BOSTON (ASRN.ORG)- “I’ve been at this for 30 years and the last five years have been truly remarkable,” says Kenneth Anderson, MD, Harvard Cancer Center (HCC). He is speaking of the stretch of successes in the field of multiple myeloma novel therapeutics. For Anderson, success has meant significant improvements for patients. Following the program’s “bench to bedside” philosophy of expediting basic, preclinical, and clinical research, patients with multiple myeloma now survive seven to eight years after diagnosis compared with three to four years historically.
HCC has been at the core of getting four novel therapies combined into several new FDA-approved treatment protocols for multiple myeloma, all within the last half-decade. Explains Anderson, “Our bench to bedside studies have established a new paradigm for more rapid and precise cancer drug development and led to the introduction of novel life-prolonging therapies for myeloma patients.”
This is good news for the more than 750 new patients with multiple myeloma. HCC currently offers 20 ongoing clinical trials involving four cornerstones in myeloma treatment: novel agents, immunotherapies, stem cell transplantation, and supportive therapies.
New drug therapy bonanza
Multiple myeloma is the second most common blood cancer in the United States. About 20,000 new cases of multiple myeloma are diagnosed each year and about 10,500 Americans die from the disease annually. Though myeloma is still not yet a curable illness, the program’s efforts are aimed squarely at changing the statistics.
Since 2003, four drugs are now FDA-approved treatment options for myeloma patients largely based on work initiated and conducted through the program:
• the immunomodulator lenalidomide (Revlimid)
• the first proteasome inhibitor, bortezomib (Velcade)
• thalidomide (Thalomid)
• pegylated liposomal doxorubicin (Doxil)
“The trials behind these new targeted therapies have already changed the natural history of myeloma to a chronic illness in many patients and have a high promise for cure,” says Anderson. These drugs are now used as part of several FDA-approved combinations that have largely been responsible for the dramatic survival improvement.
Rapid progress continues with new drug combinations. A recently completed trial of bortezomib, lenalidamide and dexamethasone as an initial therapy yielded promising results. “One hundred percent of patients respond and 71% of patients get a complete or very good partial response, which is really unprecedented,” says Anderson, in collaboration with colleagues in France, are about to initiate another 1,000-patient trial in newly diagnosed patients with this same drug cocktail. “However, they will all have autologous peripheral blood stem cells collection and half of them will go on to get a stem cell transplant and half will not,” explains Anderson. This trial should allow researchers to understand if induction therapy with high-dose chemotherapy therapy and stem cell transplantation–a standard myeloma treatment for many patients—is still needed in the new reality of high frequency of responses with these novel treatments.
Working closely with Paul Richardson, MD, Anderson has shown that a drug called tanespimycin enhances sensitivity to bortezomib and may have a role in refractory/relapsed myeloma. Tanespimycin disrupts HSP90, a key molecular chaperone for signal transduction proteins. Phase II clinical trials show efficacy of combined therapy in bortezomib-refractory myeloma, and an international randomized phase III trial is ongoing for registration of this combination.
Constantine Mitsiades, MD, PhD; Laurence Catley, MD; James Bradner, MD; and Teru Hideshima, MD, PhD at DFCI have demonstrated the importance of the aggresome cascade for protein catabolism; identified histone deacetylase 6 (HDAC 6) to be essential in the chaperoning of ubiquinated proteins for aggresomal degradation; and work extensively on new drug classes, such as the HDAC 6 inhibitors. "Their studies show that dual inhibition of proteasomes and aggresomes with bortezomib and the HDAC inhibitors vorinostat and panibinostat induces synergistic cytotoxicity,” says Anderson. These researchers have rapidly translated these studies to ongoing international phase II and III clinical trials. To date, these studies show that the combination of bortezomib with either vorinostat or panibinostat can sensitize or even overcome bortezomib resistance, again setting the stage for clinical translation of a new class of cancer therapeutics.
Targeting the bone marrow milieu
Anderson credits the advances made in basic multiple myeloma research, particularly understanding how cells interact in the bone marrow, as fundamental to discovering new advances and novel therapies for myeloma. Noopur Raje, MD, focuses on this area of research in myeloma. “We believe the bone microenvironment plays a very significant role in the growth and proliferation of multiple myeloma cells,” says Raje. “Our focus is to try to alter this bone microenvironment or tumor niche to make it unfriendly to tumor cells.”
She comments that nearly 100% of patients with myeloma suffer from a tremendous imbalance in bone modeling and remodeling causing serious morbidity. “That imbalance predisposes towards increased multiple myeloma cell growth,” explains Raje. Her lab focuses specifically on osteoclasts, the bone resorbing cells that cause bone destruction, and osteoblasts, cells that help with bone healing and bone formation.
Her laboratory has identified several cytokines, including the B-cell activating factor (BAFF) and Activin A, that are upregulated in the context of these cell-cell interactions. Clinical trials are ongoing with neutralizing antibodies to BAFF (LY 2127399) and Activin A (ACE-011) to decrease osteoclasts and increase osteoblast numbers. “Osteoblasts are either non-existent or function very poorly in myeloma,” explains Raje. “But we have identified cytokines and gene targets that we think, if modulated, would increase this osteoblast population and rebalance the bone resorption/formation equation.”
Immunotherapies boosting therapeutic response
“Success in myeloma treatment will ultimately come by hitting the disease from multiple angles, through different pathways, different vulnerabilities,” according to David Avigan, MD. “It may involve combining biologic agents—like lenalidomide and bortezomib to cytoreduce the disease—followed by autologous stem cell transplant therapy where you may improve the immunologic milieu, and then vaccinate and provide immunomodulatory therapies afterwards.”
Avigan’s laboratory is taking on the task of developing a personalized myeloma vaccine that can reeducate the immune system to recognize and destroy myeloma cells. Working closely with Donald Kufe, MD and Jacalyn Rosenblatt, MD, his approach involves vaccination with a hybridoma created from patient-derived dendritic cells, which are potent immune system educators, fused with patient-derived myeloma cells.
The vaccine, developed in partnership with colleagues in Haifa, Israel, is now in a 40-patient phase II trial. Following standard high-dose induction chemotherapy, the first cohort of patients in the trial received a transplant, then a series of vaccines after the transplant. “In the initial group of patients, a significant proportion of patients were able to achieve complete remission several of which only achieved remission after completing the post-transplant vaccines,” explains Avigan. “This suggests that the vaccine may be impacting disease that is left over after the transplant."
Going forward, Avigan will be looking at other ways to further potentiate a vaccine response. He is studying the PD-1/PD-L-1 inhibitory pathway known to inhibit T-cell function. “The next study will be combining our vaccine with transplant and a PD-1 blocking antibody called CT-011,” says Avigan.
Nikhil Munshi, MD, is pursuing another myeloma vaccine option as well. He uses serum from patients with precancerous monoclonal gammopathy of undetermined significance (MGUS) or active disease screened against a myeloma library of antigens to identify those producing an immune response. “We’d like to see if we can figure out why 70% of patients with MGUS never proceed to myeloma,” explains Munshi. Using this approach he and his colleagues have identified several myeloma-specific antigens—notably XBP1, CD138, CS1, OFD-1—that produce significant immune reactions from these serum screens.
“In the broader goal, we would end up with a cocktail of antigens that we could use to vaccinate every patient,” he says. “Coupled with our research on improving the immune system in these patients we are hoping it may be used especially for pre-myeloma or ‘smoldering’ myeloma to prevent these patients from disease progression.”
Over the years, Munshi has collected genomic information on myeloma patients who have been followed for five to six years. “That has given us a significant database to identify new targets and treatments,” he says. Moving forward, his big focus is to understand the genomic changes within the cells of myeloma patients. “The myeloma genome changes in individual patients over time,” he explains. “We hope to understand the processes that drive the evolution of genome and then find methods to stop that evolution.” He says that the shifting genome observed in myeloma patients leads to resistant disease and ultimately to patient mortality. “In three to six years we want to have agents that prevent this evolution and prevent development of drug resistance or more aggressive disease.”
Munshi sums it up for many HCC colleagues working in myeloma, “This is absolutely a fascinating time to be doing myeloma research. Every coming year appears more promising than the last.” Considering the last five years, that speaks volumes for patients.
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Charles L. Berman
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