Novel biologically based therapies target both the multiple myeloma (MM) cell and its microenvironment. Understanding the cellular and molecular mechanisms of their anti-MM activity has already and will continue to aid in the identification of novel targets and strategies to overcome drug resistance and improve patient outcome.
Dr. William S. Dalton and coworkers at the H. Lee Moffitt Cancer Center have studied several mechanisms whereby MM cells themselves resist chemotherapy, including reducing uptake of drug into the tumor cell, altering the breakdown of the drug once it is in the patient, altering the target of the drug within the MM cell, and repairing the drug-induced ill effects in MM cells. Dr. Dalton discussed two factors within the bone marrow microenvironment of MM cells that also allow them to resist chemotherapy. First, cytokines such as interleukin-6 (IL-6) allow MM cells to resist death by turning on the JAK/STAT circuit and ultimately increasing the protective Bclx protein in MM cells. In contrast, blocking this circuit using the drug AG490 can restore sensitivity to drug-induced MM cell death. However, in some cases, AG490 can induce dormancy of tumor cells and actually then protect them from death, demonstrating the need to study the MM cell in its natural bone marrow environment. Importantly, direct contact and binding of the MM cell to bone marrow cells and noncellular proteins in the bone marrow results in cell adhesion-mediated drug resistance. Delineating those circuits mediating this protective effect may suggest treatments that are based on blocking adhesion of MM cells to bone marrow cells and proteins as well as interrupting those circuits triggered by adherence that enhance MM cell survival.
Dr. Pieter Sonneveld and colleagues (University Hospital, Rotterdam) further discussed mechanisms whereby MM cells escape from chemotherapy. His group was among the first to show that MM cells can become educated, or drug resistant, via the induction of pumps inside tumor cells that exclude chemotherapy and thereby confer protection. He described lung resistance protein (LRP), which is present in MM cells even before treatment. LRP protects tumor cells against melphalan, an agent commonly used to treat MM. LRP is also called major vault protein (MVP); together with other proteins, it appears to block transport of drug from the tumor cell surface to the cytoplasm inside, eventually inhibiting their entry to the nuclear compartment. Understanding how MVP works to protect tumor cells against chemotherapy therefore offers possible new methods to interrupt its effects.
Dr. Sergio Giralt and colleagues have tested a novel radionucleide called homium 166Ho-DOTMP, which homes to the bone and delivers relatively higher doses of radiation to the bone marrow site of MM than to normal organs. He described a study evaluating the safety and efficacy of either 166Ho-DOTMP plus high-dose melphalan or of 166Ho-DOTMP plus high-dose melphalan plus total body irradiation, followed by autologous peripheral blood stem cell transplantation. High response rates were seen, which need to be further confirmed in ongoing clinical trials. Continuous bladder irrigation appeared to be necessary to avoid side effects, including bloody bladder inflammation or kidney-related complications, the hemolytic uremic syndrome.
Dr. Ozaki from the University of Tokushima (Japan) described a protein called HM-1.24 on the surface of MM cells that can serve as a target for their selective removal. He showed data on an antibody directed at HM-1.24 that was humanized and so could theoretically work much like Rituxan serotherapy, which targets B-cell lymphoma. This antibody or serotherapy approach has great potential, as once MM cells have reacted with HM1.24 antibody, they are marked for removal by the patient's own immune system. This treatment approach warrants further study to extend these promising preliminary findings.
Dr. John Lust and coworkers from the Mayo Clinic presented studies on chemoprevention, the use of drugs to prevent the evolution of MM from the precursor lesion called monoclonal gammopathy of undetermined significance (MGUS). Their working hypothesis is that MM patients' bone marrow produces IL-1b, which in turn stimulates IL-6 production. IL-6 is the major growth and survival factor for human MM cells, and its secretion correlates with progressively active MM; therefore, blocking this process might inhibit development of active MM. He presented the design of ongoing trials using two drugs, DHEA to downregulate IL-6 and Biaxin to downregulate IL-1b. These studies may provide the framework for the use of inhibitors of IL-1b or IL-6 to block progression of MM or, importantly, to prevent the development of MM in those patients with MGUS destined to progress to MM.
Finally, Dr. Kenneth Anderson presented data on several classes of novel drugs that have in common targeting not only the tumor cell but also the microenvironment. These drugs directly induce MM cell death or dormancy and also inhibit the ability of MM cells to localize in bone marrow, the production of cytokines in the bone marrow that promote MM growth and survival, and new blood vessel formation or angiogenesis and, in some cases, stimulate the patient's own immune responses against MM.
First, thalidomide and its potent immunomodulatory drug (IMiD) derivatives directly induce death or dormancy, even in drug-resistant MM cells and patient cells; abrogate increased IL-6 and vascular endothelial growth factor (VEGF) secretion triggered by MM cell binding to bone marrow cells; stimulate autologous natural killer cell-mediated anti-MM immunity; and inhibit new blood vessel formation in MM bone marrow. They add to dexamethasone, both in the lab and when used together to treat patients. In a Phase I dose-escalation trial designed to define the highest tolerated dose of IMiD, 7 of 11 patients whose disease was unresponsive to any other therapy have achieved either stabilization or response. Importantly, side effects have so far been minimal.
Second, NF-kB activation is a switch that mediates growth, survival, and drug resistance in MM cells, as well as the increase in IL-6 production and secretion triggered by adherence of MM cells to bone marrow cells. Proteasome inhibitor PS-341 blocks this switch and in the laboratory kills even MM cells resistant to all known therapies. These drugs block the production of IL-6 and other cytokines in the bone marrow that the MM cell uses to grow and survive. Importantly, PS-341 blocks adherence of MM cells to bone marrow cells, which makes them susceptible to killing by chemotherapy. Excitingly, early Phase II trial results suggest that patients with MM relapsing after conventional treatments can benefit from proteasome inhibitor therapy, and ongoing trials will rapidly define their ultimate utility.
Third, MM cells secrete VEGF, which may account, at least in part, for the increased bone marrow angiogenesis in MM; it also triggers growth and motility of MM cells in the bone marrow. Based on both the direct effect of VEGF on MM cells and its effects on the bone marrow neighborhood, inhibitors of VEGF are soon to be tested clinically against MM.
Fourth, 2-methoxy estradiol (2ME) is a hormone that induces death of drug-resistant MM cells and also inhibits angiogenesis in the bone marrow. This drug is under testing at the Mayo Clinic and at Dana-Farber Cancer Institute. Arsenic trioxide also induces death of drug-resistant MM cells and acts to inhibit new blood vessel and cytokine production in the bone marrow; early clinical testing in MM patients is now ongoing. Tumor necrosis factor alpha (TNF a) is another novel therapeutic possibility in MM, since it increases the binding affinity of MM cells to bone marrow cells and related protection against drugs resulting from this binding. TRAIL/Apo2L is a drug that also induces death of drug-resistant MM cells without adversely affecting normal blood cells; it will soon enter clinical testing in MM and other cancers.
Finally, AE-491 is a derivative of shark cartilage that is a very potent inhibitor of angiogenesis and tumor growth; a multicenter international trial of this agent in MM has already begun. These drugs are examples of biologically based therapies with novel mechanisms of action against the MM cell and/or the bone marrow microenvironment that are or will soon be in clinical trials. They represent bench-to-bedside research in a new treatment paradigm for MM targeting both the tumor cell and its bone marrow milieu and offer great promise to improve outcomes for patients with MM.