SPECIAL FOCUS y The comprehensive clinical management of MM
Interview
Multiple myeloma: genome sequencing, drug development and the future outlook Expert Review of Hematology Downloaded from informahealthcare.com by Mercer University on 11/13/14 For personal use only.
Expert Rev. Hematol. 7(1), 9–11 (2014)
Alexander Keith Stewart Mayo Clinic,13400 East Shea Boulevardm, Scottsdale, AZ, USA [email protected]
Interview by Jonathan Patience, Commissioning Editor Keith Stewart is the Dean for Research at Mayo Clinic (AZ, USA). He holds the Vasek and Anna Maria Polak Endowed Professorship in Cancer Research. He received his medical degree at Aberdeen University Medical School and trained in internal medicine and hematology in Glasgow, Kingston, Toronto and Boston. He was a consultant at the Toronto General and Princess Margaret Hospitals from 1992 to 2005 and a Professor in the Faculty of Medicine at the University of Toronto. He joined Mayo Clinic in Arizona in 2005. His lab-based research has focused on the genomics and developmental therapeutics of multiple myeloma. He has led numerous clinical trials from ‘first in man’, through to large international Phase III studies. Funding for his research includes the National Cancer Institute, the Leukemia and Lymphoma Society (LLS) and the Multiple Myeloma Research Foundation (MMRF). In addition, he is an associate editor of Blood, the journal of the American Society of Hematology (ASH).
Could you briefly describe your professional background & what led you to pursue a career in hematologic oncology? I went to medical school in Scotland at Aberdeen University and did my internship at Glasgow Royal Infirmary, where I worked on the hematology ward with Alan Burnett, who had just started a bone marrow transplant unit in the early 1980s. That experience was really what got me interested in the treatment of leukemia and bone marrow transplant and led to my decision to pursue a career in hematology. Subsequently, I moved to Canada and did the rest of my training there, as well as a research stint in Boston (MA, USA) for 2 years with Robert Schwartz. I then took my first consultancy position at Toronto General Hospital (Ontario, Canada), where I began to specialize in multiple myeloma. Are there any particular people that have influenced your research? Lots of people. I think of the people that stand out, one is Robert Schwartz, who I informahealthcare.com
10.1586/17474086.2014.873285
did my research training with in Boston. Schwartz was the chief of hematology at the New England Medical Center at Tufts University (Boston, MA, USA). Subsequently, in Toronto, Armand Keating would have been a big influence on my career and research. I was lucky at Toronto, it was a wonderful scientific community and there were many very successful researchers there at the time, smarter than me, who I could learn from and apply my own focused research. For example, Tak Mak, John Dick, Jim Woodget and many others there who were publishing in the top scientific journals, many of whom I learned from. I also admired and was influenced by the work of my current colleagues Leif Bergsagel and Rafael Fonseca. What do you think has been your biggest achievement in the field so far? The thing that is freshest in my mind is the sequencing of the first myeloma genome. That was a feat that I was notably proud of. We went on to show that
Ó 2014 Informa UK Ltd
ISSN 1747-4086
9
Interview
Stewart
Expert Review of Hematology Downloaded from informahealthcare.com by Mercer University on 11/13/14 For personal use only.
myeloma is not a single clonal entity and is rather heterogeneous. We then described a phenomenon called clonal tides where different clones of the tumor come and go in response to chemotherapy [1,2]. There are also other achievements that have been important. Most recently, our contribution to the discovery that cereblon was a target for the immune modulator class of drugs that we use, that is, thalidomide, lenalidomide and pomalidomide [3,4]. Briefly, what is the focus of your current work? What do you hope to achieve? We are implementing a 70 gene mutation panel for clinical use, investigating the downstream effectors of cereblon in myeloma cytotoxicity and developing novel G-protein-coupled receptor kinase 6 (GRK6) kinase inhibitors. In the clinic, we are exploring many novel agents including new oral proteasome inhibitors, new kinase inhibitors and monoclonal antibodies. What discoveries do you think have paved the way for your current work? We work on the discovery of new drug targets in myeloma and the application of drugs towards that, so I think the most important recent work was the discovery that cereblon was the target of thalidomide teratogenicity made by a Japanese group, that was published in Science (2010) [5]. That really stimulated us to dive into that area and it is a heavy focus of our laboratory right now in trying to understand how that interaction results in the death of the cancer cell and what we can do to overcome that. The human genome project and the ability to do deep sequencing has also had a profound impact on the work we are currently performing. Genomics is part of that discovery effort. Could you tell us more about your work on the cancer genome? What have been your biggest discoveries recently? We sequenced a number of myeloma genomes in our own laboratory, and I think, more importantly, we were part of the international effort through the Myeloma Research Foundation to sequence the first 38 myeloma genomes. What was a little bit disappointing was that we were unable to identify a singly unifying mutation or target that explained everything. However, we were able to define the landscape of mutation in the myeloma genome and subsequently, through using technologies such as RNA interference and gene silencing, to identify some novel targets as a result of that [6,7]. Then, as I mentioned earlier, our contribution was to show for the first time in patients as we followed them over time, how the genome shifts, changes, mutates and evolves. We termed this phenomenon ‘clonal tides’; there are multiple clones of tumor at diagnosis and with the application of therapy, some of them regress and some of them advance. There were some clinical implications to that, which were that one needed to use more than one or two drugs to try and eradicate the disease and that clones could emerge that were drug-sensitive and had been suppressed during treatment; then, when the treatment is removed, those
10
clones could re-emerge and might respond to the same drug again [1,2]. So those were important observations. And how do you see these being applied to the clinic? The discoveries have led to a better understanding of what happens at the genomic level when we treat patients with drugs and provides more of a hypothetical model for how one would treat the disease in order to eradicate it. It does start to impact the way we treat the disease, which now is more defined by using multiple drugs immediately and continuing them for much longer than we used to do. Does this work apply to personalized medicine? As I mentioned earlier, we didn’t really find a single mutation that would point to one drug that would fit all patients, so what we learned is that every patient is unique and different, and that every patient will perhaps need some broad-based therapy which is targeting all the tumor clones through the plasma cell biology general pathways. However, there are patients who have specific mutations; for example, in the genome sequencing project, we have found that 4% of patients have a RAF mutation, which is targetable with commercially available drugs. There have already been some case reports of patients responding to that therapy. So, we start to enter an era of adding RAF to other targets we know about such as FGFR3, CD38, the proteasome and now cereblon, which is a novel target which we didn’t know we had, but now we do [1,2]. So I think we have entered an era where there is not a one-size-fits-all approach but the treatment has to be tailored to the individual genomic profiles of the patients. Could you tell us more about your work identifying new molecules that have therapeutic potential? One of things we’ve been doing, and I think it is a trend in academia, is beginning to do some drug discovery on our own backs. As part of that we have performed genome-wide RNA interference experiments to identify new targets. In particular, we’ve become interested in two kinases: one is called cyclindependent kinase 5, the other is called GRK6. For cyclindependent kinase 5, which we identified early on as target of myeloma cells, we were lucky enough to learn that there was a drug already available from pharmaceuticals, called dinaciclib, and we were able to take that into clinical trials and show already that there has been some clinical activity with that agent [8]. For GRK6, which was another kinase we identified as of interest, there were no commercially available small-molecule inhibitors, so, with the help of the Leukemia and Lymphoma Society in the USA, we performed some drug library screening and have identified some lead compounds, which we hope to take to the clinic in the next 18 months to 2 years [6]. Finally, with cereblon, we believe that that is a target, Although we have drugs that bind that target through the thalidomide class of drugs, we believe we can use that information to try and develop more focused, less toxic versions of those drugs. So those are some of the things that we are currently working on.
Expert Rev. Hematol. 7(1), (2014)
Expert Review of Hematology Downloaded from informahealthcare.com by Mercer University on 11/13/14 For personal use only.
Multiple myeloma
You have been working on a number of clinical trials recently. Are there any that you feel are showing particular promise over the rest? We’ve been lucky enough to work with some of the recent agents that have been approved, particularly carfilzomib, which we were engaged with from Phase I right through to Phase III of clinical testing, and that drug is now approved in the USA and hopefully will be approved soon in the EU. We were also quite heavily involved with pomalidomide, which was US FDA approved in the US and just recently approved in the EU; we treated many patients on those trials. With regards to the things that are not yet approved, I think the ones that hold the most promise are probably the monoclonal antibodies that are emerging, particularly antibodies targeting the cell surface marked with CD38 on plasma cells. Those are the drugs that seem to have the most hope and also take us into a new class of agent, which is something we desperately need. Unlike lymphoma, breast cancer and other major tumors, there are no monoclonal antibodies commercially available for the treatment of myeloma and I think this is a deficiency that we need to correct. The early clinical trial results with these monoclonal antibodies look very promising [9]. In your opinion, what has been the most important finding in the last 5 years of multiple myeloma research? I think the most important finding in the last 5 years is probably the sequencing of the myeloma genome. Even though it didn’t find us a specific target, I think it is a historic event in that once a genome had been defined it is not going to change much over time. It has thrown up many potential targets that we do not have drugs for yet but are certainly areas where we need to find agents against. Again, I think the understanding of how drugs work has been a second major breakthrough. Again, pointing to cereblon for the immunomodulatory drugs and then the proteasome inhibitor which is the second major class of drugs that we use in that field. There have been some References 1.
2.
Egan JB, Shi CX, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 2012; 120(5):1060-6 Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120(5): 1067-76
3.
Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011;118(18):4771-9
4.
Schuster SR, Kortuem KM, Zhu YX, et al. The clinical significance of cereblon expression in multiple myeloma. Leuk Res 2013; [Epub ahead of print]
informahealthcare.com
important papers recently that point to the mechanisms of resistance for those drugs, and particularly the recent work by Rodger Tiedemann [10]. Tiedemann has worked with us previously but is now in Toronto; he has shown that the mechanisms of resistance are due to a mother progenitor cell that doesn’t respond to the drug, but lurks in the shadows waiting to come back once the drug is gone. I think that cell therefore becomes an important target. Those things all put together: the genome, the discovery of the progenitor cell and the discovery of the targets of the drugs, has really opened a door to a whole new room, which we were unaware existed until very recently. Finally, what do you see as the major topics for multiple myeloma research over the next 5 years? Well I think in the clinic, the clinical development of the monoclonal antibodies is probably most critical. With regards to the basic research, I think it is capitalizing on the discoveries we’ve just described. It’s finding new drugs against mutated genomic targets that have now been identified. It’s developing more specific inhibitors of cereblon and with less toxicity. It’s probably figuring out ways to target the progenitor cells which survive the onslaught of chemotherapy. I think we are very close to a cure for myeloma; it’s probably going to take just one or two more breakthroughs to get there. Hopefully, in the next 5 years we’ll get close to those milestones. Financial & competing interests disclosure
The author has received honorarium from Celgene, Bristol–Myers Squibb, Millennium/Takeda and Array Pharma. The author has no other 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.
5.
Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science 2010; 327(5971):1345-50
6.
Tiedemann RE, Zhu YX, Schmidt J, et al. Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. Blood 2010;115(8): 1594-604
7.
Zhu YX, Tiedemann R, Shi CX, et al. RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. Blood 2011;117(14):3847-57
8.
Interview
Kumar SK, LaPlant BR, Chng WJ, et al. Phase 1/2 Trial of a novel CDK inhibitor dinaciclib (SCH727965) in patients with relapsed multiple myeloma demonstrates
encouraging single agent activity [abstract 76]. 2012 American Society of Hematology Annual Meeting and Exposition; 8–11 December 2012; Atlanta, GA, USA 9.
Plesner T, Lokhorst H, Gimsing P, et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma data from a dose-escalation phase I/II study [abstract 73]. 2012 American Society of Hematology Annual Meeting and Exposition. 8–11 December 2012; Atlanta, GA, USA
10.
Leung-Hagesteijn C, Erdmann N, Cheung G, et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 2013; 24(3):289-304
11
Interview
Multiple myeloma: genome sequencing, drug development and the future outlook Expert Review of Hematology Downloaded from informahealthcare.com by Mercer University on 11/13/14 For personal use only.
Expert Rev. Hematol. 7(1), 9–11 (2014)
Alexander Keith Stewart Mayo Clinic,13400 East Shea Boulevardm, Scottsdale, AZ, USA [email protected]
Interview by Jonathan Patience, Commissioning Editor Keith Stewart is the Dean for Research at Mayo Clinic (AZ, USA). He holds the Vasek and Anna Maria Polak Endowed Professorship in Cancer Research. He received his medical degree at Aberdeen University Medical School and trained in internal medicine and hematology in Glasgow, Kingston, Toronto and Boston. He was a consultant at the Toronto General and Princess Margaret Hospitals from 1992 to 2005 and a Professor in the Faculty of Medicine at the University of Toronto. He joined Mayo Clinic in Arizona in 2005. His lab-based research has focused on the genomics and developmental therapeutics of multiple myeloma. He has led numerous clinical trials from ‘first in man’, through to large international Phase III studies. Funding for his research includes the National Cancer Institute, the Leukemia and Lymphoma Society (LLS) and the Multiple Myeloma Research Foundation (MMRF). In addition, he is an associate editor of Blood, the journal of the American Society of Hematology (ASH).
Could you briefly describe your professional background & what led you to pursue a career in hematologic oncology? I went to medical school in Scotland at Aberdeen University and did my internship at Glasgow Royal Infirmary, where I worked on the hematology ward with Alan Burnett, who had just started a bone marrow transplant unit in the early 1980s. That experience was really what got me interested in the treatment of leukemia and bone marrow transplant and led to my decision to pursue a career in hematology. Subsequently, I moved to Canada and did the rest of my training there, as well as a research stint in Boston (MA, USA) for 2 years with Robert Schwartz. I then took my first consultancy position at Toronto General Hospital (Ontario, Canada), where I began to specialize in multiple myeloma. Are there any particular people that have influenced your research? Lots of people. I think of the people that stand out, one is Robert Schwartz, who I informahealthcare.com
10.1586/17474086.2014.873285
did my research training with in Boston. Schwartz was the chief of hematology at the New England Medical Center at Tufts University (Boston, MA, USA). Subsequently, in Toronto, Armand Keating would have been a big influence on my career and research. I was lucky at Toronto, it was a wonderful scientific community and there were many very successful researchers there at the time, smarter than me, who I could learn from and apply my own focused research. For example, Tak Mak, John Dick, Jim Woodget and many others there who were publishing in the top scientific journals, many of whom I learned from. I also admired and was influenced by the work of my current colleagues Leif Bergsagel and Rafael Fonseca. What do you think has been your biggest achievement in the field so far? The thing that is freshest in my mind is the sequencing of the first myeloma genome. That was a feat that I was notably proud of. We went on to show that
Ó 2014 Informa UK Ltd
ISSN 1747-4086
9
Interview
Stewart
Expert Review of Hematology Downloaded from informahealthcare.com by Mercer University on 11/13/14 For personal use only.
myeloma is not a single clonal entity and is rather heterogeneous. We then described a phenomenon called clonal tides where different clones of the tumor come and go in response to chemotherapy [1,2]. There are also other achievements that have been important. Most recently, our contribution to the discovery that cereblon was a target for the immune modulator class of drugs that we use, that is, thalidomide, lenalidomide and pomalidomide [3,4]. Briefly, what is the focus of your current work? What do you hope to achieve? We are implementing a 70 gene mutation panel for clinical use, investigating the downstream effectors of cereblon in myeloma cytotoxicity and developing novel G-protein-coupled receptor kinase 6 (GRK6) kinase inhibitors. In the clinic, we are exploring many novel agents including new oral proteasome inhibitors, new kinase inhibitors and monoclonal antibodies. What discoveries do you think have paved the way for your current work? We work on the discovery of new drug targets in myeloma and the application of drugs towards that, so I think the most important recent work was the discovery that cereblon was the target of thalidomide teratogenicity made by a Japanese group, that was published in Science (2010) [5]. That really stimulated us to dive into that area and it is a heavy focus of our laboratory right now in trying to understand how that interaction results in the death of the cancer cell and what we can do to overcome that. The human genome project and the ability to do deep sequencing has also had a profound impact on the work we are currently performing. Genomics is part of that discovery effort. Could you tell us more about your work on the cancer genome? What have been your biggest discoveries recently? We sequenced a number of myeloma genomes in our own laboratory, and I think, more importantly, we were part of the international effort through the Myeloma Research Foundation to sequence the first 38 myeloma genomes. What was a little bit disappointing was that we were unable to identify a singly unifying mutation or target that explained everything. However, we were able to define the landscape of mutation in the myeloma genome and subsequently, through using technologies such as RNA interference and gene silencing, to identify some novel targets as a result of that [6,7]. Then, as I mentioned earlier, our contribution was to show for the first time in patients as we followed them over time, how the genome shifts, changes, mutates and evolves. We termed this phenomenon ‘clonal tides’; there are multiple clones of tumor at diagnosis and with the application of therapy, some of them regress and some of them advance. There were some clinical implications to that, which were that one needed to use more than one or two drugs to try and eradicate the disease and that clones could emerge that were drug-sensitive and had been suppressed during treatment; then, when the treatment is removed, those
10
clones could re-emerge and might respond to the same drug again [1,2]. So those were important observations. And how do you see these being applied to the clinic? The discoveries have led to a better understanding of what happens at the genomic level when we treat patients with drugs and provides more of a hypothetical model for how one would treat the disease in order to eradicate it. It does start to impact the way we treat the disease, which now is more defined by using multiple drugs immediately and continuing them for much longer than we used to do. Does this work apply to personalized medicine? As I mentioned earlier, we didn’t really find a single mutation that would point to one drug that would fit all patients, so what we learned is that every patient is unique and different, and that every patient will perhaps need some broad-based therapy which is targeting all the tumor clones through the plasma cell biology general pathways. However, there are patients who have specific mutations; for example, in the genome sequencing project, we have found that 4% of patients have a RAF mutation, which is targetable with commercially available drugs. There have already been some case reports of patients responding to that therapy. So, we start to enter an era of adding RAF to other targets we know about such as FGFR3, CD38, the proteasome and now cereblon, which is a novel target which we didn’t know we had, but now we do [1,2]. So I think we have entered an era where there is not a one-size-fits-all approach but the treatment has to be tailored to the individual genomic profiles of the patients. Could you tell us more about your work identifying new molecules that have therapeutic potential? One of things we’ve been doing, and I think it is a trend in academia, is beginning to do some drug discovery on our own backs. As part of that we have performed genome-wide RNA interference experiments to identify new targets. In particular, we’ve become interested in two kinases: one is called cyclindependent kinase 5, the other is called GRK6. For cyclindependent kinase 5, which we identified early on as target of myeloma cells, we were lucky enough to learn that there was a drug already available from pharmaceuticals, called dinaciclib, and we were able to take that into clinical trials and show already that there has been some clinical activity with that agent [8]. For GRK6, which was another kinase we identified as of interest, there were no commercially available small-molecule inhibitors, so, with the help of the Leukemia and Lymphoma Society in the USA, we performed some drug library screening and have identified some lead compounds, which we hope to take to the clinic in the next 18 months to 2 years [6]. Finally, with cereblon, we believe that that is a target, Although we have drugs that bind that target through the thalidomide class of drugs, we believe we can use that information to try and develop more focused, less toxic versions of those drugs. So those are some of the things that we are currently working on.
Expert Rev. Hematol. 7(1), (2014)
Expert Review of Hematology Downloaded from informahealthcare.com by Mercer University on 11/13/14 For personal use only.
Multiple myeloma
You have been working on a number of clinical trials recently. Are there any that you feel are showing particular promise over the rest? We’ve been lucky enough to work with some of the recent agents that have been approved, particularly carfilzomib, which we were engaged with from Phase I right through to Phase III of clinical testing, and that drug is now approved in the USA and hopefully will be approved soon in the EU. We were also quite heavily involved with pomalidomide, which was US FDA approved in the US and just recently approved in the EU; we treated many patients on those trials. With regards to the things that are not yet approved, I think the ones that hold the most promise are probably the monoclonal antibodies that are emerging, particularly antibodies targeting the cell surface marked with CD38 on plasma cells. Those are the drugs that seem to have the most hope and also take us into a new class of agent, which is something we desperately need. Unlike lymphoma, breast cancer and other major tumors, there are no monoclonal antibodies commercially available for the treatment of myeloma and I think this is a deficiency that we need to correct. The early clinical trial results with these monoclonal antibodies look very promising [9]. In your opinion, what has been the most important finding in the last 5 years of multiple myeloma research? I think the most important finding in the last 5 years is probably the sequencing of the myeloma genome. Even though it didn’t find us a specific target, I think it is a historic event in that once a genome had been defined it is not going to change much over time. It has thrown up many potential targets that we do not have drugs for yet but are certainly areas where we need to find agents against. Again, I think the understanding of how drugs work has been a second major breakthrough. Again, pointing to cereblon for the immunomodulatory drugs and then the proteasome inhibitor which is the second major class of drugs that we use in that field. There have been some References 1.
2.
Egan JB, Shi CX, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 2012; 120(5):1060-6 Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120(5): 1067-76
3.
Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011;118(18):4771-9
4.
Schuster SR, Kortuem KM, Zhu YX, et al. The clinical significance of cereblon expression in multiple myeloma. Leuk Res 2013; [Epub ahead of print]
informahealthcare.com
important papers recently that point to the mechanisms of resistance for those drugs, and particularly the recent work by Rodger Tiedemann [10]. Tiedemann has worked with us previously but is now in Toronto; he has shown that the mechanisms of resistance are due to a mother progenitor cell that doesn’t respond to the drug, but lurks in the shadows waiting to come back once the drug is gone. I think that cell therefore becomes an important target. Those things all put together: the genome, the discovery of the progenitor cell and the discovery of the targets of the drugs, has really opened a door to a whole new room, which we were unaware existed until very recently. Finally, what do you see as the major topics for multiple myeloma research over the next 5 years? Well I think in the clinic, the clinical development of the monoclonal antibodies is probably most critical. With regards to the basic research, I think it is capitalizing on the discoveries we’ve just described. It’s finding new drugs against mutated genomic targets that have now been identified. It’s developing more specific inhibitors of cereblon and with less toxicity. It’s probably figuring out ways to target the progenitor cells which survive the onslaught of chemotherapy. I think we are very close to a cure for myeloma; it’s probably going to take just one or two more breakthroughs to get there. Hopefully, in the next 5 years we’ll get close to those milestones. Financial & competing interests disclosure
The author has received honorarium from Celgene, Bristol–Myers Squibb, Millennium/Takeda and Array Pharma. The author has no other 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.
5.
Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science 2010; 327(5971):1345-50
6.
Tiedemann RE, Zhu YX, Schmidt J, et al. Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. Blood 2010;115(8): 1594-604
7.
Zhu YX, Tiedemann R, Shi CX, et al. RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. Blood 2011;117(14):3847-57
8.
Interview
Kumar SK, LaPlant BR, Chng WJ, et al. Phase 1/2 Trial of a novel CDK inhibitor dinaciclib (SCH727965) in patients with relapsed multiple myeloma demonstrates
encouraging single agent activity [abstract 76]. 2012 American Society of Hematology Annual Meeting and Exposition; 8–11 December 2012; Atlanta, GA, USA 9.
Plesner T, Lokhorst H, Gimsing P, et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma data from a dose-escalation phase I/II study [abstract 73]. 2012 American Society of Hematology Annual Meeting and Exposition. 8–11 December 2012; Atlanta, GA, USA
10.
Leung-Hagesteijn C, Erdmann N, Cheung G, et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 2013; 24(3):289-304
11
