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Study Design and Statistical Analysis Plans

Overview

The CoMMpass study (Protocol MMRF-11-001) was designed as a prospective, longitudinal, observational study in newly diagnosed multiple myeloma (MM) patients. The study's Statistical Analysis Plans (SAPs) established the clinical, operational, and analytical framework that guided:

  • Patient enrollment and eligibility
  • Timing and structure of follow-up assessments
  • Methods for clinical data derivation and outcome calculations
  • Integration of molecular profiling
  • Interim Analyses (IAs) and final analyses
  • Standards for data quality, statistical methodology, and subgroup evaluation

The SAPs ensured that all clinical and molecular data collected across more than a decade were handled with scientific rigor, consistency, and transparency, and they defined the timing and scope of each Interim Analysis (IA) - the structured “data cuts” released to investigators, collaborators, and eventually the broader research community.

Study Rationale and Objectives

The rationale for CoMMpass stems from the significant genetic and clinical heterogeneity of multiple myeloma. While precision medicine approaches have transformed treatment for many malignancies, similar advances in MM have been limited by incomplete integration of genomic data into clinical decision-making.

The CoMMpass study was created to address this gap by deeply profiling patients at diagnosis and over time, enabling an evidence-based understanding of how molecular alterations influence treatment response, relapse, and survival.

Primary Objective

To identify the molecular profiles and clinical characteristics that define subgroups of multiple myeloma patients at diagnosis and at relapse.

Secondary Objectives

  • Evaluate the utility of molecular profiles and baseline characteristics as predictors of clinical benefit, including:

    • Response rates
    • Progression-free survival (PFS)
    • Overall survival (OS)

  • Assess the utility of biomarkers derived from blood and bone marrow in predicting response and relapse.

  • Identify potential targets for novel therapeutics within molecularly defined patient subsets
  • Characterize bone disease and response to bone-directed therapies across genomic subtypes.
  • Analyze health-related quality of life (HRQoL) and resource utilization across the cohort.

These objectives evolved over time, with each interim analysis building upon discoveries from earlier data cuts, allowing the study to adapt and refine its analytic priorities.

Study Design

Population

The study enrolled newly diagnosed, symptomatic multiple myeloma patients who had not yet initiated systemic therapy. Key inclusion criteria included:

  • Age ≥18 years

  • Measurable disease defined by at least one of the following:

  • Serum M-protein ≥1 g/dL

  • Urine M-protein ≥200 mg/24 hours
  • Abnormal free light chain ratio with elevated involved FLC
  • Planned first-line systemic therapy including an IMiD® (lenalidomide, pomalidomide, thalidomide) and/or a proteasome inhibitor (bortezomib, carfilzomib)

Exclusion Criteria

  • Prior systemic treatment for MM (except bisphosphonates or a limited steroid dose)
  • Another malignancy within 5 years (with specific exceptions)
  • Enrollment in a blinded first-line therapeutic clinical trial
  • Smoldering MM (SMM), unless previously consented for tissue banking only

Follow-up

Patients were followed prospectively for at least 5 years, with the study later amended to extend follow-up to 8 years.

Clinical and molecular assessments were scheduled:

  • At screening
  • At baseline (pre-treatment)
  • Quarterly (aligned with standard-of-care visits) for surviving and enrolled patients
  • At disease progression, relapse, or study exit

Active data collection concluded at the end of 2023, marking the transition to final harmonization and integration.

Data Collected

The CoMMpass protocol captured a broad spectrum of clinical and molecular data, including:

  • Demographics and medical history
  • Baseline disease characteristics
  • Laboratory values and cytogenetics/FISH

  • Bone marrow aspirates and peripheral blood samples for:

    • Whole Genome Sequencing
    • Whole Exome Sequencing
    • RNA sequencing
    • Flow cytometry and immunophenotyping

  • Treatment data

    • Initial regimen
    • Subsequent lines of therapy
    • Stem cell transplant status

  • Response assessments, disease status, and survival endpoints

  • Adverse events, including documentation of severe/CTCAE grade ≥3 events
  • Resource utilization (hospitalizations, ER visits)
  • Quality of life measured using EORTC QLQ-C30 questionnaires

Populations for Analysis

SAPs defined the following analysis sets:

  • Screened Population
  • Enrolled Population
  • Per-Protocol Population (patients satisfying all major protocol requirements)

These sets were used to calculate clinical outcomes, derive survival analyses, and perform molecular subgroup characterization.

Role of Interim Analyses

The Statistical Analysis Plans defined a structured series of Interim Analyses (IA2–IA24) that served as official “data cuts.”

Each IA included cumulative clinical data, molecular profiling, derived endpoints, and updates from the evolving sequencing and QC pipelines.

Interim analyses enabled:

  • Progressive refinement of statistical models
  • Adding newly accrued patients and follow-up visits
  • Introducing new molecular assays and bioinformatic methods
  • Early dissemination of insights to collaborators and partners
  • Support for clinical trials, translational projects, and grant-funded work

This IA framework formed the backbone of CoMMpass data-sharing and is directly reflected in the Data Releases & Interim Analysis section of this documentation.