The Changing Landscape of Myeloma Therapy
http://www.100md.com
《新英格兰医药杂志》
The introduction of melphalan and prednisone for the treatment of multiple myeloma was followed by only minor advances in the management of the disease for almost 20 years.1 The failure of other agents, alone or in combination, to extend survival beyond three years prompted a new treatment strategy in the early 1980s: myeloablative doses of melphalan supported by an infusion of autologous hematopoietic stem cells. After this approach was found to be superior to conventional chemotherapy for the initial treatment of myeloma, the efficacy of two sequential courses of high-dose therapy, each supported by an infusion of autologous stem cells, was tested. As compared with a single infusion of stem cells, two infusions significantly prolonged both overall and event-free survival, particularly among patients who did not enter remission after receiving the first transplant.2,3 The benefit of melphalan-based double autologous transplantations was greatest in patients whose myeloma cells had a normal karyotype: these patients had an estimated probability of remaining in remission at 10 years of nearly 20 percent, suggesting that long-term control and even cure of myeloma are possible with double autologous stem-cell transplantation.4
More recent advances in the management of myeloma include the identification of new ways to overcome drug resistance.1 Also important is recognition of the pivotal role of the bone marrow microenvironment in promoting the growth, survival, and resistance of myeloma cells to conventional chemotherapy. As a result of this work, new classes of agents for the treatment of myeloma have been introduced. These include thalidomide; lenalidomide, a potent analogue of thalidomide; and the proteasome inhibitor bortezomib. Once the activity of these drugs in advanced and refractory myeloma was confirmed,5 studies of their efficacy in earlier phases of the disease were initiated. Meanwhile, the concept of targeting the bone marrow microenvironment (the "soil") in a way that interferes with the growth of the myeloma "seed" emerged as the rationale for trials of new agents in combination with established therapies in an attempt to enhance cytotoxicity, reverse drug resistance, and increase the probability of curing myeloma.
Thalidomide, an old drug with an infamous past, has been redeemed as a treatment for not only relapsed or refractory myeloma but also newly diagnosed disease. As an initial treatment to prepare patients for autologous stem-cell transplantation, thalidomide in combination with dexamethasone resulted in higher response rates than the combination of vincristine, doxorubicin, and dexamethasone or dexamethasone alone.6,7 Maintenance therapy with thalidomide after autologous transplantation prolonged event-free survival, as compared with no maintenance therapy.8 The antimyeloma activity of thalidomide prompted its integration into high-dose treatment protocols that were pioneered by Barlogie and colleagues at the University of Arkansas.
In this issue of the Journal, Barlogie et al. report on the effect of adding thalidomide to intensive chemotherapy, administered before and after melphalan-based double autologous stem-cell transplantation.9 Patients with newly diagnosed myeloma were randomly assigned to receive thalidomide or no thalidomide from the outset until disease progression or undue adverse effects occurred. In comparison with the control group (which did not receive thalidomide), the group of patients who received thalidomide during primary remission-induction therapy, between the two transplantations, with consolidation therapy, and as maintenance treatment had a significantly higher rate of both complete response (62 percent vs. 43 percent) and five-year event-free survival (56 percent vs. 44 percent). Nevertheless, overall survival curves in the two groups were nearly identical, owing in part to the poorer outcome after relapse in the thalidomide group. In particular, thalidomide-treated patients had a lower rate of response to salvage therapy and shorter overall survival after relapse than the control patients.
These results indicate that contrary to a widely held belief, a complete response is not a valid surrogate for overall survival in clinical trials. The higher rate of failure to respond to salvage therapy in the thalidomide group needs to be investigated further, especially with respect to the salvage potential of new drugs in patients who had received thalidomide as initial treatment. In this regard, it is worth noting that in a comparison of bortezomib with dexamethasone as second-line therapy for myeloma, response rates to bortezomib were superior to those observed with dexamethasone regardless of the type of first-line therapy, with the exception of prior thalidomide treatment.10 It will also be important to assess whether relapses of aggressive myeloma, such as those reported by Barlogie et al., also occur when thalidomide is reserved for maintenance therapy8 or combined initially with chemotherapy at conventional doses.11
Another matter of importance concerns the dose- and duration-related toxicity of thalidomide, a complication that led to its discontinuation in 30 percent of patients within the first two years and in more than 60 percent within four years in the study by Barlogie and colleagues. As in previous reports, deep-vein thrombosis and peripheral neuropathy were the chief adverse effects of thalidomide therapy. Lenalidomide has recently been incorporated into salvage and initial treatment for myeloma.12,13 In both settings, lenalidomide combined with high-dose dexamethasone was associated with high response rates and almost no severe neurotoxic effects. However, severe neutropenia occurred in 12.0 to 16.5 percent of patients who received lenalidomide.12,13
The landscape of myeloma treatment has changed substantially over the past few years. New agents have moved rapidly from the bench to the bedside, and they are important additions to the treatments now available for myeloma. Genomic and proteomic studies incorporated into trials of these agents will help to identify molecular mechanisms of drug sensitivity and resistance, and they will aid in the design of treatment for individual patients. Currently, the main clinical challenges are determining the optimal dose of new agents, whether they should be given sequentially or in combination, and how they should be integrated with old therapies. Two treatment strategies are being explored. The first aims to eradicate the tumor with the use of a combination of all, or most of, the available agents and high-dose therapy with stem-cell transplantation. Whether such an approach can modify the course of myeloma is uncertain, as reflected in the study by Barlogie et al. The second approach is to reserve the use of new agents for the sequential treatment of relapses as a means of controlling the growth or regrowth of tumor, thereby converting myeloma into an indolent disease.
It is important to note that the message of the study by Barlogie et al. is one of hope. Through biologic and clinical research in myeloma, we are uncovering effective new treatments that promise long-term benefit to a substantial proportion of patients with a cancer for which palliation was a reasonable goal even as recently as a decade ago.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Institute of Hematology and Medical Oncology Seràgnoli, University of Bologna, Bologna, Italy.
References
Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860-1873.
Attal M, Harousseau J-L, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003;349:2495-2502.
Cavo M, Cellini C, Zamagni E, et al. Superiority of double over single autologous stem cell transplantation as first-line therapy for multiple myeloma. Blood 2004;104:155a-155a.
Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood 2004;103:20-32.
Richardson PG, Sonneveld P, Schuster MS, et al. Bortezomib or high-dose dexamethasone for relapsed myeloma. N Engl J Med 2005;352:2487-2498.
Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005;106:35-39.
Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431-436.
Attal M, Harousseau J-L, Leyvraz S, et al. Maintenance treatment with thalidomide after autologous transplantation for myeloma: final analysis of a prospective randomized study of the "Intergroupe Francophone du Myelome." Blood 2005;106:335a-335a.
Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021-1030.
Sonneveld P, Richardson PG, Schuster MW, et al. Bortezomib at first relapse is superior to high-dose dexamethasone and more effective than when given later in relapsed multiple myeloma. Haematologica 2005;90:Suppl 1:146-146.
Palumbo A, Bringhen S, Musto P, et al. Oral melphalan, prednisone and thalidomide for multiple myeloma. Blood 2005;106:230a-230a.
Dimopoulos MA, Spencer A, Attal M, et al. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study (MM-010). Blood 2005;106:6a-6a.
Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005;106:4050-4053.(Michele Cavo, M.D., and M)
More recent advances in the management of myeloma include the identification of new ways to overcome drug resistance.1 Also important is recognition of the pivotal role of the bone marrow microenvironment in promoting the growth, survival, and resistance of myeloma cells to conventional chemotherapy. As a result of this work, new classes of agents for the treatment of myeloma have been introduced. These include thalidomide; lenalidomide, a potent analogue of thalidomide; and the proteasome inhibitor bortezomib. Once the activity of these drugs in advanced and refractory myeloma was confirmed,5 studies of their efficacy in earlier phases of the disease were initiated. Meanwhile, the concept of targeting the bone marrow microenvironment (the "soil") in a way that interferes with the growth of the myeloma "seed" emerged as the rationale for trials of new agents in combination with established therapies in an attempt to enhance cytotoxicity, reverse drug resistance, and increase the probability of curing myeloma.
Thalidomide, an old drug with an infamous past, has been redeemed as a treatment for not only relapsed or refractory myeloma but also newly diagnosed disease. As an initial treatment to prepare patients for autologous stem-cell transplantation, thalidomide in combination with dexamethasone resulted in higher response rates than the combination of vincristine, doxorubicin, and dexamethasone or dexamethasone alone.6,7 Maintenance therapy with thalidomide after autologous transplantation prolonged event-free survival, as compared with no maintenance therapy.8 The antimyeloma activity of thalidomide prompted its integration into high-dose treatment protocols that were pioneered by Barlogie and colleagues at the University of Arkansas.
In this issue of the Journal, Barlogie et al. report on the effect of adding thalidomide to intensive chemotherapy, administered before and after melphalan-based double autologous stem-cell transplantation.9 Patients with newly diagnosed myeloma were randomly assigned to receive thalidomide or no thalidomide from the outset until disease progression or undue adverse effects occurred. In comparison with the control group (which did not receive thalidomide), the group of patients who received thalidomide during primary remission-induction therapy, between the two transplantations, with consolidation therapy, and as maintenance treatment had a significantly higher rate of both complete response (62 percent vs. 43 percent) and five-year event-free survival (56 percent vs. 44 percent). Nevertheless, overall survival curves in the two groups were nearly identical, owing in part to the poorer outcome after relapse in the thalidomide group. In particular, thalidomide-treated patients had a lower rate of response to salvage therapy and shorter overall survival after relapse than the control patients.
These results indicate that contrary to a widely held belief, a complete response is not a valid surrogate for overall survival in clinical trials. The higher rate of failure to respond to salvage therapy in the thalidomide group needs to be investigated further, especially with respect to the salvage potential of new drugs in patients who had received thalidomide as initial treatment. In this regard, it is worth noting that in a comparison of bortezomib with dexamethasone as second-line therapy for myeloma, response rates to bortezomib were superior to those observed with dexamethasone regardless of the type of first-line therapy, with the exception of prior thalidomide treatment.10 It will also be important to assess whether relapses of aggressive myeloma, such as those reported by Barlogie et al., also occur when thalidomide is reserved for maintenance therapy8 or combined initially with chemotherapy at conventional doses.11
Another matter of importance concerns the dose- and duration-related toxicity of thalidomide, a complication that led to its discontinuation in 30 percent of patients within the first two years and in more than 60 percent within four years in the study by Barlogie and colleagues. As in previous reports, deep-vein thrombosis and peripheral neuropathy were the chief adverse effects of thalidomide therapy. Lenalidomide has recently been incorporated into salvage and initial treatment for myeloma.12,13 In both settings, lenalidomide combined with high-dose dexamethasone was associated with high response rates and almost no severe neurotoxic effects. However, severe neutropenia occurred in 12.0 to 16.5 percent of patients who received lenalidomide.12,13
The landscape of myeloma treatment has changed substantially over the past few years. New agents have moved rapidly from the bench to the bedside, and they are important additions to the treatments now available for myeloma. Genomic and proteomic studies incorporated into trials of these agents will help to identify molecular mechanisms of drug sensitivity and resistance, and they will aid in the design of treatment for individual patients. Currently, the main clinical challenges are determining the optimal dose of new agents, whether they should be given sequentially or in combination, and how they should be integrated with old therapies. Two treatment strategies are being explored. The first aims to eradicate the tumor with the use of a combination of all, or most of, the available agents and high-dose therapy with stem-cell transplantation. Whether such an approach can modify the course of myeloma is uncertain, as reflected in the study by Barlogie et al. The second approach is to reserve the use of new agents for the sequential treatment of relapses as a means of controlling the growth or regrowth of tumor, thereby converting myeloma into an indolent disease.
It is important to note that the message of the study by Barlogie et al. is one of hope. Through biologic and clinical research in myeloma, we are uncovering effective new treatments that promise long-term benefit to a substantial proportion of patients with a cancer for which palliation was a reasonable goal even as recently as a decade ago.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Institute of Hematology and Medical Oncology Seràgnoli, University of Bologna, Bologna, Italy.
References
Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860-1873.
Attal M, Harousseau J-L, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003;349:2495-2502.
Cavo M, Cellini C, Zamagni E, et al. Superiority of double over single autologous stem cell transplantation as first-line therapy for multiple myeloma. Blood 2004;104:155a-155a.
Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood 2004;103:20-32.
Richardson PG, Sonneveld P, Schuster MS, et al. Bortezomib or high-dose dexamethasone for relapsed myeloma. N Engl J Med 2005;352:2487-2498.
Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005;106:35-39.
Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431-436.
Attal M, Harousseau J-L, Leyvraz S, et al. Maintenance treatment with thalidomide after autologous transplantation for myeloma: final analysis of a prospective randomized study of the "Intergroupe Francophone du Myelome." Blood 2005;106:335a-335a.
Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021-1030.
Sonneveld P, Richardson PG, Schuster MW, et al. Bortezomib at first relapse is superior to high-dose dexamethasone and more effective than when given later in relapsed multiple myeloma. Haematologica 2005;90:Suppl 1:146-146.
Palumbo A, Bringhen S, Musto P, et al. Oral melphalan, prednisone and thalidomide for multiple myeloma. Blood 2005;106:230a-230a.
Dimopoulos MA, Spencer A, Attal M, et al. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study (MM-010). Blood 2005;106:6a-6a.
Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005;106:4050-4053.(Michele Cavo, M.D., and M)