Multiple Myeloma Research Highlights

Highlights of Our Multiple Myeloma Research Program

As one of the largest programs of its kind in California, The Judy and Bernard Briskin Center for Multiple Myeloma Research sees over 300 new patients per year, and leads the development of a large diverse clinical trial portfolio of over 15 active phase 1/2 trials for all phases of multiple myeloma.
We aim to make multiple myeloma, and the related light-chain amyloidosis, manageable nonlethal diseases through the use of novel immunotherapeutic approaches and rational combinatorial therapies.
We achieve this goal by aggressively pursuing and encouraging new research, developing improved treatments, and collaborating with myeloma and amyloid experts nationally and internationally.
City of Hope is one of only a few dozen centers in the country that treat myeloma with a multidisciplinary team whose sole focus is treating this type of cancer.

Current Research Projects

Bispecific Antibodies

Bispecific antibodies represent a relatively new class of drugs. They are large protein-based molecules with two parts: One part binds to cancer cells, and the other binds to T cells or another component of the immune system. This way, the bispecific antibodies recruit the immune system to attack cancer. Various bispecific antibodies develop in multiple myeloma and vary regarding binding targets. Bispecific antibodies and related drugs include talquetamab, cevostemab, teclistamab, and SAR442257. The City of Hope myeloma team has been at the forefront of bispecific antibody research, participating in pivotal clinical trials that have demonstrated the therapeutic potential of these drugs. These efforts have contributed to the expected approval of teclistamab by regulatory bodies.

Radioimmunotherapy

Principal Investigator: Scott Goldsmith, M.D.
Lead Scientist: Flavia Pichiorri, Ph.D., M.S.

Daratumumab is a widely used drug for the treatment of multiple myeloma. It is an antibody that targets a protein known as CD38 on multiple myeloma cells' surfaces and recruits the immune system to fight myeloma. Unfortunately, although it is powerfully effective, most patients will eventually relapse. Our myeloma team at City of Hope discovered that CD38 is still expressed in the myeloma cells even when daratumumab loses its effectiveness. Instead, relapse occurs because the immune system has become exhausted. This finding means we have not lost CD38 as a target; we need a CD38-directed drug that does not rely on the immune system when immune exhaustion occurs.

At City of Hope, we have linked daratumumab to a radioactive element known as 225-actinium. Instead of relying on the immune system, 225-actinium-daratumumab is directly toxic to myeloma cells. Furthermore, our laboratory experiments have shown that this drug, 225-actinium-daratumumab, leads to substantial tumor regressions. We are now conducting a phase 1, first-in-human trial of 225-actinium-daratumumab in patients with advanced disease to learn more about its safety and tolerability and to assess its effectiveness preliminarily.

Leflunomide: A Drug Approved to Treat Arthritis

Principal Investigator: Michael Rosenzweig, M.D., M.S.
Lead Scientist: Flavia Pichiorri, Ph.D., M.S.

Leflunomide is a disease-modifying anti-rheumatic drug that has been FDA-approved for treating rheumatoid arthritis, both as a single agent and in combination with methotrexate, since 1998. Although the mechanisms of action for leflunomide are not entirely defined, the primary clinical mechanism of action is the inhibition of pyrimidine synthesis by targeting dihydroorotate dehydrogenase. In addition, Leflunomide's DNA- and RNA-inhibitory effects make it an attractive potential anti-cancer therapy. Preclinical studies have demonstrated the anti-cancer activity of leflunomide in central nervous system tumors, including glioma, as well as hematologic malignancies, including chronic lymphocytic leukemia and multiple myeloma. At City of Hope, we have confirmed the anti-myeloma activity of leflunomide by demonstrating its ability to inhibit cancer growth and induce apoptosis. Furthermore, we have demonstrated the potential synergy of leflunomide with other anti-myeloma agents, such as dexamethasone and lenalidomide. We continue to actively investigate leflunomide as an anti-myeloma therapy in the laboratory and the clinic, as a phase 1 trial of leflunomide is nearing completion. We have found that relapsed or refractory multiple myeloma patients tolerate and show clear clinical benefits from the treatment with leflunomide. Additional studies of leflunomide to treat this malignancy and high-risk smoldering disease are currently in development.

T Cell Immunotherapy

Principal Investigator: Maung Myo Htut, M.D.

As the new frontier in cancer treatment, T cell immunotherapy utilizes the patient's immune system, genetically engineering immune T cells to be more specific and efficient at killing myeloma cancer cells. These modified T cells will replicate inside the body, hunting down and killing cancer cells and providing long-term surveillance.

T cell immunotherapy has shown tremendous promise in leukemia and lymphoma patients in diseases targeting the CD19 tumor marker within the last five years. Research in City of Hope's Cancer Immunotherapeutics Program has yielded a growing portfolio of active clinical trials for targeting new tumor markers and a variety of blood and solid organ cancers, including glioma, lymphoma, childhood neuroblastoma, colorectal, breast, and prostate cancers. In addition, we are adding new protocols for lung cancer, ovarian cancer, leukemias, and pediatric or neonatal brain tumors.

In addition, preclinical studies at City of Hope have investigated the optimal multiple myeloma tumor markers to target T cell immunotherapy. Based on laboratory studies, we have selected the CS-1 protein as a promising target and the first to advance to clinical trials of T cell immunotherapy for myeloma. CS-1 (SLAMF-7) is an ideal target as it is universally expressed on myeloma cells but not normal cells. We plan to open a phase 1 trial evaluating the safety and tolerability of modified T cells targeting CS-1 in late 2018 for patients with advanced myeloma. Meanwhile, we continue to study additional myeloma targets for T cell immunotherapy to address that myeloma between patients and even within an individual patient is very heterogeneous, possibly requiring targeting multiple tumor makers for complete eradication. City of Hope is one of only a few centers in the U.S. that uses modified T cells to treat advanced myeloma. We are embarking on the first of a series of planned trials to employ genetically engineered T cells that recognize and destroy myeloma cells bearing selected tumor markers on their cell surfaces.

CELMoDs

Principal Investigator: Murali Janakiram, M.D.

CAR T cells are dramatically transforming the multiple myeloma treatment landscape, as most patients, even those with multiple relapses, experience complete or partial responses with CAR T cell therapy. However, one drawback of CAR T cells is that they tend not to last long in the body, and as a result, the duration of response may be somewhat limited. However, certain drugs can potentially extend the persistence of CAR T cells. City of Hope researchers have identified that drugs like Cereblon E3 Ligase Modulating Drugs (CELMoDs) may enhance CAR T cell activity. We are developing a clinical trial in which we give a CELMoD after infusion of CAR T cells to study the safety and tolerability of this approach and to begin to learn whether it helps lead to tumor control.

Geriatrics

Principal Investigator: Nitya Nathwani, M.D.

Cancer is a disease associated with aging, and multiple myeloma is a disease in older adults. In older individuals with multiple myeloma, it is vital to identify who is vulnerable to toxicity, and we need to modify therapy based on functional status, cognitive status, and a patient's unique social situation. In addition, we need to balance increasing longevity and to maintain quality of life. A comprehensive geriatric assessment and frailty evaluation is a good measure of toxicity and survival in older adults receiving treatment for multiple myeloma. However, comprehensive geriatric assessments are not routinely used in clinical practice because they can be time-consuming and complex, and there needs to be more clarity about the tools and technologies available to aid their use. We have partnered with an innovative technology company, Carevive, and incorporated a touchscreen-based geriatric assessment tool tailored for multiple myeloma patients, with the potential to make chemotherapy safer and more effective for seniors with multiple myeloma. With the help of this technology, the results are displayed in a single screenshot to facilitate treatment decision-making. We have accrued over 50 patients to this multi-center study led by The Judy and Bernard Briskin Center for Multiple Myeloma Research.

Daratumumab Sensitivity

Principal Investigator: Amrita Krishnan, M.D.
Lead Scientist: Flavia Pichiorri, Ph.D., M.S.

The remarkable efficacy of daratumumab is transforming the treatment landscape for multiple myeloma. However, this agent has not yet changed the reality that most multiple myeloma patients will eventually encounter disease relapse and resistance. In order to attain the goal of indefinite control or even cure of myeloma, we need to learn more about how this malignancy gains resistance to even power drugs such as daratumumab. Our laboratory research is shedding light on the mechanisms by which myeloma overcomes the effects of this antibody. These insights will likely lead to new therapeutic interventions to help sustain daratumumab's effectiveness.