Targeting MRD: Functional Profiling to Guide the Next Generation of Therapies in Hematological Malignancies
As therapeutic options for hematologic malignancies advance, the clinical relevance of minimal residual disease (MRD) continues to grow. In multiple myeloma (MM), increasing numbers of patients achieve deep remissions, and MRD detection is rapidly shifting from a prognostic biomarker to a therapeutic decision point. Shortly, MRD may emerge as a defined therapeutic indication across multiple cancers.
However, this evolution brings new challenges: The malignant cells that persist after treatment may harbor resistance mechanisms, and toxicity is less acceptable since patients are asymptomatic. The next generation of MRD-directed therapies must therefore demonstrate not only efficacy but also an acceptable safety profile.
The Dual Need: Efficacy and Selectivity
To address this, Vivia Biotech has developed a proprietary ex vivo assay that enables the simultaneous assessment of drug activity and hematotoxicity in bone marrow samples from MRD+ patients. Unlike conventional cytotoxicity assays that use isolated cells, our approach preserves the whole bone marrow, providing a physiologically relevant platform to test candidate drugs.
This platform supports early go/no-go decisions in compound prioritization by capturing both direct tumor cell killing and unintended effects on healthy hematopoietic populations.
Detecting Functional Resistance to Daratumumab in MRD+ Samples
One of the first applications of this MRD-adapted assay was to characterize the activity of daratumumab, a widely used anti-CD38 monoclonal antibody, in post-treatment MM patient samples. While daratumumab often induces MRD-negativity, our assay revealed functional resistance in some MRD+ patients: Daratumumab selectively depleted normal plasma cells, while malignant plasma cells persisted.
This finding highlights the importance of functionally evaluating therapeutic selectivity, rather than relying solely on target expression or response rates.
Selective Depletion of Normal Plasma Cells by Daratumumab in MRD+ Bone Marrow
Flow cytometry analysis of total plasma cells (left) and the phenotypic distribution of normal (CD19⁺CD45⁺, blue) vs. pathological (CD19⁻CD45⁻/dim, red) plasma cells (right) in a multiple myeloma MRD+ bone marrow sample. After 4–6 hours of incubation with daratumumab (25 μg/mL), the normal plasma cell population is notably reduced, while pathological plasma cells remain unaffected. This profile suggests functional resistance of residual malignant cells to daratumumab and selective activity against healthy plasma cell subsets.
Translational Value for Drug Development
This type of insight is critical for guiding MRD-focused drug development. Our assay enables biotech and pharmaceutical partners to:
- Functionally profile drug responses in MRD+ patient samples using clinically relevant microenvironments.
- Simultaneously assess efficacy and hematologic toxicity across cell populations.
- Identify resistance patterns that are not evident from target expression alone.
- Molecular characterization of MRD+ resistant clones.
- De-risk candidate selection and optimize combination strategies.
Conclusion
MRD is no longer just a marker of prognosis; it is rapidly becoming a functional therapeutic space.
Vivia Biotech’s MRD-adapted ex vivo assay provides a translationally relevant tool to support this shift, bridging preclinical decision-making with real patient biology. Whether to uncover resistance, validate mechanisms of action, or de-risk hematologic toxicity, this platform offers critical data for the largest future indications.