FUTURE MEDICINE: Prof.S.SCHEY on MULTIPLE MYELOMA

International Journal of Hematologic Oncology April 2013, Vol. 2, No. 2, Pages 109-112 , DOI 10.2217/ijh.13.7 (doi:10.2217/ijh.13.7) Interview: A lifetime of working to improve outcomes in multiple myeloma Steve Schey* Steve Schey speaks to Roshaine Gunawardana, Managing Commissioning Editor: Professor Stephen Schey is Consultant Haematologist and Honorary Senior Lecturer at King’s College Hospital and King’s College School of Medicine, King’s College London (London, UK). Schey qualified at St George’s Hospital (London, UK) in 1974, and later travelled to Australia where he worked at the Institute of Clinical Pathology and Medical Research in Sydney as Clinical Lecturer in Haematology. Subsequently, he returned to London to work at the Royal Free Hospital as Transplant Co-ordinator before working at the Royal Marsden (London, UK) and later the Middlesex Hospital (London, UK). Schey took up a Senior Lecturer post in 1985 and subsequently served as Director of Clinical Haematology for the Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust from 1993 to 2004. Schey has contributed his services to a number of national and international professional bodies. He was chair of the UK Myeloma Forum from 2003 to 2009, following two terms as the Secretary from 1997. This was a productive period during which Schey managed the development of guidelines, clinical trials and advocacy for the UK Myeloma Forum patients and healthcare professionals. He has been Clinical Research Lead for the South East London Cancer Network since 2005. He also served on the National Cancer Research Institute (NCRI) Haemoncology Cancer Steering Group between 2002 and 2010, the NCRI Industry Adoption Panel and was Chairman of the NCRI Myeloma Clinical Trials Committee until 2010. Schey was a member of the American Society for Hematology (ASH) Scientific Committee for Immunosecretory Disorders. He is currently the Professor of Plasma Cell Dyscrasias at King’s College London. Q What led to your initial interest in hematology and how did this evolve into a more specific interest in hemoncology? Previous sectionNext section I fell into hematology fortuitously when I took time out in the late 1970s and early 1980s to travel around the world. I initially had a job as a lecturer in medicine at Princess Alexandra Hospital (Brisbane, Australia) and was offered a post in the Institute of Pathology and Medical Research (Sydney, Australia) as a clinical lecturer in hematology at the Institute of Clinical Pathology and Medical Research in Westmead Hospital (Sydney, Australia) by the Director at that time, Dr Wilbur Hughes. He was a superb teacher and I was fortunate enough to become involved in establishing the Bone Marrow Transplant Unit at Westmead and to then be offered a job back in the UK at the Royal Free Hospital in London (London, UK) as Transplant Coordinator by Professor Grant Prentice. My training and exposure to such leaders in the field of this exciting, newly emerging therapeutic area of hemopoeitic stem cell transplantation, here and subsequently at the Middlesex Hospital (London, UK), resulted in me developing an interest in malignant hematology. When I obtained my first consultant job at Guy’s Hospital (London, UK) in 1985, I realized that myeloma was a field where progress had not been made in the previous 25 years, unlike many other hematological tumors, and I resolved to focus my efforts on investigating this malignancy to improve outcomes. Q Some of your research interests include multiple myeloma and the bone marrow microenvironment. Can you briefly describe your latest research in these areas? The crosstalk between multiple myeloma (MM) cells and the cells in the bone marrow (BM) microenvironment, such as osteoblasts, osteoclasts, stromal cells and endothelial cells, are mediated by both soluble factors, as well as by cell–cell contact-dependent mechanisms, such as cellular adhesion molecules and interactions with extracellular matrix proteins. Such interactions result in antiapoptotic signaling and drug resistance, and myeloma cell survival, proliferation and apoptosis can therefore be modulated by both interacting directly with the myeloma cell itself and indirectly through influencing the cellular milieu of the BM. The myeloma group at King’s College London (London, UK) has been studying: ▪ The coordination between integrin-mediated adhesions and actin dynamics leading to cell polarity, directional migration and tissue invasion; ▪ The reciprocal communication between the cytoplasm and the nucleus through the organization of adhesion/cytoskeletal complexes leading to changes in protein levels that regulate the migratory/adhesive properties and tumor-initiating potential of cancer cells. We are currently studying the dynamics of adhesion and cytoskeletal remodeling in myeloma- and tumor-associated myeloid cells (macrophages, dendritic cells and osteoclasts) within the BM microenvironment. We believe these interactions are crucial for the proliferative potential of myeloma cells, their adhesion-dependent drug resistance and tissue invasion. They are also critical for specific features of myeloma, such as hyperactivation of osteoclasts leading to bone lytic lesions and fractures in patients. Currently under investigation is the myeloma cell podia. We are the first group to have identified and characterize podia as the structures that myeloma cells form to interact with BM stromal cells leading to cell adhesion-mediated drug resistance [1]. We combine our basic science with translational research to identify new anticancer therapies by performing functional studies to determine whether specific signaling pathways that are associated with cell adhesion in the tumor microenvironment can be used as therapeutic targets. In order to validate the identified targets we have developed a fluorescence-based experimental model based on fluorimetry, flow cytometry and image analysis that employs mCherry-labeled stromal cells (e.g., BM fibroblastic stromal cells) cocultured in direct contact with enhanced GFP-labeled tumor cell lines for accurate assessment of proliferation and viability in both cell compartments and adhesion of tumor cells. In addition, we use fluorescent-based image analysis to determine morphological changes that predict cell function (e.g., morphology of the actin cytoskeleton and nuclearity of osteoclasts to predict their bone resorption activity). Using this platform we have revealed that dexamethasone induces HS5 fibroblast proliferation and contact with MM cells via a process involving Src/c-Abl kinases. Osteoclasts also inhibited dexamethasone-induced apoptosis in myeloma cells while retaining their normal morphology and functionality in bone resorption. Myeloma resistance to dexamethasone supported by HS5 cells and osteoclasts was reversed by treatment with the Src/c-Abl inhibitor dasatinib but not with bortezomib. This model is scalable to high-throughput application and can be used for more accurate screening of drug efficacy in MM [2]. Effective candidates identified in vitro are then tested in vivo using a myeloma mouse model that we use for basic in vivo studies on adhesion and migration, and use this information to identify combinations that will lead to clinical trials. This new experimental platform provides a more focused model for screening of new therapeutics for improved efficacy of tumor cell killing within the BM microenvironment. Q Your expertise also extends to hemopoeitic stem cell transplantation. How have you seen this technique and its application develop in recent years? Previous sectionNext section The year before I qualified in 1968 the first successful hemopoeitic cell transplant was performed on three patients with severe combined immunodeficiency disease in The Netherlands and the USA. Over the last 40 years there has been an explosion in our knowledge of hemopoiesis and immune biology that has seen better tissue typing and an expanding source of hemopoietic stem cells that has made this approach safer and available to a much increased number of patients. While autologous and allogeneic stem cell transplantation are set to play a role in patient management in the future, current research is looking at identifying which patients are most likely to benefit and, equally as important, who is not likely to benefit from transplantation and at what point in the pathway it should be applied. Biological and genetic engineering of the graft in the future may also be utilized to capitalize on the graft-versus-tumor effect to eradicate tumor stem cells. Q In your experience, what are the main challenges associated with the treatment of MM patients? Previous sectionNext section The massive increase in our understanding of the biology as well as the molecular and cytogenetic anomalies that underlie myeloma has resulted in an appreciation of the fact that myeloma is a heterogeneous disease. This knowledge has, in turn, led to the development of a large number of different classes of novel therapeutic agents and the concept of targeted therapy. Unfortunately, cytogenetic mutations are rarely single abnormalities, may vary in different parts of the tumor, and evolve and change over time, maybe even being driven by treatment. Hence, if one molecular pathway is therapeutically blocked the tumor can overcome this by utilizing a previously redundant pathway for progression or survival. For this reason no single drug is likely to be effective in all patients at all stages of the disease and this is the rationale that has led to combination treatment. Given the large and increasing number of new drugs that are in development, the challenge is to select and optimize appropriate drug combinations and to design and conduct clinical trials to identify the most effective combinations going forward. Although responses utilizing triple agents are approaching 100%, virtually all patients will relapse and die of their disease. We know that the microenvironmental tumor niche is able to protect the myeloma progenitor/stem cell from the effects of antitumor drugs, therefore, we need to devise ways of attacking the tumor precursors in their BM niche if we are to prevent relapse and cure the disease. The challenge is to develop strategies utilizing agents that will either attack the tumor cell in the BM niches or render them susceptible to currently available treatments. Q You have been the chief investigator and coinvestigator for several clinical trials. Why does drug-development research appeal to you? Previous sectionNext section The exciting thing about hematology is that when you see a patient you have the opportunity to follow them through all stages of the diagnostic and therapeutic pathway, first by assessing them clinically and then by performing and analyzing the laboratory investigations in order to come to a diagnosis. Patient-orientated clinical research offers the opportunity to then treat patients in novel ways to improve outcomes while investigating mechanisms of action. Q Could you outline the aims of the recent Phase III trial (MM-003) investigating pomalidomide in combination with low-dose dexamethasone? Previous sectionNext section The recent Phase III (MM-003) pomalidomide trial was a multicenter, randomized, open-label study comparing the efficacy and safety of pomalidomide in combination with low-dose dexamethasone versus high-dose dexamethasone in subjects with refractory, or relapsed and refractory MM [3]. Patients were eligible if they progressed on treatment or relapsed within 60 days of discontinuing their last antimyeloma treatment, which had to have included bortezomib and lenalidomide, either alone or in combination. Treatment was continued until disease progression or unacceptable toxicity occured. The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, time to progression and safety. Recent retrospective data published by a multicenter international myeloma working group [4] showed that in 286 myeloma patients who relapsed and/or were refractory to bortezomib, and relapsed or refractory to or ineligible to receive an immunomodulatory drug, the median overall survival and event-free survival were 9 and 5 months, respectively. This demonstrates an unmet need for patients who are no longer eligible or are unresponsive to current treatment options. Q How does pomalidomide differ from other available drugs, such as lenalidomide, and what were the main outcomes of the trial? Previous sectionNext section Pomalidomide is a new third-generation immunomodulatory agent originally known as CC-4047 that demonstrates in vitro anti-MM activity, and when compared with thalidomide and lenalidomide (Actimid™), has enhanced immunomodulatory activity through multiple mechanisms, including a direct apoptotic activity via caspase-8, inhibition of NF-κB activation and angiogenesis, and reduction of secretion of stromal cell stimulatory cytokines. Our first-in-man Phase I study of pomalidomide as a single agent in patients with relapsed/refractory MM established the maximum tolerated dose as 2 mg daily on days 1–28 of a 28-day cycle, and a subsequent study of 5 mg on alternate days was shown to be equally efficacious. The drug was well tolerated, the main side effect being myelosuppression, particularly neutropenia, but with a low rate of febrile neutropenia. Subsequently, it has been shown that when given in combination with dexamethasone in the relapsed/refractory setting it can induce partial responses in up to 67% of patients and very good partial responses or better in 33% of patients with median progression-free survivals of up to 12 months. Pomalidomide also shows activity in patients who are refractory to lenalidomide. More recently, the Mayo Group have shown refractoriness to both lenaolidomide and bortezomib using two different doses of pomalidomide in patients, with rates of minimal response in the 4- and 2-mg cohorts of 49 and 43%, respectively, including very good partial remission and partial response rates of 28.5 and 26%, respectively [5]. Furthermore, the responses occur rapidly within 2 months of initiating therapy and the median duration of response was not reached in the 2-mg dose study. Follow-up was only for 6 months but overall survival rates were 67 and 78% in the 4- and 2-mg cohorts. The average previous number of therapies in this current trial was five and 72% of patient entered were refractory to prior use of both lenalidomide and bortezomib. After a median follow-up of 18 months a significant increase in progression-free survival of 15.7 weeks in the combination of pomalidomide with low-dose steroid versus 8 weeks in the high-dose steroid arm (hazard ratio: 0.45; p < 0.001) was reported. Median overall survival was not reached in the combination arm, compared with a median of 35 weeks in the comparator arm (hazard ratio: 0.53; p < 0.001). An independent review by the study’s Data Safety Monitoring Board recommended that all patients in the high-dose steroid arm be switched over to treatment with pomalidomide and low-dose steroid, leading to a discontinuation of the comparator arm. The combination was well tolerated, although neutropenia (reported in 42% of patients on the combination and 15% in the comparator arm), thrombocytopenia (21 vs 24%, respectively) and fever (7 vs 0%, respectively) were reported in both arms. The primary reason for discontinuation was progressive disease (in 35 vs 49 patients, respectively). A total of 25% of patients died in both arms during the study, primarily from progressive disease and infections. Q Celgene (NJ, USA) anticipates a decision by the European regulatory authorities in the second half of 2013. Given the results of the trial, are you confident of a positive decision? Previous sectionNext section As we have become more successful with improved progression-free and overall survival in patients with myeloma, there is an increasing unmet need for agents and strategies to treat patients who have become resistant or refractory to currently available agents. Pomalidomide and the newer third-generation proteasome inhibitors are active in a significant proportion of these patients and have an excellent toxicity profile. I think that the improved survival and quality of life reported in those patients responding to treatment will result in a positive outcome from the regulatory authorities. Q If approved, how do you see pomalidomide impacting the MM patient population? Previous sectionNext section Given the plethora of active agents that are now available, we expect the vast majority of patients to respond to first-line therapy. However, the disease remains incurable with currently available treatments but patients are living 5–8 years longer than previously with a median overall survival of 7–10 years from diagnosis, with an excellent quality of life. I see pomalidomide being used in the intermediate future for patients who relapse or are refractory to our standard first-line agents, such as bortezomib and lenalidomide, and owing to its excellent tolerability and potent immunomodulatory activity I suspect this agent will have a role in long-term maintenance going forward. Q How would you like to see research in this field developing over the next 5–10 years? Previous sectionNext section I believe that the immune system will prove to be important in controlling myeloma progression and pomalidomide will be a valuable tool to explore this avenue of research. In clinical practice I believe pomalidomide will be used to maintain responses post-stem cell transplantation and possibly in preventing progression in high-risk monoclonal gammopathy. The excellent toxicity profile of pomalidomide makes it an ideal drug for long-term use as maintenance or to enhance immune strategies utilizing cellular and antibody therapy. Disclaimer The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd. Financial & competing interests disclosure S Schey has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.