Welcome to The Ghobrial Lab
Changing the Natural History of Multiple Myeloma Through Early Detection and Interception
About the Ghobrial Lab
Our mission is to transform multiple myeloma from a cancer diagnosed after symptomatic disease develops into one that can be detected early, accurately predicted, and ultimately intercepted before progression.
The Ghobrial Lab studies the earliest stages of multiple myeloma and related plasma-cell disorders, from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) through symptomatic disease.
Our research brings together population screening, prospective longitudinal cohorts, genomics, immunology, single-cell technologies, computational modeling, and innovative clinical trials to answer three fundamental questions:
Who will develop disease? Why will they progress? Can we intervene before symptomatic cancer develops?
Through large-scale studies such as PROMISE and PCROWD, we identify and longitudinally follow individuals with precursor conditions, creating an opportunity to study the evolution of cancer before and during malignant transformation. We integrate clinical biomarkers with genomic, immune, and microenvironmental changes to understand why some precursor conditions remain stable for decades while others progress rapidly.
These discoveries are translated into increasingly precise approaches to risk prediction, including PANGEA, which uses changes in clinical biomarkers over time to dynamically predict an individual's risk of progression.
Our ultimate goal is cancer interception: identifying individuals at highest risk and intervening at the earliest and most biologically favorable stage, when malignant clones may be less complex, immune function more intact, and the potential for durable disease control—or even eradication—may be greatest.
Our work is now testing this concept clinically through trials of targeted therapies, immunotherapies, bispecific antibodies, and cellular therapies in high-risk precursor disease.
Our vision is a future in which multiple myeloma can be detected before symptoms develop, progression can be predicted with precision, and effective intervention can prevent the development of symptomatic cancer.
Our Research
Our research program follows the continuum of cancer development from early detection → longitudinal characterization → prediction → biological discovery → therapeutic interception.
Early Detection and Population Screening
Can we identify individuals at increased risk of developing multiple myeloma before symptoms occur?
PROMISE is a large-scale screening initiative focused on populations at increased risk of multiple myeloma, including individuals of African ancestry and those with a family history of plasma-cell disorders.
By studying precursor conditions at the population level, we aim to understand who develops monoclonal gammopathy, identify biological and inherited determinants of risk, and develop strategies for earlier detection.
Longitudinal Cohorts: Understanding Progression
Why do some precursor conditions remain stable while others become cancer?
Through PCROWD, our prospective cohort of individuals with MGUS and SMM, we collect serial blood, bone marrow, and clinical data over time.
These longitudinal samples allow us to reconstruct the evolution of multiple myeloma and investigate the genomic, epigenetic, immune, and microenvironmental changes that occur during progression.
Rather than comparing patients only after different disease states have developed, longitudinal sampling allows us to observe malignant transformation as it occurs within individual patients.
Precision Risk Prediction
Can we identify which patients are destined to progress?
Accurately predicting progression is essential to cancer interception. We develop and validate models that integrate clinical, genomic, immune, and longitudinal biomarkers to distinguish individuals whose precursor disease is likely to remain stable from those at greatest risk of developing symptomatic myeloma.
Our PANGEA models incorporate changes in biomarkers over time, moving risk prediction from a single static assessment toward a dynamic and individualized estimate of progression risk.
Our goal is to determine not only who is at risk, but when intervention may provide the greatest benefit.
Genomics and Clonal Evolution
What biological events transform a precursor condition into cancer?
We study the genomic and evolutionary history of plasma-cell disorders from MGUS through SMM and multiple myeloma.
Our research examines:
- early genomic events that initiate precursor disease
- clonal heterogeneity and evolution
- mechanisms of early plasma-cell dissemination
- acquisition and selection of high-risk genomic alterations
- molecular determinants of progression
- mechanisms of treatment response and resistance
By defining the evolutionary pathways that lead to malignancy, we aim to identify vulnerabilities that can be targeted before increasingly complex and resistant disease develops.
Immunology and the Bone Marrow Microenvironment
How does the immune system change as myeloma develops?
Progression is determined not only by changes within the plasma-cell clone but also by its interaction with the surrounding immune and bone marrow microenvironment.
Using single-cell and spatial modalities, we study interactions among plasma cells, immune cells, stromal cells, and other components of the bone marrow niche.
We seek to understand how immune surveillance is lost, how malignant cells escape immune control, and how the microenvironment promotes clonal evolution, progression, and therapeutic resistance.
These studies may reveal opportunities to restore effective anti-tumor immunity during precursor disease, when the immune system may be more capable of mounting a durable response.
Liquid Biopsy and Biomarkers
Can we monitor precursor disease without relying solely on bone marrow biopsies?
We investigate circulating tumor cells, cell-free DNA, proteomic biomarkers, and immune signatures as minimally invasive approaches for detecting and monitoring plasma-cell disorders.
Our goal is to develop biomarkers that can identify emerging high-risk disease, track clonal evolution, and ultimately help guide the timing and selection of preventive therapies.
A Platform for Cancer Interception
The central goal of the Ghobrial Lab is to intercept multiple myeloma before symptomatic disease develops.
Our cancer interception platform connects longitudinal patient cohorts, genomic and proteomic discovery, immune profiling, therapeutic development, and early-intervention clinical trials. This integrated approach allows us to ask not only who should be intercepted and when, but also what biological vulnerabilities should be targeted and how new interception therapies can be developed.
Testing Cancer Interception: ImmunoPRISM and CAR-PRISM
ImmunoPRISM and CAR-PRISM test a fundamental hypothesis of cancer interception: can powerful immunotherapies produce deeper and more durable responses when administered during precursor disease, before symptomatic multiple myeloma develops?
ImmunoPRISM evaluates immune-based therapeutic strategies in high-risk SMM, testing whether engaging the immune system earlier—when tumor burden is lower and immune function may be more intact—can eradicate disease and prevent progression.
CAR-PRISM extends this concept to cellular therapy by evaluating BCMA-directed CAR T-cell therapy in high-risk SMM. By moving CAR T-cell therapy from advanced multiple myeloma into precursor disease, we are investigating whether targeting a smaller and potentially less heterogeneous malignant population can achieve profound and durable disease eradication.
Importantly, these trials are also discovery platforms. Through longitudinal single-cell, genomic, proteomic, immune, and T-cell analyses, we seek to understand why early immunotherapy works, which patients benefit, what determines durable response, and how resistance emerges.
Together, these studies establish a clinical framework for testing whether the timing of therapy can fundamentally change its ability to alter the natural history of cancer.
Discovering the Next Generation of Interception Therapies
Our large longitudinal cohorts and deeply characterized patient samples provide an opportunity to move beyond existing therapies and discover entirely new ways to intercept disease.
By integrating genomic, transcriptomic, single-cell, immune, surface-proteomic, immunopeptidomic, and T-cell receptor data across MGUS, SMM, and multiple myeloma, we are building a multidimensional map of the vulnerabilities that emerge during malignant transformation.
We use these data to pursue three complementary therapeutic strategies.
1. Discover Novel Cell-Surface Targets
We aim to systematically define the surface proteomic landscape of malignant plasma cells across the spectrum from precursor disease to multiple myeloma.
By directly profiling proteins expressed on the surface of primary tumor cells and integrating these findings with genomic, transcriptomic, immune, and plasma proteomic data, we seek to identify targets that are selectively expressed on emerging malignant clones and enriched in patients at greatest risk of progression.
These discoveries can provide the foundation for new antibodies, bispecific antibodies, antibody-drug conjugates, CAR T-cell therapies, and other targeted immune therapeutics designed specifically for cancer interception.
2. Identify Cancer Dependencies and Therapeutic Susceptibilities
Not every therapeutic target needs to be expressed on the cell surface. We are also using large-scale molecular and functional datasets to identify critical dependencies—biological pathways and proteins that malignant plasma cells require for survival.
These susceptibility targets provide opportunities to exploit fundamental weaknesses of the malignant clone.
IRF4 is an example of this strategy. Multiple myeloma cells are highly dependent on the transcription factor IRF4, but transcription factors have historically been difficult to target pharmacologically. Our recent work helped develop a first-in-class IRF4 degrader, demonstrating that a fundamental myeloma dependency can be converted into a novel therapeutic strategy.
We aim to systematically identify additional dependencies and translate them into small molecules, targeted protein degraders, and other novel therapeutics that can eliminate high-risk precursor clones before progression.
3. Discover Cancer Antigens and Develop TCR-Based Therapies
Many important cancer proteins are located inside the cell and therefore cannot be targeted by antibodies, bispecifics, or conventional CAR T cells.
To access this largely untapped therapeutic landscape, we are comprehensively defining the antigens presented by HLA molecules on the surface of plasma cells.
Using immunopeptidomics integrated with genomic and transcriptomic sequencing, we aim to identify cancer-restricted antigens across MGUS, SMM, and multiple myeloma, including mutation-derived neoantigens and noncanonical or cryptic antigens that would not be predicted from conventional genomic analysis alone.
We then determine whether these antigens can be recognized by T cells and identify the T-cell receptors (TCRs) capable of recognizing them. Candidate antigen–TCR pairs are functionally tested using engineered TCR-T cells to determine whether they can selectively recognize and eliminate tumor cells.
Validated targets can ultimately be advanced into TCR-engineered cellular therapies or cancer vaccination strategies.
This approach dramatically expands the potential therapeutic landscape beyond cell-surface proteins and creates the possibility of developing highly specific immune therapies against vulnerabilities that emerge during the earliest stages of malignant transformation.
Our ultimate goal is to make multiple myeloma a preventable malignancy. Detect earlier. Predict better. Intercept before cancer develops.
