safety run-in cohort.²
• One patient experienced grade 1 Bell’s palsy (self-limiting and resolved within 2 weeks).²
• One patient experienced grade 4 immune-related thrombocytopenia (resolved within 2 weeks).²
• Hematologic toxicities included transient grade 3 neutropenia without any febrile neutropenia.²
• One patient experienced transient grade 3 aspartate aminotransferase (AST)/alanine transaminase (ALT) elevation, which was resolved.²
• There were no grade 3 infections reported to date.²
• There were no secondary malignancies reported to date.²

Cytokine Release Syndrome

• All 6 patients experienced CRS, with 4 patients having grade 1 CRS and 2 patients having grade 2 CRS. No patients experienced grade 3 or higher CRS.²
• Four patients received tocilizumab, and 2 patients received dexamethasone.²

Efficacy

• The median follow-up for the safety run-in cohort was 10.5 months.²
• Stem cell collection was successful in all eligible patients, with an average stem cell yield of 8.94×10⁶ cluster of differentiation (CD)34+ cells/kg.²
• The ORR was 100%, and all 6 patients achieved CR as their best response.²
• All 6 patients achieved MRD-negativity at the 10^-6 threshold. The first 3 patients had sustained MRD-negativity after 1 year of follow-up. The remaining patients were
  MRD-negative at the time of the last follow-up.²
• To date, no patients experienced biochemical or SLIM-CRAB progression.²

Pharmacokinetics

• CAR+ T cells expanded after CARVYKTI infusion in patients with high-risk SMM at both doses.²
• Variable peak expansion and persistence were observed among patients.²
  • The median time to peak expansion (t_max) was approximately 14 days (range, 14-14), with a mean (standard deviation [SD]; range) peak concentration (C_max) of 4212 cells/μL (4773; 580-13555).
  • At peak expansion, most T cells were CAR+ T cells (mean [SD; range], 83% [14; 57-97]).
• CAR+ CD4+ and CAR+ CD8+ T cells expanded after CARVYKTI infusion, with a preferential expansion of CAR+ CD4+ T cells at t_max in patients with high-risk SMM.²

LitErature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 26 December 2024.