1. Understanding MM Initiation (Preclinical Phase):
We examined bone marrow samples from healthy individuals to investigate whether MM shares origins with other clonal blood disorders like CHIP (Clonal Hematopoiesis of Indeterminate Potential). Our findings showed that while CHIP is common in older individuals, it does not share a progenitor with plasma cell neoplasms, suggesting separate evolutionary trajectories. Additionally, by using mutational timing analyses, we estimated that the earliest genetic lesions leading to MM can arise decades before diagnosis, although these early cells are extremely rare and currently difficult to detect.
2. Monitoring Early Disease (Smoldering Myeloma Studies):
We assembled and analyzed samples from patients with high-risk MGUS, SMM, and overt MM. Genomic and single-cell analyses showed that while some initiating mutations are shared, those driving progression are distinct and often involve complex genetic changes, including chromothripsis and aberrant DNA repair signatures. These alterations are frequently missed by standard diagnostic methods. We are working with collaborators to develop clinical-grade tools to detect such changes. This work is being supported by a European Research Council “Proof of Concept” grant. One consistent clinical observation was that a decline in hemoglobin often precedes progression—this is now being validated in risk models.
3. Single-Cell Studies:
Using a novel B-cell receptor (BCR) barcoding strategy, we successfully distinguished malignant plasma cells from normal ones at the single-cell level. Surprisingly, even non-clonal plasma cells displayed abnormal gene expression patterns, particularly in pathways related to immune function. These findings may explain the impaired immune responses observed in MM patients, even at asymptomatic stages. We are currently analyzing how these cellular states evolve over time and contribute to immune suppression and progression.
4. Targeting Disease Drivers and Testing New Drugs:
We found KRAS mutations to be enriched in progressive MM cases. In collaboration with partners, we tested KRAS-targeting compounds in cell models. We also developed a computational framework that links patient-derived molecular profiles with known cell lines to predict treatment responses. This led to identification of biomarkers for sensitivity to venetoclax, an emerging therapy for MM patients with specific genetic subtypes. We further studied FAM46C, a tumor suppressor gene often inactivated in MM, and demonstrated its role in regulating plasma cell proliferation and drug target gene expression, underscoring its potential as a therapeutic target.
5. 3D Disease Modeling:
To better replicate the bone marrow niche, we created a 3D culture system using silk-based scaffolds that support the survival and function of patient-derived plasma cells and other BM components. This model allows for more realistic in vitro study of disease biology and drug responses. Initial results are promising, and we plan to scale this platform for broader functional and therapeutic screening.
