Research for Multiple Myeloma
Myeloma is not a single disease. Patients fall into subgroups of myeloma that respond differently to different treatments (inter-patient heterogeneity). Yet, even within an individual patient the myeloma cells may represent numerous genetically distinct clones, all of which interact with the various cells in the bone marrow microenvironment and which can change over time. The goal is to target all the different myeloma cell clones in the specific context of their bone marrow microenvironment.
The multiple myeloma program at Mount Sinai aims to cure myeloma and prevent it from developing in the first place. Our bench-to-bedside precision medicine approach integrates advances in genomics and immunotherapy to change the landscape for all patients, including those with resistant disease and those with pre-myeloma conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We are investigating novel agents such as monoclonal antibodies for relapsed and refractory disease, and immunotherapy initiatives such as CAR-T cell therapy and personalized vaccine-based preventive strategies. Our research focus includes:
Vaccine/Immunotherapy
We have identified immunogenic mutation-derived antigens from a large set of myeloma patients. Based on that information, and in collaboration with Nina Bhardwaj, MD, PhD, the Cancer Vaccine Laboratory, and the Vaccine and Cell Therapy Laboratory, we are developing personalized immunotherapy strategies for preventing myeloma progression, using a combination of peptide based vaccines and checkpoint inhibitors. Checkpoint inhibitors block normal proteins on cancer cells, or the proteins on the T-cells that respond to them. Checkpoint inhibitors seek to overcome one of cancer's main defenses against an immune system attack.
Important features includes:
- Identifying mutations in the genes of patients’ tumors
- Manufacturing patient-specific vaccines customized to the mutations
- Preventing myeloma progression
Building disease models that identify genomic and epigenomic changes that are causing relapse and resistance to treatment
A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. Epigenetics refers to modifications to the genome that can be passed on to future cells. Epigenetic changes can be influenced by many factors including age, the environment, and disease state, and can influence myeloma behavior.
Important feaures include:
- Identifying U.S. Food and Drug Administration (FDA)-approved drugs that modulate key drivers of disease resistance
- Discovering new disease biomarkers that form the basis for development of new targeted drugs
Next-generation genomic sequencing (NGS) technologies and advances in computational biology have enabled us to study the entire genome at an unprecedented level. In collaboration with Joel Dudley, PhD, director of the Institute for Next Generation Healthcare, we have created MMNet, the first high-resolution network model of myeloma. We have identified new insights into myeloma disease biology and molecular features for stratifying patients, as well as molecular targets for therapeutic alternatives. We are using the results from MMNet to apply a NGS approach for precision medicine applications and are achieving remarkable remissions for patients with highly refractory myeloma.
Identifying intra-patient tumor heterogeneity
Not all myeloma cells within an individual patient are identical. They can have different characteristics and degrees of aggressive behavior. This heterogeneity may contribute to drug resistance and disease relapse, progression from precursor conditions to active myeloma, and residual disease. We use advanced sequencing technology to identify the wide mutational spectrum and subpopulations of cells within an individual. Drilling down to the molecular detail of DNA and RNA via single cell analysis helps us uncover genomic variation. We are developing precision-medicine treatment approaches that target these subpopulations, as well as the bone marrow environment in which they develop, and diminish, the opportunity for aggressive cells that have become resistant to standard treatment to grow.
Mount Sinai Expertise
Our patients benefit from our in-depth collaborations with expert scientists across the Mount Sinai Health System. Some of the institutes and laboratories that we partner with are:
- Icahn Institute for Genomics and Multiscale Biology
- Institute for Next Generation Healthcare
- Vaccine and Cell Therapy Laboratory
- Cancer Immunology Program
- Cancer Immunology Immunotherapy Group
- The Dendritic Cell and Macrophage Biology Laboratory
- Human Immune Monitoring Core