Our Approach

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A Complex Challenge

While we have more genomic information about multiple myeloma than many other neoplastic diseases, this knowledge has not yet translated into more effective therapies. Numerous studies have highlighted the biological complexity of multiple myeloma that arises as a result of several disrupted cancer pathways. In addition, the disease shows great heterogeneity, reflected by its wide panel of genetic alterations and the individual differences in overall response and survival of patients receiving the same treatment. In fact, we have not identified “driver” mutations or thematic pathways, and there is no actionable genetic signature for multiple myeloma. Epigenetics represents the system that controls gene expression (i.e. turns them on or off). Recent work suggest that epigenetics changes observed in myeloma cells are critical for response or resistance to therapy.

Scientific Approach:

For decades, the study of the complex biology of multiple myeloma has consumed scientists and physicians in the field. The cure for multiple myeloma – and ultimately many other cancers – will be discovered through a multipronged and sequential approach to achieve the following:

Eradication of cancer cells
Manipulation of the microenvironment (removal of hiding niches) to preclude their return
Strengthening the immune response to prevent recurrence and maintain a disease-free state (immuno-oncology)

The link between the cellular microenvironment and effective immune surveillance appears now to hold the key to a cure for multiple myeloma and other related blood disorders.

Step One...

calls for target identification and drug discovery, including protein degradation, IMIDs, PPMs, Ubiquitin ligase, small molecules, and epigenetics modifiers. Combinations of these novel agents already allow us to reach much better and deeper response than conventional chemotherapy. Unfortunately, even after response to treatment, residual cancer cells or myeloma cells not visible by conventional measurements can remain. This is referred to as minimal residual disease. Recent technologies with sequencing allows us to identify one cell in 100,000 and will help us develop better strategies to increase the depth of response. This is happening in many cancers and will in myeloma as well, as patients who achieved a molecular remission have a much better outcome.

Step Two

presents significant challenges. The multiple myeloma microenvironment offers an extraordinary degree of sanctuary to neoplastic plasma cells. Interaction of myeloma cells with numerous elements of the marrow niche all lead to chemoresistance in multiple myeloma. The primary question, therefore, is how do myeloma cells condition the microenvironment and how does the microenvironment offer protection to those cells.

Step Three

holds the key to a long-term cure for multiple myeloma by restoring the immune system’s natural ability to eliminate cancer cells. Cancer cells, including myeloma cells, shut down the immune response during their development. This induces a state of tolerance from the immune system which allows cancer cells to escape and continue to grow. Thanks to progress in understanding the biology of the immune response, new tools have been developed, particularly antibodies that unleash the immune system and have shown very impressive anti-tumor activity across multiple cancers including in myeloma.

As part of the next step of developing immunotherapeutics, we must better understand the interaction of myeloma cells and the immune system, particularly the role of the microbiome (collective bacteria we have in our body, particularly our colon) which appears critical in regulating some of these complex dialogues between the immune system, the host, and the cancer cells.

Further, one of the key strategies to improve the outcome and cure multiple myeloma might be in the understanding of the early phase of myeloma including MGUS or smoldering myeloma. Here again it appears that the progression of the disease relies on complex successive events including additional genetics and epigenetics changes as well as the loss of immunosurveillance.

The Multiple Myeloma Division at JTCC has already developed relationships that have brought advanced immunotherapeutics to patients. This includes a robust bone marrow transplant program, CAR-T cells, NK-cell based therapies, monoclonal antibodies and checkpoint inhibitors. Studies exploring the role of immune effector cells, the quality of the T-cell repertoire and the microbiome in the context of transplant and immunotherapies are already being explored under the auspices of Drs. Robert Korngold and Rena Feinman.