ADVANCES IN MULTIPLE MYELOMA:

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1 MYELOMA AND THE NEWLY DIAGNOSED PATIENT: A FOCUS ON TREATMENT AND MANAGEMENT S. Vincent Rajkumar, MD LEARNING OBJECTIVES Upon completion of this educational activity, participants should be able to: Discuss an evidence-based approach to the management of newly diagnosed myeloma and diagnostically differentiate smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance, and solitary plasmacytoma from multiple myeloma (MM) Describe the optimum pretransplant induction regimen for MM Discuss outcomes for early vs delayed transplantation and 1 vs 2 transplants Discuss the role of maintenance therapy in MM and supportive care strategies for patients with MM bone disease, such as the use of bisphosphonates Describe the role of thalidomide in SMM ABSTRACT Introduction Multiple myeloma accounts for 1% of all malignancies and 10% of malignant hematologic neoplasms. 1,2 In 2001, approximately 14,400 new cases of myeloma will be diagnosed in the United States and more than 11,200 patients will die of the disease. 2 At present, there is no treatment to the cure of myeloma, and median survival with standard therapy is approximately 4 years. An evidence-based approach to the management of newly diagnosed myeloma, which was developed at the Mayo Clinic, is summarized below. MGUS Patients with a serum M-protein less than 3g/dL, bone marrow plasma cells less than 10%, and no evidence of anemia, hypercalcemia, renal failure, or bone lesions are considered to have monoclonal gammopathy of undetermined significance (MGUS). These patients need indefinite follow-up, as 20% to 25% will eventually progress to overt myeloma, amyloidosis, or a non-hodgkin lymphoma at a rate of 1% per year. 3,4 The serum M-protein in MGUS is rechecked at 6 months. If it remains stable, it is checked yearly thereafter.

2 SMM Patients who have a serum M-protein of 3g/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 multiple myeloma (SMM). 4,5 These patients have a higher risk of transformation to myeloma than do those with MGUS. Many patients meet criteria for Durie-Salmon Stage 1 myeloma. SMM patients can be observed without therapy for months to years, and close follow-up is recommended. Solitary Plasmacytoma 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 in the affected area, followed by close observation. These patients also are at risk for overt multiple myeloma, particularly if they have a residual MGUS after radiation therapy. Figure 1 provides a schematic approach to the management of patients with newly diagnosed myeloma. The first step in managing myeloma is to determine if the patient needs therapeutic intervention. Patients with SMM are usually closely observed without therapy. These patients also are candidates for clinical trials that use novel agents to delay progression to active myeloma. Once therapy is indicated, the physician must determine if the patient is a candidate for autologous stem cell transplantation. Patients who are not candidates for autologous stem cell transplantation should receive standard dose therapy with melphalan and prednisone. The overall response rate with this regimen is about is 50%. 6 The complete response rate is less than 10%, and the median survival is about 3 years. 7 The 5-year survival rate in patients treated with this therapy is 24%. 6 More aggressive combination chemotherapy regimens such as vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) result in superior response rates (60% to 70%), but offer no substantial survival benefit. 6,8,9 High-dose therapy followed by autologous stem cell transplantation improves response rate and survival in myeloma, but it is not a cure Response rates exceed 75% to 90%, 7,8 and complete response rates range from 20% to 40%. 11,13 A French randomized trial in previously untreated myeloma patients showed improved survival with autologous marrow transplantation compared with conventional chemotherapy with 5-year survival rates of 52% and 12%, respectively. 13 Based on these results, stem cell transplantation is now standard therapy for patients younger than 65 years with good performance status. Optimum Pretransplant Induction Regimen Although the combination of vincristine, Adriamycin, and dexamethasone (VAD) is considered the standard pretransplant induction therapy, it is cumbersome to administer and is associated with substantial toxicity. Lack of response to initial VAD (primary refractory disease) does not predict poor survival following transplantation, and patients are treated

3 with transplantation regardless of response status to VAD. 14 Dexamethasone accounts for a significant proportion of the activity of VAD; although the response rate may be lower, there is no effect on overall survival. 15 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, the combination of thalidomide and dexamethasone resulted in a 64% response rate. 16 In this study, thalidomide was given orally at a fixed dose of 200 mg/d. Dexamethasone was given orally at a dose of 40 mg/d orally 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 upcoming Eastern Cooperative Oncology Group randomized trial will compare dexamethasone and thalidomide plus dexamethasone as induction therapy for myeloma. Early vs Delayed Transplantation Stem cell transplantation for myeloma is often performed early in the course of the disease, fo l l owing 3 to 4 cycles of induction ch e m oth e ra p y. Howeve r, it is possible to delay t ra n s p l a n ta t i o n until relapse without compromising survival, provided 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 2 strategies. 17,18 The choice between the 2 options is based on patient preference and other clinical conditions. One vs Two Transplants Currently, the role of tandem transplantation is not fully understood. Preliminary data from 4 randomized trials were presented at the recent International Myeloma Workshop in Banff, Alberta, Canada (May 2001). The trials indicate some improvement in response rates and possibly event-free survival with tandem transplantation. However, none of the trials showed an improvement in overall survival using an intentto-treat analysis. Final results of the trials will provide an answer to this important question. Since the role of twin/tandem transplantation is not settled, it is wise to harvest enough stem cells for 2 transplants. At the Mayo Clinic, a single transplant is completed and the second transplant is reserved for relapse. Role of Allogenic Transplantation Allogenic transplantation may lead to prolonged disease-free survival in a relatively small percentage of patients. 19,20 High treatment-related mortality and toxicity has limited the role of the procedure as initial treatment. There is recent interest in studying non-myeloablative (mini) allogenic transplantation for selected patients with myeloma, either immediately following autologous stem cell transplantation 21 or at relapse. Currently, the role of allogenic stem cell transplantation as initial therapy in myeloma must be considered investigational.

4 Maintenance Therapy The role of maintenance therapy in myeloma remains investigational. Several studies show that interferon-alpha as maintenance therapy prolongs plateau phase in myeloma However, other studies fail to show such an effect, and overall survival was not prolonged in any study A meta-analysis studying the role of interferon-alpha is ongoing. A nationwide, large randomized trial in the United States that evaluated the role of interferon-alpha as maintenance therapy in myeloma is awaiting analysis. At low doses, prednisone also has been studied as maintenance therapy. 29 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 Bisphosphonates such as pamidronate are routinely used in myeloma for patients with multiple lytic bone lesions. The goal of therapy is to prevent or delay progression of lytic bone lesions. 30 Pamidronate is shown to reduce skeletal complications and improve the quality of life of patients with myeloma. 31,32 Other supportive care strategies such as pain control measures and erythropoietin therapy should be considered. Role of Thalidomide in Smoldering Multiple Myeloma Thalidomide is being studied as a single agent for patients with SMM. Initial reports show a response rate of approximately 35%. 33,34 Because the main goal of therapy in patients with SMM is to delay the need for chemotherapy, more data on the durability of re s p o n s e a re needed befo re recommending this st ra tegy for sta n d a rd clinical practice.

5 Future Directions The primary goal in myeloma is cure. Future studies will help define the role of novel agents, improve transplant conditioning regimens, and develop effective maintenance therapy. Figure 1. Mayo Clinic approach to newly diagnosed multiple myeloma.

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