Research Highlights

Highlights of our multiple myeloma research program

  • As one of the largest programs of its kind in California, the center 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

Leflunomide – A drug approved to treat arthritis (Michael Rosenzweig, M.D., M.S.)

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

Metformin and Ritonavir – A drug approved to treat diabetes and one to treat HIV (Nitya Nathwani, M.D.)

Cancer cells need glucose to keep growing. This is why PET scans, which can measure glucose activity, are often used to track a cancer's progress in the body.

Stopping cancer by cutting off its glucose supply may be an attractive and less toxic treatment option when standard treatments fail or the patient develops resistance.

Metformin is a first-line treatment for type 2 diabetes and one of the most widely used pharmaceuticals in the world. It suppresses glucose production by the liver.

Metformin's potential as an anti-cancer drug has been studied since 2005 when it was shown that diabetes patients taking metformin had a lower cancer rate than patients on other drugs. Metformin has been shown to inhibit proliferation of several cancer cell lines, including breast, colon, ovarian, pancreatic, lung and prostate cancer.

Our multiple myeloma researchers are investigating the use of metformin in combination with ritonavir, an antiretroviral protease inhibitor used to treat HIV.

Numerous studies have shown ritonavir to possess cancer-fighting properties separate from inhibition of HIV protease. In fact, ritonavir is already being used in combination with the myeloma drug bortezomib to fight renal cancer, so the prospect of employing it against multiple myeloma is especially attractive.

While there is extensive clinical experience with both metformin and ritonavir, this is the first trial in which they are being combined.

T Cell Immunotherapy (Myo Htut, M.D.)

Truly the new frontier in cancer treatment, T cell immunotherapy utilizes the patient’s own 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 are designed with the intention of providing long-term cancer surveillance.

T cell immunotherapy is showing tremendous promise in leukemia and lymphoma patients in the last five years, in diseases that target the CD19 tumor marker. 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. Additional protocols for lung cancer, ovarian cancer, leukemias and pediatric/neonatal brain tumors are being added.

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, the CS-1 protein has been selected as a promising target and the first to advance to clinical trials of T cell immunotherapy for myeloma. CS-1 (also known as SLAMF-7) is an ideal target as it is universally expressed on myeloma cells but not on 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 the fact that myeloma between patients and even within an individual patient is very heterogeneous, possibly requiring targeting of multiple tumor makers for complete eradication. City of Hope is one of only a few centers in the U.S. where modified T cells are being used for treatment of advanced myeloma. Now 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.

Geriatrics (Nitya Nathwani, M.D.)

Cancer is a disease associated with aging, and multiple myeloma is a disease of older adults. In older individuals with multiple myeloma, it is important to identify who is vulnerable to toxicity, and we need to modify therapy on the basis of functional status, cognitive status and a patient's unique social situation.  We need to strike a balance between increasing longevity and maintaining quality of life. A comprehensive geriatric assessment and evaluation of frailty 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 is lack of clarity about the tools and technologies available to aid with their use. We have partnered with an innovative technology company, Carevive, and incorporated a touchscreen-based geriatric assessment tool, specifically 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 Briskin Center for Multiple Myeloma Research.
 
Radiolabeled daratumumab
 
With more patients being treated with new agents, we are beginning to see different patterns of relapse, such as extramedullary disease and oligosecretory relapses. Hence, new methods of detection of multiple myeloma may be valuable. Furthermore, since a new benchmark of multiple myeloma treatment is the goal of achieving a minimal residual disease (MRD) negative state, novel methods to detect MRD would be useful. However, irrespective of the sensitivity of MRD detection, the technique is limited by the nature of these tests in that they are marrow-based. They cannot account for a “patchy,” non-homogenous bone marrow infiltration. Positron emission tomography/computed tomography (PET/CT) is often used as a non-invasive monitoring strategy to assess cancer cell dissemination, but the ability to detect malignancies is partially dependent on the metabolic activity of the cancer cells. Lesions with a low metabolic rate may therefore result in false negatives. We conjugated the clinically significant CD38-directed human antibody daratumumab to the DOTA chelator and labeled with the positron-emitting radionuclide Copper-64 (64Cu-DOTA-Dara). We discovered that 64Cu-DOTA-Dara efficiently binds CD38, which is found on the surface of multiple myeloma cells. Biodistribution studies in a mouse model revealed that 64Cu-DOTA-Dara was mainly detected in the bones associated with tumor. We further learned that PET/CT based on our radioantibody displays a higher resolution and specificity to detect multiple myeloma cell dissemination in comparison to traditional PET/CT. We are beginning a clinical trial using 64Cu-DOTA-Dara as a novel imaging agent for multiple myeloma.
 
Daratumumab sensitivity
 
The remarkable efficacy of daratumumab is transforming the treatment landscape for multiple myeloma. However, this agent as yet has not changed the reality that the vast majority of 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 the ways in which 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. We envision that these insights will lead to new therapeutic interventions that will help sustain daratumumab’s effectiveness.