MULTIPLE MYELOMA
Introduction: Recent Advances in the Understanding and Management of Multiple Myeloma
W
hen I entered the myeloma field in 2001, the disease was mostly managed with conventional chemotherapy with the addition of high-dose chemotherapy in younger, transplanteligible patients. Life expectancy was in 3- to 4-year range, not very different than two to three decades earlier. The introduction of thalidomide in late 1990s, the first of the novel agents for myeloma, coincided with an increased awareness of the disease among the general public, in part thanks to the efforts of a few champions with this diagnosis. The increased awareness led to expanded research funding generated by existing and new organizations and newly formed consortia committed to accelerating the development of new drugs and new treatments. Indeed, in a little more than just 10 years, the landscape of multiple myeloma is dramatically different. We have witnessed the development of new therapies at an unprecedented speed, which has led to the approval of a number of new drugs and combinations, starting with bortezomib, followed by lenalidomide, then bortezomib with liposomal doxorubicin, and most recently carfilzomib and pomalidomide. The development of new drugs and treatments helped trigger an increase in broader research efforts leading to significant advances in our understanding of the biology of the disease. In particular, we have increased our insight into the genetic and molecular foundations of myeloma, including characterization of its heterogeneity. Importantly, we have learned about the value of generating a strong preclinical rationale before moving to clinical evaluations, establishing the framework of “bench-to-bedside” development of new drugs and treatments. This was well illustrated in the development and ultimate approval of the combination of bortezomib and pegylated liposomal doxorubicin for treatment of relapsed
Conflicts of interest: A.J.J. served on advisory boards or as a consultant for Bristol-Myers Squibb, Celgene, Janssen-Cilag, Millennium Pharmaceuticals, and Onyx Pharmaceuticals, and has speaking engagements with Celgene and Onyx Pharmaceuticals with honoraria. 0093-7754/ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2013.08.003
myeloma. Most importantly, the increasing number of therapies and improved understanding of how to treat myeloma, led to a dramatic improvement in not only our ability to control the disease and limit organ damage but to produce meaningfully and dramatically prolonged patient survival, which by some recent projections has at least tripled compared to where we were just over a decade ago. These improvements are so promising that some of us, recently more and more, dare to set a goal of “functional cure” for new therapies. In this issue of Seminars in Oncology a group of established leaders in multiple myeloma research, together with their colleagues, review the progress in their specific areas of expertise and interest. This issue is divided into sections, with the first one or two articles of each section focused on a review of recent progress in an area, and the last providing additional discussion or commentary regarding the most challenging or controversial issues covered by the other experts. We start with a review of the current understanding of the biology of the disease and its implication for the development of treatment strategies. This section is followed by the review of our understanding of the heterogeneity of myeloma and its implications for the development of biology-based personalized therapy. Next we summarize the important developments in the treatment of newly diagnosed patients with myeloma and discuss “hot topics” such as the importance of complete response and depth of response, the role of transplant, and the projections of the evolution of initial treatment strategies, for both “transplant” and “nontransplant” patients. We then review the progress in the treatment of relapsed and relapsed refractory myeloma with a special attention to recently approved agents and the most promising agents in development for treatment of the disease. We conclude with a commentary on how the most recently developed and currently evaluated agents are predicted to contribute to further progress in the treatment of myeloma and how we see their integration into existing treatment paradigms. Despite the advances of the last decade, challenges remain. The majority of patients are still
Seminars in Oncology, Vol 40, No 5, October 2013, pp 535-536
535
536
expected to relapse and in the course of their disease the established treatments become less and less effective with shorter and shorter duration of response. In addition, a relatively small (10%– 15%) yet significant proportion of patients with poor risk factors, which is becoming better defined, are expected to have much shorter life expectancy than standard-risk patients, and unfortunately, their median overall survival is not very different from a decade ago. We hope that this issue of Seminars in Oncology not only provides a concise summary of
A.J. Jakubowiak
the state of the field but will help to generate new ideas, providing additional stimulus to further innovations that lead to further prolongation of life for all myeloma patients, including patients with highrisk disease, and hopefully to finding a cure.
Andrzej J. Jakubowiak, MD, PhD The University of Chicago Chicago, IL Guest Editor
Introduction: Recent Advances in the Understanding and Management of Multiple Myeloma
W
hen I entered the myeloma field in 2001, the disease was mostly managed with conventional chemotherapy with the addition of high-dose chemotherapy in younger, transplanteligible patients. Life expectancy was in 3- to 4-year range, not very different than two to three decades earlier. The introduction of thalidomide in late 1990s, the first of the novel agents for myeloma, coincided with an increased awareness of the disease among the general public, in part thanks to the efforts of a few champions with this diagnosis. The increased awareness led to expanded research funding generated by existing and new organizations and newly formed consortia committed to accelerating the development of new drugs and new treatments. Indeed, in a little more than just 10 years, the landscape of multiple myeloma is dramatically different. We have witnessed the development of new therapies at an unprecedented speed, which has led to the approval of a number of new drugs and combinations, starting with bortezomib, followed by lenalidomide, then bortezomib with liposomal doxorubicin, and most recently carfilzomib and pomalidomide. The development of new drugs and treatments helped trigger an increase in broader research efforts leading to significant advances in our understanding of the biology of the disease. In particular, we have increased our insight into the genetic and molecular foundations of myeloma, including characterization of its heterogeneity. Importantly, we have learned about the value of generating a strong preclinical rationale before moving to clinical evaluations, establishing the framework of “bench-to-bedside” development of new drugs and treatments. This was well illustrated in the development and ultimate approval of the combination of bortezomib and pegylated liposomal doxorubicin for treatment of relapsed
Conflicts of interest: A.J.J. served on advisory boards or as a consultant for Bristol-Myers Squibb, Celgene, Janssen-Cilag, Millennium Pharmaceuticals, and Onyx Pharmaceuticals, and has speaking engagements with Celgene and Onyx Pharmaceuticals with honoraria. 0093-7754/ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2013.08.003
myeloma. Most importantly, the increasing number of therapies and improved understanding of how to treat myeloma, led to a dramatic improvement in not only our ability to control the disease and limit organ damage but to produce meaningfully and dramatically prolonged patient survival, which by some recent projections has at least tripled compared to where we were just over a decade ago. These improvements are so promising that some of us, recently more and more, dare to set a goal of “functional cure” for new therapies. In this issue of Seminars in Oncology a group of established leaders in multiple myeloma research, together with their colleagues, review the progress in their specific areas of expertise and interest. This issue is divided into sections, with the first one or two articles of each section focused on a review of recent progress in an area, and the last providing additional discussion or commentary regarding the most challenging or controversial issues covered by the other experts. We start with a review of the current understanding of the biology of the disease and its implication for the development of treatment strategies. This section is followed by the review of our understanding of the heterogeneity of myeloma and its implications for the development of biology-based personalized therapy. Next we summarize the important developments in the treatment of newly diagnosed patients with myeloma and discuss “hot topics” such as the importance of complete response and depth of response, the role of transplant, and the projections of the evolution of initial treatment strategies, for both “transplant” and “nontransplant” patients. We then review the progress in the treatment of relapsed and relapsed refractory myeloma with a special attention to recently approved agents and the most promising agents in development for treatment of the disease. We conclude with a commentary on how the most recently developed and currently evaluated agents are predicted to contribute to further progress in the treatment of myeloma and how we see their integration into existing treatment paradigms. Despite the advances of the last decade, challenges remain. The majority of patients are still
Seminars in Oncology, Vol 40, No 5, October 2013, pp 535-536
535
536
expected to relapse and in the course of their disease the established treatments become less and less effective with shorter and shorter duration of response. In addition, a relatively small (10%– 15%) yet significant proportion of patients with poor risk factors, which is becoming better defined, are expected to have much shorter life expectancy than standard-risk patients, and unfortunately, their median overall survival is not very different from a decade ago. We hope that this issue of Seminars in Oncology not only provides a concise summary of
A.J. Jakubowiak
the state of the field but will help to generate new ideas, providing additional stimulus to further innovations that lead to further prolongation of life for all myeloma patients, including patients with highrisk disease, and hopefully to finding a cure.
Andrzej J. Jakubowiak, MD, PhD The University of Chicago Chicago, IL Guest Editor
