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Myeloma and the newly diagnosed patient: A focus on treatment and management
Myeloma and the Newly Diagnosed Patient: A Focus on Treatment and Management S. Vincent Rajkumar, Robert A. Kyle, and Morie A. Gertz An evidence-based approach to the management of newly diagnosed multiple myeloma, developed at the Mayo Clinic (Rochester, MN), is summarized in this article. The optimum pretransplant induction regimen for multiple myeloma is described, and outcomes for early and delayed transplantation, one versus two transplants, the role of thalidomide in smoldering multiple myeloma, and the role of maintenance therapy are discussed. The role of supportive care strategies for patients with bone disease, such as the use of bisphosphonates, is also discussed. Semin Oncol 29 (suppl 17):5-10. Copyright 2002, Elsevier Science (USA). All rights reserved.
M
ULTIPLE MYELOMA (MM) accounts for 1% of all malignancies and 10% of malignant hematologic neoplasms.1,2 At present, there is no cure for MM, and median survival with standard therapy is approximately 4 years. Several clinical questions must be answered when assessing a newly diagnosed MM patient. Figure 1 provides a schematic of an evidence-based approach for the management of newly diagnosed patients with MM, developed at the Mayo Clinic (Rochester, MN). The first step in managing patients with MM is to determine if the patient needs therapeutic intervention. For example, patients with monoclonal gammopathy of undetermined significance (MGUS) have a serum monoclonal protein less than 3 g/dL, bone marrow plasma cells less than 10%, and no evidence of anemia, hypercalcemia, renal failure, or bone lesions. These patients do not have myeloma, but need indefinite follow-up, because 20% to 25% will eventually progress to myeloma, amyloidosis, or a nonHodgkin lymphoma at a rate of 1% per year.3,4 The serum monoclonal protein in MGUS is rechecked at 6 months; if it remains stable, it is checked yearly thereafter. Patients with a serum monoclonal protein of 3 g/dL or higher and/or 10% or more of plasma cells in the bone marrow without anemia, bone lesions, hypercalcemia, or renal insufficiency are considered to have smoldering MM (SMM).4,5 These patients have a higher risk of transformation to myeloma than those with MGUS, and many patients meet criteria for Durie-Salmon stage I myeloma. Smoldering MM patients can be observed without therapy for months to years, and close follow-up is recommended. This course is supSeminars in Oncology, Vol 29, No 6, Suppl 17 (December), 2002: pp 5-10
ported by evidence from a study that showed many SMM patients live for several years without evidence of progression.6 In a small, randomized trial, Hjorth et al7 showed that delaying therapy and treating patients at the time of disease progression does not adversely affect survival. Data from Witzig and Kyle8 showed that median time to progression for patients with SMM is approximately 2 years. Therefore, there is a need to enroll SMM patients in clinical trials that investigate therapy that will delay the progression to myeloma. Such trials, already under way in the United States and in many other countries, involve the use of thalidomide, pamidronate, and zoledronic acid. Initial reports from studies evaluating the use of thalidomide as a single agent for patients with SMM show a response rate of approximately 35%.9,10 Because the primary goal of therapy in patients with SMM is to delay the need for chemotherapy, more data on the durability of response are needed before recommending this strategy for standard clinical practice. Patients with a single plasmacytoma, with no evidence of other bone or extramedullary lesions, are considered to have a solitary plasmacytoma. The usual treatment consists of radiation therapy to the affected area, followed by close observation. These patients are at risk for overt MM, particularly if they have a residual monoclonal protein after radiation therapy. Once MGUS, SMM, and solitary plasmacytoma have been excluded and a diagnosis of myeloma is made, physicians must determine if their patients are candidates for autologous stem cell transplantation. Patients who are not candidates for autologous stem cell transplantation, such as those at extreme age, with renal failure, or with poor performance status, should receive standard dose ther-
From the Mayo Medical School, Rochester, MN; and the Department of Medicine and Laboratory Medicine, and the Division of Hematology, Mayo Clinic, Rochester, MN. Address reprint requests to S. Vincent Rajkumar, MD, Mayo Medical School, 200 First St SW, Rochester, MN 55905. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2906-1703$35.00/0 doi:10.1053/sonc.2002.34070 5
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RAJKUMAR, KYLE, AND GERTZ
Fig 1. Mayo Clinic approach to newly diagnosed MM. MM, multiple myeloma; SMM, smoldering multiple myeloma; MP, melphalan and prednisone; Dex, dexamethasone; VAD, vincristine, adriamycin, and dexamethasone. Adapted and reprinted with permission from Rajkumar SV, Kyle RA: “Management of Patients With Asymptomatic or Newly Diagnosed Myeloma: Understanding the Disease and Update on Novel Treatment Approaches,” Seton Hall University School of Graduate Medical Education, American Academy of CME, and OmegaMed, Inc, 2002.
apy with melphalan and prednisone. The overall response rate with this regimen is approximately 50%.11 The complete response rate is less than 10%, and median survival is about 3 years.12 The 5-year survival rate in patients treated with this therapy is 24%.11 As shown in Fig 2, more aggressive combination chemotherapy regimens such as vincristine, carmustine, melphalan, cyclophosphamide, and prednisone result in superior response rates (60% to 70%) but offer no survival benefit.11,13,14 High-dose therapy followed by autologous stem cell transplantation improves response rate and survival in myeloma, but it is not a cure.15-17 Response rates exceed 75% to 90%,12,13 and complete response rates range from 20% to 40%.16,18 As shown in Fig 3, a randomized, controlled trial conducted by the Intergroupe Francais du Myelome in 200 patients younger than 65 years who
had Durie-Salmon stage II or III myeloma showed that high-dose chemotherapy followed by autologous bone marrow transplantation resulted in better response rates (81%, including complete responses in 22% and very good partial responses in 16%) compared with 57% (complete responses in 5% and very good partial responses in 9%) in the group treated with conventional chemotherapy (P ⬍ .001). The probability of 5-year overall survival was 52% in the high-dose group and 12% in the conventional-dose group (P ⫽ .03), and 5-year event-free survival was 28% in the high-dose group and 10% in the conventional-dose group (P ⫽ .01). Treatment-related mortality was similar in the two groups.18 Based on these results, stem cell transplantation is now standard therapy for patients younger than 65 years with good performance status. The combination of vincristine, adriamycin,
MYELOMA AND THE NEWLY DIAGNOSED PATIENT
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Fig 2. Survival curve for 30 trials that compare combination chemotherapy (cct) versus melphalan plus prednisone (MP). There is no significant difference in survival between patients allocated to cct or MP. Reprinted with permisison by Lippincott Williams & Wilkins, © 1998.11
and dexamethasone (VAD) is considered the standard pretransplant induction therapy with a response rate of 55%. However, VAD is cumbersome to administer. Because it requires an indwelling intravenous catheter, VAD is associated with sepsis, thrombosis, and substantial toxicity, and 27% of patients must be hospitalized. Several preliminary reports suggest that induction therapy may not be necessary. Lack of response to initial VAD (primary refractory disease) does not predict poor survival following transplantation, and patients may be treated with transplantation regardless of response status to VAD.19 However, strong evidence against the use of induction therapy is lacking. Interestingly, dexamethasone accounts for almost 85% of the activity of VAD and is less toxic; although the response rate may be lower, there is no effect on overall survival.20 For
this reason, dexamethasone is a good substitute for VAD as pretransplant induction therapy. Recent interest has focused on the combination of thalidomide and dexamethasone as induction therapy. In a Mayo Clinic study of 50 patients with newly diagnosed myeloma (most with Salmon-Durie stage III), the combination of thalidomide and dexamethasone resulted in a 64% response rate.21 In this study, thalidomide was given orally at a fixed dosage of 200 mg/d. Dexamethasone was given at an oral dosage of 40 mg/d on days 1 to 4, 9 to 12, 17 to 20 (odd cycles), and 40 mg/d on days 1 to 4 (even cycles), repeated monthly. Grade 3 or higher toxicity was observed in 16 patients (32%); the most frequent were venous thrombosis (10%), constipation (8%), rash (6%), and dyspnea (4%). An ongoing Eastern Cooperative Oncology Group randomized trial compares dexamethasone versus
8
RAJKUMAR, KYLE, AND GERTZ
Fig 3. Overall survival according to treatment group. Highdose chemotherapy followed by autologous bone marrow transplantation resulted in better response rates compared with conventional chemotherapy. The numbers shown below the time points are probabilities of overall survival (the percentage of patients surviving) and 95% confidence intervals. Reprinted with permission from Attal M, Marousseau JL, Stoppa AM, et al: “A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome,” New England Journal of Medicine, vol 335, pp 91-97. Copyright © 1996, Massachusetts Medical Society. All rights reserved.18
thalidomide plus dexamethasone as induction therapy for myeloma. Stem cell transplantation for myeloma is often performed early in the course of the disease, following three to four cycles of induction chemotherapy. However, it is possible to delay transplantation until relapse without compromising survival, provided that hematopoietic stem cells are harvested and cryopreserved early in the disease course. Data from randomized trials comparing early versus delayed transplantation indicate that there is no significant difference in outcome between the two strategies.22,23 The choice between the two options is based on patient preference and other clinical conditions. Currently, the role of tandem transplantation is not fully understood. Preliminary data from four
randomized trials were presented at the International Myeloma Workshop in Banff, Alberta, Canada, in May 2001 (Table 1).24-27 The trials indicate some improvement in response rates and possibly event-free survival with tandem transplantation. However, none of the trials showed an
Table 1. Stem Cell Transplant: One Versus Two. Results of Four Randomized Trials Study
No. of Patients
IFM24 Bologna 9625 Dutch-Belgium26 Fermand27
400 320 255 230
Age (yrs) ⬍ ⱕ ⱕ ⬍
60 60 65 56
MYELOMA AND THE NEWLY DIAGNOSED PATIENT
improvement in overall survival with intensive therapy using an intent-to-treat analysis. Final results of the trials will answer this important question. Because the role of twin/tandem transplantation is undetermined, enough stem cells for two transplants can be harvested. At the Mayo Clinic, patient preference is considered; however, typically, a single transplant is completed and the second transplant is reserved for relapse. If patients do not prefer an immediate transplant, chemotherapy, such as melphalan plus prednisone, is administered after stem cell harvest, and transplantation is reserved for relapse. Allogenic transplantation may lead to prolonged disease-free survival in a relatively small percentage of patients.28,29 High treatment-related mortality and toxicity has limited the role of the procedure as initial treatment. Recent interest has focused on nonmyeloablative (mini) allogenic transplantation for selected patients with myeloma, either immediately following autologous stem cell transplantation at the time when there is minimal disease30 or at relapse. Data from Maloney et al31 showed a treatment-related mortality of less than 10% (45% of patients developed acute grade II-IV graft versus host disease and 55% developed chronic graft versus host disease requiring therapy). The response rate was 84%, with a complete remission rate of 53% and a partial remission rate of 31% in 32 patients with a median age of 55 years (range, 39 to 71 years) who were previously treated for stage II/III myeloma (43% refractory or relapsed disease) and were receiving nonmyeloablative allogeneic hematopoietic stem cell transplantation.31 Currently, the role of allogenic stem cell transplantation in myeloma must be considered investigational. The role of post-transplant maintenance therapy in myeloma is critical, yet remains investigational because there is no standard post-transplant therapy. Transplant alone does not provide a cure; Moreau et al32 have shown that the 10-year overall survival and event-free survival rates are 24.9% and 3.1%, respectively, and median survival and event-free survival are 49 and 17 months, respectively. Several studies have shown that, as maintenance therapy, interferon-␣ prolongs plateau phase in myeloma.33-36 However, other studies have failed to show such an effect and overall survival was not prolonged in any study.37-39 A meta-analysis studying the role of interferon-␣ is ongoing. A nationwide, large, randomized trial in
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the United States that evaluated the role of interferon-␣ as maintenance therapy in myeloma is awaiting analysis. At low doses, prednisone also has been studied as maintenance therapy.40 Clinical trials are being designed to study the role of thalidomide, dendritic cell vaccination, and other novel approaches as maintenance therapy following stem cell transplantation or conventional chemotherapy. Supportive care strategies are important for the management of MM patients. Bisphosphonates such as pamidronate are routinely used in myeloma for patients with bone disease. The goal of therapy is to prevent or delay lesions.41 Pamidronate is shown to reduce skeletal complications and improve the quality of life of patients with myeloma.42,43 Other supportive care strategies, such as pain control measures and erythropoietin therapy, should be considered. REFERENCES 1. Bataille R, Harousseau JL: Multiple myeloma. N Engl J Med 336:1657-1664, 1997 2. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001 3. Kyle RA: “Benign” monoclonal gammopathy after 20 to 35 years of follow-up. Mayo Clin Proc 68:26-36, 1993 4. Rajkumar SV, Dispenzieri A, Fonseca R, et al: Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia 15:1274-1276, 2001 5. Greipp PR, Kyle RA: Staging, kinetics, and prognosis of multiple myeloma, in Wiernik PH, Canellos GP, Dutcher JP, et al (eds): Neoplastic Diseases of the Blood. New York, NY, Churchill Livingstone, 1996, pp 537-559 6. Kyle R, Greipp P: Smoldering multiple myeloma. N Engl J Med 302:1347-1349, 1980 7. Hjorth M, Hellquist L, Holmberg E: Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I – A randomized study: Myeloma Group of Western Sweden. Eur J Haematol 50:95-102, 1993 8. Witzig TE, Kyle RA: Detection of peripheral blood plasma cells as a predictor of disease course in patients with smouldering multiple myeloma. Br J Haematol 87:266-272, 1994 9. Rajkumar SV, Hayman S, Fonseca R, et al: Thalidomide plus dexamethasone (Thal/Dex) and thalidomide alone (Thal) as first line therapy for newly diagnosed myeloma (MM). Blood 96:168a, 2000 (abstr A722) 10. Weber DM, Rankin K, Gavino M, et al: Angiogenesis factors and sensitivity to thalidomide in previously untreated multiple myeloma (MM). Blood 96:168a, 2000 (abstr) 11. Myeloma Trialists’ Collaborative Group: Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6,633 patients from 27 randomized trials. J Clin Oncol 16:3832-3842, 1998 12. Kovacsovics T, Delaly A: Intensive treatment strategies in myeloma. Semin Hematol 34:49-60, 1997
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13. Alexanian R, Dimopoulos M: The treatment of multiple myeloma. N Engl J Med 330:484-489, 1994 14. Oken MM, Harrington DP, Abramson N, et al: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: Results of Eastern Cooperative Oncology Group Study E2479. Cancer 79:1561-1567, 1997 15. Harousseau JL, Attal M: The role of autologous hematopoietic stem cell transplantation in multiple myeloma. Semin Hematol 34:61-66, 1997 16. Barlogie B, Jagannath S, Epstein J, et al: Biology and therapy of multiple myeloma in 1996. Semin Hematol 34:6772, 1997 17. Gertz MA, Pineda AA, Chen MG, et al: Refractory and relapsing multiple myeloma treated by blood stem cell transplantation. Am J Med Sci 309:152-161, 1995 18. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996 19. Rajkumar SV, Fonseca R, Lacy MQ, et al: Autologous stem cell transplantation for relapsed and primary refractory myeloma. Bone Marrow Transplant 23:1267-1272, 1999 20. Alexanian R, Dimopoulos MA, Delasalle K, et al: Primary dexamethasone treatment of multiple myeloma. Blood 80:887-890, 1992 21. Rajkumar SV, Hayman S, Gertz MA, et al: Combination therapy with thalidomide plus dexamethasone (thal/dex) for newly diagnosed myeloma (MM). Blood 98: 2266-2268, 2001 22. Fermand JP, Ravaud P, Chevret S, et al: Early versus late high dose therapy (HDT) and autologous peripheral blood stem cell transplantation in multiple myeloma (MM): Results of a prospective randomized trial. Blood 88:685a, 1996 (suppl 11) 23. Facon T, Mary JY, Harousseau JL, et al: Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): Preliminary results of a prospective randomized trial (CIAM) protocol. Blood 88:685a, 1996 (suppl) (abstr) 24. Attal M, Harousseau JL, Facon T: Single versus double transplant in myeloma: A randomized trial of the “Intergroupe Francais Du Myelome” (IFM). VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 28 25. Cabo M, Tosi P, Zamagni E, et al: The “Bologna 96” clinical trial of single versus double PBSC transplantation for previously untreated MM: Results of an interim analysis. VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 29 26. Segeren CM, Sonneveld P, van der Holt B, et al: Intensive versus double intensive therapy in previously untreated multiple myeloma: A prospective randomized phase III study in 450 patients. VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 31 27. Fermand JP, Marolleau JP, Alberti C: Single versus tandem high-dose therapy (HDT) supported with autologous blood stem cell (ABSC) transplantation using unselected or CD-34 enriched ABSC: Preliminary results of a two by two design randomized trial in 230 young patients with multiple myeloma. VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 147 28. Bensinger WI, Buckner CD, Anasetti C, et al: Alloge-
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neic marrow transplantation for multiple myeloma: An analysis of risk factors on outcome. Blood 88:2787-2793, 1996 29. Cavo M, Bandini G, Benni M, et al: High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma. Bone Marrow Transplant 22:27-32, 1998 30. Molina A, Sahebi F, Maloney DG, et al: Non-myeloablative peripheral blood stem cell (PBSC) allografts following cytoreductive autotransplants for treatment of multiple myeloma (MM). Blood 96:168a, 2000 (abstr A2063) 31. Maloney DG, Sahebi F, Stockerl-Goldstein KE: Combining an allogeneic graft-vs-myeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma. Presented at the American Society of Hematology 43rd Annual Meeting, December 2001, Orlando, FL (abstr 1822) 32. Moreau P, Misbahi R, Milpied N: Long-term results (10 years) of high-dose therapy in 127 patients with de novo multiple myeloma. Presented at the American Society of Hematology 43rd Annual Meeting, December 2001, Orlando, FL (abstr 2863) 33. Shustik C: Interferon in the treatment of multiple myeloma. Cancer Control 5:226-234, 1998 34. Mandelli F, Avvisati G, Amadori S, et al: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 322:1430-1434, 1990 35. Browman GP, Bergsagel D, Sicheri D, et al: Randomized trial of interferon maintenance in multiple myeloma: A study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 13:2354-2360, 1995 36. Westin J, Rodjer S, Turesson I, et al: Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: A randomized study – Cooperative Study Group. Br J Haematol 89:561-568, 1995 37. Salmon SE, Crowley JJ, Grogan TM, et al: Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: A Southwest Oncology Group study. J Clin Oncol 12:2405-2414, 1994 38. Peest D, Deicher H, Coldewey R, et al: A comparison of polychemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma: A prospective trial of the German Myeloma Treatment Group. Eur J Cancer 2:146-151, 1995 39. Ludwig H, Cohen AM, Polliack A, et al: Interferonalpha for induction and maintenance in multiple myeloma: Results of two multicenter randomized trials and summary of other studies. Ann Oncol 6:467-476, 1995 40. Salmon SE, Crowley JJ, Balcerzak SP, et al: Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: A Southwest Oncology Group Study. J Clin Oncol 16:890-896, 1998 41. Kyle RA: The role of bisphosphonates in multiple myeloma. Ann Intern Med 132:734-736, 2000 42. Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma: Myeloma Aredia Study Group. N Engl J Med 334:488-493, 1996 43. Berenson JR, Lichtenstein A, Porter L, et al: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events: Myeloma Aredia Study Group. J Clin Oncol 16:593-602, 1998
M
ULTIPLE MYELOMA (MM) accounts for 1% of all malignancies and 10% of malignant hematologic neoplasms.1,2 At present, there is no cure for MM, and median survival with standard therapy is approximately 4 years. Several clinical questions must be answered when assessing a newly diagnosed MM patient. Figure 1 provides a schematic of an evidence-based approach for the management of newly diagnosed patients with MM, developed at the Mayo Clinic (Rochester, MN). The first step in managing patients with MM is to determine if the patient needs therapeutic intervention. For example, patients with monoclonal gammopathy of undetermined significance (MGUS) have a serum monoclonal protein less than 3 g/dL, bone marrow plasma cells less than 10%, and no evidence of anemia, hypercalcemia, renal failure, or bone lesions. These patients do not have myeloma, but need indefinite follow-up, because 20% to 25% will eventually progress to myeloma, amyloidosis, or a nonHodgkin lymphoma at a rate of 1% per year.3,4 The serum monoclonal protein in MGUS is rechecked at 6 months; if it remains stable, it is checked yearly thereafter. Patients with a serum monoclonal protein of 3 g/dL or higher and/or 10% or more of plasma cells in the bone marrow without anemia, bone lesions, hypercalcemia, or renal insufficiency are considered to have smoldering MM (SMM).4,5 These patients have a higher risk of transformation to myeloma than those with MGUS, and many patients meet criteria for Durie-Salmon stage I myeloma. Smoldering MM patients can be observed without therapy for months to years, and close follow-up is recommended. This course is supSeminars in Oncology, Vol 29, No 6, Suppl 17 (December), 2002: pp 5-10
ported by evidence from a study that showed many SMM patients live for several years without evidence of progression.6 In a small, randomized trial, Hjorth et al7 showed that delaying therapy and treating patients at the time of disease progression does not adversely affect survival. Data from Witzig and Kyle8 showed that median time to progression for patients with SMM is approximately 2 years. Therefore, there is a need to enroll SMM patients in clinical trials that investigate therapy that will delay the progression to myeloma. Such trials, already under way in the United States and in many other countries, involve the use of thalidomide, pamidronate, and zoledronic acid. Initial reports from studies evaluating the use of thalidomide as a single agent for patients with SMM show a response rate of approximately 35%.9,10 Because the primary goal of therapy in patients with SMM is to delay the need for chemotherapy, more data on the durability of response are needed before recommending this strategy for standard clinical practice. Patients with a single plasmacytoma, with no evidence of other bone or extramedullary lesions, are considered to have a solitary plasmacytoma. The usual treatment consists of radiation therapy to the affected area, followed by close observation. These patients are at risk for overt MM, particularly if they have a residual monoclonal protein after radiation therapy. Once MGUS, SMM, and solitary plasmacytoma have been excluded and a diagnosis of myeloma is made, physicians must determine if their patients are candidates for autologous stem cell transplantation. Patients who are not candidates for autologous stem cell transplantation, such as those at extreme age, with renal failure, or with poor performance status, should receive standard dose ther-
From the Mayo Medical School, Rochester, MN; and the Department of Medicine and Laboratory Medicine, and the Division of Hematology, Mayo Clinic, Rochester, MN. Address reprint requests to S. Vincent Rajkumar, MD, Mayo Medical School, 200 First St SW, Rochester, MN 55905. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2906-1703$35.00/0 doi:10.1053/sonc.2002.34070 5
6
RAJKUMAR, KYLE, AND GERTZ
Fig 1. Mayo Clinic approach to newly diagnosed MM. MM, multiple myeloma; SMM, smoldering multiple myeloma; MP, melphalan and prednisone; Dex, dexamethasone; VAD, vincristine, adriamycin, and dexamethasone. Adapted and reprinted with permission from Rajkumar SV, Kyle RA: “Management of Patients With Asymptomatic or Newly Diagnosed Myeloma: Understanding the Disease and Update on Novel Treatment Approaches,” Seton Hall University School of Graduate Medical Education, American Academy of CME, and OmegaMed, Inc, 2002.
apy with melphalan and prednisone. The overall response rate with this regimen is approximately 50%.11 The complete response rate is less than 10%, and median survival is about 3 years.12 The 5-year survival rate in patients treated with this therapy is 24%.11 As shown in Fig 2, more aggressive combination chemotherapy regimens such as vincristine, carmustine, melphalan, cyclophosphamide, and prednisone result in superior response rates (60% to 70%) but offer no survival benefit.11,13,14 High-dose therapy followed by autologous stem cell transplantation improves response rate and survival in myeloma, but it is not a cure.15-17 Response rates exceed 75% to 90%,12,13 and complete response rates range from 20% to 40%.16,18 As shown in Fig 3, a randomized, controlled trial conducted by the Intergroupe Francais du Myelome in 200 patients younger than 65 years who
had Durie-Salmon stage II or III myeloma showed that high-dose chemotherapy followed by autologous bone marrow transplantation resulted in better response rates (81%, including complete responses in 22% and very good partial responses in 16%) compared with 57% (complete responses in 5% and very good partial responses in 9%) in the group treated with conventional chemotherapy (P ⬍ .001). The probability of 5-year overall survival was 52% in the high-dose group and 12% in the conventional-dose group (P ⫽ .03), and 5-year event-free survival was 28% in the high-dose group and 10% in the conventional-dose group (P ⫽ .01). Treatment-related mortality was similar in the two groups.18 Based on these results, stem cell transplantation is now standard therapy for patients younger than 65 years with good performance status. The combination of vincristine, adriamycin,
MYELOMA AND THE NEWLY DIAGNOSED PATIENT
7
Fig 2. Survival curve for 30 trials that compare combination chemotherapy (cct) versus melphalan plus prednisone (MP). There is no significant difference in survival between patients allocated to cct or MP. Reprinted with permisison by Lippincott Williams & Wilkins, © 1998.11
and dexamethasone (VAD) is considered the standard pretransplant induction therapy with a response rate of 55%. However, VAD is cumbersome to administer. Because it requires an indwelling intravenous catheter, VAD is associated with sepsis, thrombosis, and substantial toxicity, and 27% of patients must be hospitalized. Several preliminary reports suggest that induction therapy may not be necessary. Lack of response to initial VAD (primary refractory disease) does not predict poor survival following transplantation, and patients may be treated with transplantation regardless of response status to VAD.19 However, strong evidence against the use of induction therapy is lacking. Interestingly, dexamethasone accounts for almost 85% of the activity of VAD and is less toxic; although the response rate may be lower, there is no effect on overall survival.20 For
this reason, dexamethasone is a good substitute for VAD as pretransplant induction therapy. Recent interest has focused on the combination of thalidomide and dexamethasone as induction therapy. In a Mayo Clinic study of 50 patients with newly diagnosed myeloma (most with Salmon-Durie stage III), the combination of thalidomide and dexamethasone resulted in a 64% response rate.21 In this study, thalidomide was given orally at a fixed dosage of 200 mg/d. Dexamethasone was given at an oral dosage of 40 mg/d on days 1 to 4, 9 to 12, 17 to 20 (odd cycles), and 40 mg/d on days 1 to 4 (even cycles), repeated monthly. Grade 3 or higher toxicity was observed in 16 patients (32%); the most frequent were venous thrombosis (10%), constipation (8%), rash (6%), and dyspnea (4%). An ongoing Eastern Cooperative Oncology Group randomized trial compares dexamethasone versus
8
RAJKUMAR, KYLE, AND GERTZ
Fig 3. Overall survival according to treatment group. Highdose chemotherapy followed by autologous bone marrow transplantation resulted in better response rates compared with conventional chemotherapy. The numbers shown below the time points are probabilities of overall survival (the percentage of patients surviving) and 95% confidence intervals. Reprinted with permission from Attal M, Marousseau JL, Stoppa AM, et al: “A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome,” New England Journal of Medicine, vol 335, pp 91-97. Copyright © 1996, Massachusetts Medical Society. All rights reserved.18
thalidomide plus dexamethasone as induction therapy for myeloma. Stem cell transplantation for myeloma is often performed early in the course of the disease, following three to four cycles of induction chemotherapy. However, it is possible to delay transplantation until relapse without compromising survival, provided that hematopoietic stem cells are harvested and cryopreserved early in the disease course. Data from randomized trials comparing early versus delayed transplantation indicate that there is no significant difference in outcome between the two strategies.22,23 The choice between the two options is based on patient preference and other clinical conditions. Currently, the role of tandem transplantation is not fully understood. Preliminary data from four
randomized trials were presented at the International Myeloma Workshop in Banff, Alberta, Canada, in May 2001 (Table 1).24-27 The trials indicate some improvement in response rates and possibly event-free survival with tandem transplantation. However, none of the trials showed an
Table 1. Stem Cell Transplant: One Versus Two. Results of Four Randomized Trials Study
No. of Patients
IFM24 Bologna 9625 Dutch-Belgium26 Fermand27
400 320 255 230
Age (yrs) ⬍ ⱕ ⱕ ⬍
60 60 65 56
MYELOMA AND THE NEWLY DIAGNOSED PATIENT
improvement in overall survival with intensive therapy using an intent-to-treat analysis. Final results of the trials will answer this important question. Because the role of twin/tandem transplantation is undetermined, enough stem cells for two transplants can be harvested. At the Mayo Clinic, patient preference is considered; however, typically, a single transplant is completed and the second transplant is reserved for relapse. If patients do not prefer an immediate transplant, chemotherapy, such as melphalan plus prednisone, is administered after stem cell harvest, and transplantation is reserved for relapse. Allogenic transplantation may lead to prolonged disease-free survival in a relatively small percentage of patients.28,29 High treatment-related mortality and toxicity has limited the role of the procedure as initial treatment. Recent interest has focused on nonmyeloablative (mini) allogenic transplantation for selected patients with myeloma, either immediately following autologous stem cell transplantation at the time when there is minimal disease30 or at relapse. Data from Maloney et al31 showed a treatment-related mortality of less than 10% (45% of patients developed acute grade II-IV graft versus host disease and 55% developed chronic graft versus host disease requiring therapy). The response rate was 84%, with a complete remission rate of 53% and a partial remission rate of 31% in 32 patients with a median age of 55 years (range, 39 to 71 years) who were previously treated for stage II/III myeloma (43% refractory or relapsed disease) and were receiving nonmyeloablative allogeneic hematopoietic stem cell transplantation.31 Currently, the role of allogenic stem cell transplantation in myeloma must be considered investigational. The role of post-transplant maintenance therapy in myeloma is critical, yet remains investigational because there is no standard post-transplant therapy. Transplant alone does not provide a cure; Moreau et al32 have shown that the 10-year overall survival and event-free survival rates are 24.9% and 3.1%, respectively, and median survival and event-free survival are 49 and 17 months, respectively. Several studies have shown that, as maintenance therapy, interferon-␣ prolongs plateau phase in myeloma.33-36 However, other studies have failed to show such an effect and overall survival was not prolonged in any study.37-39 A meta-analysis studying the role of interferon-␣ is ongoing. A nationwide, large, randomized trial in
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the United States that evaluated the role of interferon-␣ as maintenance therapy in myeloma is awaiting analysis. At low doses, prednisone also has been studied as maintenance therapy.40 Clinical trials are being designed to study the role of thalidomide, dendritic cell vaccination, and other novel approaches as maintenance therapy following stem cell transplantation or conventional chemotherapy. Supportive care strategies are important for the management of MM patients. Bisphosphonates such as pamidronate are routinely used in myeloma for patients with bone disease. The goal of therapy is to prevent or delay lesions.41 Pamidronate is shown to reduce skeletal complications and improve the quality of life of patients with myeloma.42,43 Other supportive care strategies, such as pain control measures and erythropoietin therapy, should be considered. REFERENCES 1. Bataille R, Harousseau JL: Multiple myeloma. N Engl J Med 336:1657-1664, 1997 2. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001 3. Kyle RA: “Benign” monoclonal gammopathy after 20 to 35 years of follow-up. Mayo Clin Proc 68:26-36, 1993 4. Rajkumar SV, Dispenzieri A, Fonseca R, et al: Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia 15:1274-1276, 2001 5. Greipp PR, Kyle RA: Staging, kinetics, and prognosis of multiple myeloma, in Wiernik PH, Canellos GP, Dutcher JP, et al (eds): Neoplastic Diseases of the Blood. New York, NY, Churchill Livingstone, 1996, pp 537-559 6. Kyle R, Greipp P: Smoldering multiple myeloma. N Engl J Med 302:1347-1349, 1980 7. Hjorth M, Hellquist L, Holmberg E: Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I – A randomized study: Myeloma Group of Western Sweden. Eur J Haematol 50:95-102, 1993 8. Witzig TE, Kyle RA: Detection of peripheral blood plasma cells as a predictor of disease course in patients with smouldering multiple myeloma. Br J Haematol 87:266-272, 1994 9. Rajkumar SV, Hayman S, Fonseca R, et al: Thalidomide plus dexamethasone (Thal/Dex) and thalidomide alone (Thal) as first line therapy for newly diagnosed myeloma (MM). Blood 96:168a, 2000 (abstr A722) 10. Weber DM, Rankin K, Gavino M, et al: Angiogenesis factors and sensitivity to thalidomide in previously untreated multiple myeloma (MM). Blood 96:168a, 2000 (abstr) 11. Myeloma Trialists’ Collaborative Group: Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6,633 patients from 27 randomized trials. J Clin Oncol 16:3832-3842, 1998 12. Kovacsovics T, Delaly A: Intensive treatment strategies in myeloma. Semin Hematol 34:49-60, 1997
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13. Alexanian R, Dimopoulos M: The treatment of multiple myeloma. N Engl J Med 330:484-489, 1994 14. Oken MM, Harrington DP, Abramson N, et al: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: Results of Eastern Cooperative Oncology Group Study E2479. Cancer 79:1561-1567, 1997 15. Harousseau JL, Attal M: The role of autologous hematopoietic stem cell transplantation in multiple myeloma. Semin Hematol 34:61-66, 1997 16. Barlogie B, Jagannath S, Epstein J, et al: Biology and therapy of multiple myeloma in 1996. Semin Hematol 34:6772, 1997 17. Gertz MA, Pineda AA, Chen MG, et al: Refractory and relapsing multiple myeloma treated by blood stem cell transplantation. Am J Med Sci 309:152-161, 1995 18. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996 19. Rajkumar SV, Fonseca R, Lacy MQ, et al: Autologous stem cell transplantation for relapsed and primary refractory myeloma. Bone Marrow Transplant 23:1267-1272, 1999 20. Alexanian R, Dimopoulos MA, Delasalle K, et al: Primary dexamethasone treatment of multiple myeloma. Blood 80:887-890, 1992 21. Rajkumar SV, Hayman S, Gertz MA, et al: Combination therapy with thalidomide plus dexamethasone (thal/dex) for newly diagnosed myeloma (MM). Blood 98: 2266-2268, 2001 22. Fermand JP, Ravaud P, Chevret S, et al: Early versus late high dose therapy (HDT) and autologous peripheral blood stem cell transplantation in multiple myeloma (MM): Results of a prospective randomized trial. Blood 88:685a, 1996 (suppl 11) 23. Facon T, Mary JY, Harousseau JL, et al: Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): Preliminary results of a prospective randomized trial (CIAM) protocol. Blood 88:685a, 1996 (suppl) (abstr) 24. Attal M, Harousseau JL, Facon T: Single versus double transplant in myeloma: A randomized trial of the “Intergroupe Francais Du Myelome” (IFM). VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 28 25. Cabo M, Tosi P, Zamagni E, et al: The “Bologna 96” clinical trial of single versus double PBSC transplantation for previously untreated MM: Results of an interim analysis. VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 29 26. Segeren CM, Sonneveld P, van der Holt B, et al: Intensive versus double intensive therapy in previously untreated multiple myeloma: A prospective randomized phase III study in 450 patients. VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 31 27. Fermand JP, Marolleau JP, Alberti C: Single versus tandem high-dose therapy (HDT) supported with autologous blood stem cell (ABSC) transplantation using unselected or CD-34 enriched ABSC: Preliminary results of a two by two design randomized trial in 230 young patients with multiple myeloma. VIIIth International Myeloma Workshop Book, Banff, Canada, 2001, p 147 28. Bensinger WI, Buckner CD, Anasetti C, et al: Alloge-
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neic marrow transplantation for multiple myeloma: An analysis of risk factors on outcome. Blood 88:2787-2793, 1996 29. Cavo M, Bandini G, Benni M, et al: High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma. Bone Marrow Transplant 22:27-32, 1998 30. Molina A, Sahebi F, Maloney DG, et al: Non-myeloablative peripheral blood stem cell (PBSC) allografts following cytoreductive autotransplants for treatment of multiple myeloma (MM). Blood 96:168a, 2000 (abstr A2063) 31. Maloney DG, Sahebi F, Stockerl-Goldstein KE: Combining an allogeneic graft-vs-myeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma. Presented at the American Society of Hematology 43rd Annual Meeting, December 2001, Orlando, FL (abstr 1822) 32. Moreau P, Misbahi R, Milpied N: Long-term results (10 years) of high-dose therapy in 127 patients with de novo multiple myeloma. Presented at the American Society of Hematology 43rd Annual Meeting, December 2001, Orlando, FL (abstr 2863) 33. Shustik C: Interferon in the treatment of multiple myeloma. Cancer Control 5:226-234, 1998 34. Mandelli F, Avvisati G, Amadori S, et al: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 322:1430-1434, 1990 35. Browman GP, Bergsagel D, Sicheri D, et al: Randomized trial of interferon maintenance in multiple myeloma: A study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 13:2354-2360, 1995 36. Westin J, Rodjer S, Turesson I, et al: Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: A randomized study – Cooperative Study Group. Br J Haematol 89:561-568, 1995 37. Salmon SE, Crowley JJ, Grogan TM, et al: Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: A Southwest Oncology Group study. J Clin Oncol 12:2405-2414, 1994 38. Peest D, Deicher H, Coldewey R, et al: A comparison of polychemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma: A prospective trial of the German Myeloma Treatment Group. Eur J Cancer 2:146-151, 1995 39. Ludwig H, Cohen AM, Polliack A, et al: Interferonalpha for induction and maintenance in multiple myeloma: Results of two multicenter randomized trials and summary of other studies. Ann Oncol 6:467-476, 1995 40. Salmon SE, Crowley JJ, Balcerzak SP, et al: Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: A Southwest Oncology Group Study. J Clin Oncol 16:890-896, 1998 41. Kyle RA: The role of bisphosphonates in multiple myeloma. Ann Intern Med 132:734-736, 2000 42. Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma: Myeloma Aredia Study Group. N Engl J Med 334:488-493, 1996 43. Berenson JR, Lichtenstein A, Porter L, et al: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events: Myeloma Aredia Study Group. J Clin Oncol 16:593-602, 1998