- Email: [email protected]
New therapeutic targets in multiple myeloma
Comment
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
cultural barriers to high-quality cost-effective health care for society as a whole, but especially for the disadvantaged and marginalised. The principles of professionalism can shape the intellectual framework that physicians bring to their clinical experiences, foster greater understanding of their responsibilities, and teach them to offer and demand moral and ethical evidence and justification for their clinical behaviour. Medical school presents a unique opportunity to establish a foundation for professionalism that students can build on throughout their careers. Even though development of professionalism has become a focus of medical school and postgraduate education of physicians, current teaching too often fails to take advantage of the actual situations that students encounter on the wards and in the clinics. Consequently, we miss powerful opportunities to equip students to apply the principles of professionalism in the social and cultural context in which they find themselves in daily practice.
Charles K Francis
Science Photo Library
Office of Health Disparities, New York Academy of Medicine, New York, NY 10029, USA [email protected] I declare that I have no conflict of interest. 1
Project of the ABIM Foundation, ACP–ASIM Foundation, and European Federation of Internal Medicine. Medical professionalism in the new millennium: a physician charter. Ann Intern Med 2002; 136: 243–46.
New therapeutic targets in multiple myeloma Kathy Giusti, president of the Multiple Myeloma Research Foundation, recently announced the creation of the Multiple Myeloma Research Consortium (MMRC),1 a nonprofit organisation that will integrate leading academic institutions to accelerate development of targeted drugs for multiple myeloma. The consortium includes multiple myeloma researchers from four institutions based in the US and Canada: Dana Farber Cancer Institute, H Lee Moffitt Cancer Center, Mayo Clinic, and University of Toronto’s Princess Margaret Hospital. Industrial partners are invited to join. MMRC’s mission is to rapidly identify and validate new molecular targets for multiple myeloma, to develop new drugs against these targets, and to expedite phase I and II clinical trials of those drugs. To meet its goals, the MMRC will collect mainly bone marrow and blood cells from patients and build a centralised tissue bank for genetic profile studies. Why should this approach be successful? The sequencing of the human genome and the new tools to identify genes and gene expression in thousands of genes make it possible to identify genetic aberrations and abnormal gene expression in malignant cells, which 1648
are potential targets for therapy. Furthermore, downstream from aberrant gene expression, an array of abnormal events promote progression and resistance to therapy. In multiple myeloma, many oncogenic events are important for pathogenesis.2,3 Most multiple myelomas have IgH (chromosome 14q) translocations that nonrandomly involve other chromosome partners. The most important of these partners are 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factors receptor 3 and MM SET domain), 16q23 (c-maf), and 20q11 (mafB). A unifying element in these possibly early events in the pathogenesis of multiple myeloma seems to be the dysregulation of cyclin D (D1, D2, D3, or all three). The cells become more susceptible to proliferative stimuli, which results in selective expansion, an important factor being interaction with bone-marrow stromal cells. Targets for multiple myeloma therapy are provided all along the pathway from the first oncogenic event to cyclin D dysregulation, malignant proliferation, myeloma cells homing to the bone marrow, interaction with the extracellular matrix proteins, and adhesion to bone-marrow stromal cells that induces a cascade of signalling substances and cytokines www.thelancet.com Vol 364 November 6, 2004
Comment
(autocrine and exocrine) which further promote progression. The myeloma group at the Dana Farber Cancer Institute will mainly study molecular targets and specific drugs against these targets to inhibit cell proliferation or induce cell death in the myeloma cell (eg, telomerase inhibitors), in the microenvironement (eg, p38MAPK inhibitors), or both (eg, the proteasome inhibitor bortezomib and the immunomodulatory drug revlimid). Many of these drugs are already in clinical trials. Thalidomide4 and bortezomib5 are established for treatment and both induce about a 30–40% response in relapsed or progressive multiple myeloma. Thus there seems to be substantial evidence that the MMRC’s goals are realistic. Giusti and Anderson should be congratulated for this important initiative. However, there is reason to be cautious. Although the first targeted drug to be developed, the tyrosine-kinase inhibitor imatinib, achieved wonderful responses in chronic myelocytic leukaemia, a long follow-up shows that cure is unlikely.6 Allogeneic transplantation is the only cure for this disease. Randomised trials in previously untreated patients with multiple myeloma show that high-dose therapy with melphalan followed by autologous stem-cell transplantation is the only new approach that prolongs overall survival compared with conventional chemotherapy.7,8 Median overall survival has now improved from 3 to about 5 years with this treatment. Significant progress has been made in allogeneic transplantation.9 Persistent molecular remission, probably a prerequisite for cure, is only obtained by this treatment.10 Post-transplant donor-lymphocyte treatment seems to further improve results and more specific cellular therapies are underway, such as therapies with natural-killer cells11 and minor histocompatibility-specific T cells.12 Therefore I hope that MMRC will not limit its activity to targeted-drug therapy, but will include other treatments such as transplantation and cell therapy too.
Gösta Gahrton Department of Medicine, Karolinska Institute, Huddinge Hospital, S 141 86 Huddinge, Sweden [email protected] I am chairman of the Myeloma Subcommittee of the European Group for Blood and Marrow Transplantation, which has a grant from Johnson & Johnson Pharmaceutical Research and Development. 1 2 3 4 5
6
About the MMRC. www.themmrc.org (accessed Oct 11, 2004). Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004; 104: 607–18. Sirohi B, Powles R. Multiple myeloma. Lancet 2004; 363: 875–87. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–17. Goldman JM. Chronic myeloid leukemia-still a few questions. Exp Hematol 2004; 32: 2–10.
www.thelancet.com Vol 364 November 6, 2004
MM cell Drugs targeting MM cell and its microenvironment Histone deacytylase inhibitors: SAHA, tubacin
Drugs targeting MM cells In nucleus: telomerase inhibitor GRN 163L Mitochondria: PK11195 and smac mimetics
Cytokine-mediated and adhesionmediated signalling PI3-K/Akt
MAPK
In cytoplasm: Hsp90 inhibitor 17AAG
JAK/STAT3
Proteasome inhibitors: bortezomib, NPI 0052
IGF-1R IGF-1
Immunomodulatory drugs: revlimid, CPS11
LFA1R
VEGF
LFA-1
IL6
VEGF inhibitors: PTK787, GW786034
MAPK
NF-B
NF-kB
Adhesion molecules
CRE C-fos SRE homology
Drugs targeting BM micoenvironment P38MAPK inhibitor: SCI 469 IKK inhibitor MLN12OB
At cell surface: IGF1R TK inhibitor AEW541, CD40 antibody
BMSC
ICAM-1
LFA-1 IGF1R
Figure: Drugs targeting pathways in multiple myeloma cells and cells in bone marrow microenvironment to be studied by Myeloma Group at the Dana Farber Cancer Institute MM=multiple myeloma, SAHA=suberoylanilide hydroxamic acid, Smac mimetics=second mitochondria-derived activator of caspase mimetics, P13-K=phosphoinositide 3-kinase, MAPK=mitogen-activated protein kinase, JAK=Janus kinase, STAT=signal transduction and activators of transcription, Hsp=heat shock protein, IGF1R=insulin-like growth factor 1 receptor, TK=tyrosine kinase, IGF=insulin-like growth factor, VEGF=vascular endothelial growth factor, IL6=interleukin 6, NF=nuclear factor, BMSC=bone-marrow stromal cell, CRE=cyclic AMP response element, SRE=serum response factor, IKK=IkappaB kinase, ICAM=intercellular adhesion molecule, LFA-1=leucocyte function-associated antigen 1, IGF-1R=insulin-like growth factor receptor 1, BM=bone marrow. Figure provided by Ken Anderson.
7
Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335: 91–97. 8 Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–83. 9 Gahrton G, Svensson H, Cavo M, et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983–93 and 1994–98 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001; 113: 209–16. 10 Corradini P, Cavo M, Lokhorst H, et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood 2003; 102:1927–29. 11 Guven H, Gilljam M, Chambers BJ, et al. Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy. Leukemia 2003; 17: 1973–80. 12 Marijt WA, Heemskerk MH, Kloosterboer FM, et al. Hematopoiesisrestricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 2003; 100: 2742–47.
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Rights were not granted to include this image in electronic media. Please refer to the printed journal.
cultural barriers to high-quality cost-effective health care for society as a whole, but especially for the disadvantaged and marginalised. The principles of professionalism can shape the intellectual framework that physicians bring to their clinical experiences, foster greater understanding of their responsibilities, and teach them to offer and demand moral and ethical evidence and justification for their clinical behaviour. Medical school presents a unique opportunity to establish a foundation for professionalism that students can build on throughout their careers. Even though development of professionalism has become a focus of medical school and postgraduate education of physicians, current teaching too often fails to take advantage of the actual situations that students encounter on the wards and in the clinics. Consequently, we miss powerful opportunities to equip students to apply the principles of professionalism in the social and cultural context in which they find themselves in daily practice.
Charles K Francis
Science Photo Library
Office of Health Disparities, New York Academy of Medicine, New York, NY 10029, USA [email protected] I declare that I have no conflict of interest. 1
Project of the ABIM Foundation, ACP–ASIM Foundation, and European Federation of Internal Medicine. Medical professionalism in the new millennium: a physician charter. Ann Intern Med 2002; 136: 243–46.
New therapeutic targets in multiple myeloma Kathy Giusti, president of the Multiple Myeloma Research Foundation, recently announced the creation of the Multiple Myeloma Research Consortium (MMRC),1 a nonprofit organisation that will integrate leading academic institutions to accelerate development of targeted drugs for multiple myeloma. The consortium includes multiple myeloma researchers from four institutions based in the US and Canada: Dana Farber Cancer Institute, H Lee Moffitt Cancer Center, Mayo Clinic, and University of Toronto’s Princess Margaret Hospital. Industrial partners are invited to join. MMRC’s mission is to rapidly identify and validate new molecular targets for multiple myeloma, to develop new drugs against these targets, and to expedite phase I and II clinical trials of those drugs. To meet its goals, the MMRC will collect mainly bone marrow and blood cells from patients and build a centralised tissue bank for genetic profile studies. Why should this approach be successful? The sequencing of the human genome and the new tools to identify genes and gene expression in thousands of genes make it possible to identify genetic aberrations and abnormal gene expression in malignant cells, which 1648
are potential targets for therapy. Furthermore, downstream from aberrant gene expression, an array of abnormal events promote progression and resistance to therapy. In multiple myeloma, many oncogenic events are important for pathogenesis.2,3 Most multiple myelomas have IgH (chromosome 14q) translocations that nonrandomly involve other chromosome partners. The most important of these partners are 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factors receptor 3 and MM SET domain), 16q23 (c-maf), and 20q11 (mafB). A unifying element in these possibly early events in the pathogenesis of multiple myeloma seems to be the dysregulation of cyclin D (D1, D2, D3, or all three). The cells become more susceptible to proliferative stimuli, which results in selective expansion, an important factor being interaction with bone-marrow stromal cells. Targets for multiple myeloma therapy are provided all along the pathway from the first oncogenic event to cyclin D dysregulation, malignant proliferation, myeloma cells homing to the bone marrow, interaction with the extracellular matrix proteins, and adhesion to bone-marrow stromal cells that induces a cascade of signalling substances and cytokines www.thelancet.com Vol 364 November 6, 2004
Comment
(autocrine and exocrine) which further promote progression. The myeloma group at the Dana Farber Cancer Institute will mainly study molecular targets and specific drugs against these targets to inhibit cell proliferation or induce cell death in the myeloma cell (eg, telomerase inhibitors), in the microenvironement (eg, p38MAPK inhibitors), or both (eg, the proteasome inhibitor bortezomib and the immunomodulatory drug revlimid). Many of these drugs are already in clinical trials. Thalidomide4 and bortezomib5 are established for treatment and both induce about a 30–40% response in relapsed or progressive multiple myeloma. Thus there seems to be substantial evidence that the MMRC’s goals are realistic. Giusti and Anderson should be congratulated for this important initiative. However, there is reason to be cautious. Although the first targeted drug to be developed, the tyrosine-kinase inhibitor imatinib, achieved wonderful responses in chronic myelocytic leukaemia, a long follow-up shows that cure is unlikely.6 Allogeneic transplantation is the only cure for this disease. Randomised trials in previously untreated patients with multiple myeloma show that high-dose therapy with melphalan followed by autologous stem-cell transplantation is the only new approach that prolongs overall survival compared with conventional chemotherapy.7,8 Median overall survival has now improved from 3 to about 5 years with this treatment. Significant progress has been made in allogeneic transplantation.9 Persistent molecular remission, probably a prerequisite for cure, is only obtained by this treatment.10 Post-transplant donor-lymphocyte treatment seems to further improve results and more specific cellular therapies are underway, such as therapies with natural-killer cells11 and minor histocompatibility-specific T cells.12 Therefore I hope that MMRC will not limit its activity to targeted-drug therapy, but will include other treatments such as transplantation and cell therapy too.
Gösta Gahrton Department of Medicine, Karolinska Institute, Huddinge Hospital, S 141 86 Huddinge, Sweden [email protected] I am chairman of the Myeloma Subcommittee of the European Group for Blood and Marrow Transplantation, which has a grant from Johnson & Johnson Pharmaceutical Research and Development. 1 2 3 4 5
6
About the MMRC. www.themmrc.org (accessed Oct 11, 2004). Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004; 104: 607–18. Sirohi B, Powles R. Multiple myeloma. Lancet 2004; 363: 875–87. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–17. Goldman JM. Chronic myeloid leukemia-still a few questions. Exp Hematol 2004; 32: 2–10.
www.thelancet.com Vol 364 November 6, 2004
MM cell Drugs targeting MM cell and its microenvironment Histone deacytylase inhibitors: SAHA, tubacin
Drugs targeting MM cells In nucleus: telomerase inhibitor GRN 163L Mitochondria: PK11195 and smac mimetics
Cytokine-mediated and adhesionmediated signalling PI3-K/Akt
MAPK
In cytoplasm: Hsp90 inhibitor 17AAG
JAK/STAT3
Proteasome inhibitors: bortezomib, NPI 0052
IGF-1R IGF-1
Immunomodulatory drugs: revlimid, CPS11
LFA1R
VEGF
LFA-1
IL6
VEGF inhibitors: PTK787, GW786034
MAPK
NF-B
NF-kB
Adhesion molecules
CRE C-fos SRE homology
Drugs targeting BM micoenvironment P38MAPK inhibitor: SCI 469 IKK inhibitor MLN12OB
At cell surface: IGF1R TK inhibitor AEW541, CD40 antibody
BMSC
ICAM-1
LFA-1 IGF1R
Figure: Drugs targeting pathways in multiple myeloma cells and cells in bone marrow microenvironment to be studied by Myeloma Group at the Dana Farber Cancer Institute MM=multiple myeloma, SAHA=suberoylanilide hydroxamic acid, Smac mimetics=second mitochondria-derived activator of caspase mimetics, P13-K=phosphoinositide 3-kinase, MAPK=mitogen-activated protein kinase, JAK=Janus kinase, STAT=signal transduction and activators of transcription, Hsp=heat shock protein, IGF1R=insulin-like growth factor 1 receptor, TK=tyrosine kinase, IGF=insulin-like growth factor, VEGF=vascular endothelial growth factor, IL6=interleukin 6, NF=nuclear factor, BMSC=bone-marrow stromal cell, CRE=cyclic AMP response element, SRE=serum response factor, IKK=IkappaB kinase, ICAM=intercellular adhesion molecule, LFA-1=leucocyte function-associated antigen 1, IGF-1R=insulin-like growth factor receptor 1, BM=bone marrow. Figure provided by Ken Anderson.
7
Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335: 91–97. 8 Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–83. 9 Gahrton G, Svensson H, Cavo M, et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983–93 and 1994–98 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001; 113: 209–16. 10 Corradini P, Cavo M, Lokhorst H, et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood 2003; 102:1927–29. 11 Guven H, Gilljam M, Chambers BJ, et al. Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy. Leukemia 2003; 17: 1973–80. 12 Marijt WA, Heemskerk MH, Kloosterboer FM, et al. Hematopoiesisrestricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 2003; 100: 2742–47.
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