PRIME Model

Predictive Relapse Indicators for Myeloma T-Cell Engagers (Blood 2025, ASH 2025)

Overview

PRIME (Predictive Relapse Indicators for Myeloma T-Cell Engagers) is a multivariable Cox model that predicts progression-free survival (PFS) in relapsed/refractory multiple myeloma patients receiving BCMA- and GPRC5D-targeting T-cell engagers. Published in Blood 2025 and presented at ASH 2025.

My Role: Contributing author on model development and validation.

The Problem

T-cell engagers (TCEs) targeting BCMA and GPRC5D have transformed RRMM treatment with unprecedented response rates. However:

  • Many patients relapse early or show only transient responses
  • No reliable predictors of treatment outcomes at TCE initiation
  • Need for personalized risk assessment to tailor treatment strategies

Study Design

Retrospective cohort study at Mount Sinai Health System:

Parameter Value
Patients Identified 325
Patients Analyzed 231 (minimal missing data)
PFS Events 125
Median PFS 17.6 months (95% CI: 12.4-24.3)
Median Follow-up 23.8 months (95% CI: 21.2-27.6)

Cohort Characteristics

  • Median age: 67.6 years
  • High-risk cytogenetics: 42.4%
  • Extramedullary disease (EMD): 22.1%
  • Prior CAR-T: ~20%
  • ≥5 prior lines of therapy: ~60%
  • Triple-class refractory: 85.3%
  • Penta-drug refractory: 39.8%
  • BCMA-targeting TCE: ~55%

Statistical Methodology

Model Development

  • Multivariable Cox model for PFS prediction
  • 13 pre-specified clinical/laboratory predictors (21 degrees of freedom)
  • Restricted cubic splines for continuous predictors (flexible modeling)
  • Riley’s shrinkage methodology to mitigate overfitting

Validation

  • Internal validation with optimism adjustment
  • C-index: 0.659 (95% CI: 0.629-0.749)

Output

  • Nomogram for individualized PFS estimates
  • Predictions at 6, 12, 24, and 48 months
  • Online calculator for clinical use (planned)

Key Predictors

Five predictors showed meaningful associations with PFS:

Predictor Comparison Hazard Ratio p-value Interpretation
ALC ≥0.9 vs <0.9 ×10³/µL 0.62 (0.43-0.90) 0.011 38% lower risk
High-risk cytogenetics Present vs absent 1.59 (1.10-2.30) 0.015 59% higher risk
EMD Present vs absent 1.54 (1.02-2.33) 0.041 54% increased hazard
LDH 600 vs 200 U/L 1.39 (1.06-1.81) 0.015 Continuous effect
Ferritin 1000 vs 100 ng/mL 1.54 (1.01-2.34) 0.045 54% increased hazard

Clinical Impact

PRIME enables personalized risk assessment for patients on TCE therapy:

  • BCMA-targeting agents: Teclistamab, elranatamab
  • GPRC5D-targeting agents: Talquetamab
  • Risk stratification at treatment initiation
  • Monitoring strategy optimization based on predicted risk
  • External validation planned with cohorts from other centers

Technical Stack

Statistics:     Multivariable Cox regression
Splines:        Restricted cubic splines
Shrinkage:      Riley's methodology
Validation:     Internal (optimism-adjusted)
Output:         Nomogram, Online calculator
Patients:       N=231 (from 325 identified)

Publication

  • Blood 2025 - “Development of Predictive Relapse Indicators for Myeloma T Cell Engagers (PRIME) Model” (Contributing Author)
  • ASH 2025 - Conference presentation

Collaborators

  • Tarek Mouhieddine (Lead Author)
  • Mount Sinai Myeloma Program