Research

The integration of immunotherapeutic strategies into the treatment landscape of multiple myeloma — such as monoclonal antibodies targeting CD38, BCMA-directed CAR T cell therapies and bispecific antibodies targeting BCMA and GPRC5D — has significantly improved clinical outcomes for many patients. In parallel, next-generation Cereblon E3 ligase modulators (CELMoDs), including iberdomide and CC-92480, have shown promising activity and represent an important expansion of available treatment options, particularly for patients with relapsed or refractory disease.

Despite these advances, most registration-enabling studies to date have relied solely on clinical eligibility criteria, without incorporating biological markers that may predict treatment response. Consequently, we lack validated biomarkers to identify patients most likely to benefit from specific immunotherapeutic agents. Moreover, our understanding of how these therapies reshape the molecular and immune landscape of the myeloma clone and its microenvironment remains limited — yet this insight is crucial for determining optimal treatment sequencing and combination strategies.

Given the growing complexity of the therapeutic landscape, there is a pressing need to employ integrated multi-omic approaches — including genomic, transcriptomic, proteomic and immune profiling — across both the tumor and its microenvironment. These comprehensive analyses will support the development of predictive algorithms to guide personalized immunotherapy strategies.

To this end, we have developed and validated platforms for single-cell transcriptomic profiling, whole exome sequencing and proteomic analysis of primary plasma cells and their bone marrow microenvironment. These tools have already played a pivotal role in advancing our precursor disease program, particularly in the study of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Building on this foundation, we are now applying these cutting-edge technologies to patients with relapsed and/or refractory multiple myeloma receiving novel immune-based therapies — many of whom are enrolled in investigator-initiated trials at UT MD Anderson.

We are conducting comprehensive multi-omic investigation of relapsed/refractory (RR) multiple myeloma to elucidate mechanisms of therapeutic resistance and identify novel targets for intervention. By integrating genomic, transcriptomic, proteomic and metabolomic data from longitudinal patient samples, we aim to achieve a robust molecular atlas that informs precision therapeutic strategies supporting following key objectives:

1. Genomic Landscape and Clonal Evolution
   We are using whole-exome and immunoglobulin sequencing of paired baseline and progression bone marrow samples to analyze clonal dynamics and mutational landscapes in RR myeloma patients treated with BCMA-targeted and other novel therapies. These efforts, in collaboration with the Advanced Technology Genomics Core (ATGC) at UT MD Anderson, will identify mutational signatures, subclonal evolution and resistance-driving genomic alterations.
2. Transcriptomic Profiling of the Tumor-Immune Ecosystem
   Single-cell RNA sequencing will profile malignant plasma cells and immune effectors in the bone marrow to identify gene expression patterns linked to treatment response or resistance. Insights will inform preclinical testing of therapeutic strategies in humanized mouse models.
3. Proteomic and Metabolic Characterization of Resistance Phenotypes
   We are using CyTOF and RPPA to validate genomic and transcriptomic findings by profiling protein expression and signaling pathways linked to resistance. Concurrently, metabolomic profiling will identify metabolic vulnerabilities associated with treatment response.