| Volume 360:2645-2654 |  | June 18, 2009 | | Number 25 |
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Autologous Hematopoietic Stem-Cell Transplantation for Multiple Myeloma
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This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations.
A previously healthy 59-year-old man presents with persistent pain in his lower back and fatigue. A complete blood count reveals a hemoglobin level of 9.8 g per deciliter. A monoclonal protein (M component) is detected on serum protein electrophoresis and is characterized as an IgG kappa by immunofixation. A radiologic skeletal bone survey shows diffuse lytic bone lesions of the vertebrae and the pelvis. The diagnosis of multiple myeloma is confirmed by bone marrow aspiration, which reveals an infiltrate of 32% plasma cells. The serum calcium and creatinine levels are normal, the albumin level is 3.7 g per deciliter, and the beta2-microglobulin level is 2.8 mg per liter. Fluorescence in situ hybridization of bone marrow plasma cells shows deletion of chromosome 13, with no adverse prognostic factors. Considering the patient's relatively young age and the absence of coexisting illnesses, a hematologist recommends induction therapy followed by high-dose therapy with autologous hematopoietic stem-cell transplantation as the initial treatment.
The Clinical Problem
Multiple myeloma is a malignant disorder in which plasma cells accumulate in the bone marrow and produce an entire immunoglobulin (usually IgG or IgA) or only immunoglobulin light chains (kappa or lambda).1 Multiple myeloma accounts for approximately 10% of hematologic cancers and 1% of all cancers. The annual incidence is 4 to 6 cases per 100,000 population. The American Cancer Society has estimated that more than 19,000 new cases were diagnosed in the United States in 2008. Multiple myeloma is primarily a disease of the elderly, with a median age range at diagnosis of 65 to 70 years. The disease does not occur in children.
Common complications of multiple myeloma include osteolytic bone lesions, anemia, renal insufficiency, and infections. Signs and symptoms vary greatly, and the presentation may range from incidental abnormalities that are detected on routine blood screening to severe clinical manifestations, including paraplegia related to spinal cord compression. Multiple myeloma is frequently a painful and disabling disease because of bone involvement, which is a common feature. The prognosis for patients with multiple myeloma remains poor. The disease is uniformly fatal, with a median survival of approximately 3 years with conventional chemotherapy, although the outlook has improved somewhat with the advent of newer therapies during the past 10 years.
Pathophysiology and Effect of Therapy
On the basis of clinical and genetic data, it has been shown that almost all cases of multiple myeloma arise from an asymptomatic premalignant disorder characterized by a proliferation in the bone marrow of monoclonal plasma cells derived from post–germinal-center B cells. This condition is called monoclonal gammopathy of unknown significance (MGUS), and the rate of conversion from MGUS to overt multiple myeloma is 1% per year. In the general model of myeloma pathogenesis, MGUS progresses to nonsymptomatic, or "smoldering," multiple myeloma, then to symptomatic intramedullary myeloma, and finally to extramedullary myeloma and plasma-cell leukemia.2 It should be noted that in many patients with multiple myeloma, the MGUS and "smoldering" stages are clinically unrecognized because of their asymptomatic nature.
Recent technological advances have shown that genetic abnormalities are present in all patients with multiple myeloma. The disease is actually characterized by constant genetic change, such as gains or losses of chromosomes in various combinations and specific translocations affecting primarily the immunoglobulin heavy chain (IgH) locus at 14q32.3 and juxtaposing strong immunoglobulin gene enhancers against different genes, which leads to dysregulation of their expression.3,4 Some of these chromosomal changes are important prognostic factors. Hyperdiploidy (an increased number of chromosomes) is associated with a better prognosis. A deletion of chromosome 17p13 (found in 10% of patients) and translocations involving chromosome 14q32.3 and either chromosome 4p16.3 (found in 15% of patients) or chromosome 16q23 (found in 5% of patients) are associated with a worse prognosis.5 A wide variety of additional genetic changes occur at later stages of the disease, such as mutations of oncogenes (including members of the RAS family), secondary translocations in the MYC gene, and inactivation of the tumor suppressor p53 gene (Figure 1A).5,6,7
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(MIP-1
B nuclear factor kappa B, RUNX2 runt-related transcription factor 2, SDF-1Multiple myeloma is relatively resistant to most conventional chemotherapeutic agents. Since the majority of plasma cells are not dividing, cell-cycle–dependent cytotoxic agents are of limited effectiveness. Alkylating agents (melphalan and cyclophosphamide) and corticosteroids are the most effective conventional agents for the treatment of this disease.
Drug resistance in myeloma is related to other contributing factors besides the paucity of actively dividing cells. Interleukin-6 is a potent survival factor in myeloma cells and induces resistance to drug-induced apoptosis. In addition, the interaction of myeloma cells with extracellular matrix proteins and bone marrow stromal cells, as well as osteoblasts, osteoclasts, and endothelial cells, plays a crucial role in the pathogenesis of myeloma and drug resistance. The bone marrow microenvironment not only physically interacts with myeloma cells but also secretes antiapoptotic factors8,9,10 (Figure 1B).
One way to overcome drug resistance in myeloma is to exploit the concept of dose intensity. Since the nonhematologic toxicity of melphalan is moderate, high doses of intravenous melphalan have been used to increase the rate of destruction of tumor cells. However, this treatment induces severe and prolonged myelosuppression.
The rates of death and complications that are associated with high-dose chemotherapy with melphalan are markedly reduced by the infusion of autologous hematopoietic stem cells that are collected before the administration of melphalan and are reinfused after such treatment.11,12 Homing of hematopoietic stem cells to the bone marrow microenvironment is poorly understood. However, there is evidence that the binding of the chemokine stromal-cell–derived factor 1 (SDF-1) to CXC chemokine receptor 4 (CXCR4), which is expressed on hematopoietic stem cells,13 has a role (Figure 2).14 Autologous stem-cell transplantation has no antitumor effect by itself and is just a form of supportive management after high-dose therapy. By restoring a functioning bone marrow soon after treatment, autologous stem-cell therapy makes it possible to administer a dose of melphalan that would otherwise be lethal.
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Although the efficacy of high-dose therapy is mostly related to damage to tumor-cell DNA, it has been shown recently that agents such as thalidomide, bortezomib, and lenalidomide act not only on myeloma cells but also on the microenvironment.8 These agents may thus offer another means of overcoming drug resistance.
Clinical Evidence
For more than three decades, a combination of oral melphalan and prednisone has been the standard treatment for multiple myeloma, and more complex combination chemotherapy regimens have not significantly improved survival.11,12 With this approach, complete remissions are rare (occurring in less than 5% of patients), and all patients ultimately have a relapse.
Almost 25 years ago, a key therapeutic advance was the introduction of high-dose melphalan therapy supported by autologous hematopoietic stem-cell transplantation.15,16 The Intergroupe Francophone du Myélome was the first to conduct a randomized trial showing the superiority of this approach, as compared with conventional chemotherapy, in terms of the response rate, event-free survival, and overall survival.17 These results were confirmed 7 years later by the British Medical Research Council.18 An important finding from these studies was a significant increase in the rate of complete remission (negative findings on immunofixation) or very good partial remission (reduction of the M component by more than 90%) with autologous stem-cell transplantation, results that were significantly correlated with prolonged progression-free survival and overall survival.
Five other published randomized studies have compared conventional chemotherapy with autologous stem-cell transplantation.19,20,21,22,23 Overall, transplantation improved the response rate (60 to 80% vs. 50 to 55%), the rate of complete or very good partial remission (40 to 45% vs. <20%)> 30 months vs. 15 to 20 months). However, overall survival was significantly improved in only three of all seven trials.17,18,20 This is partly explained by the positive effect of transplantation at relapse in patients who were initially treated with conventional chemotherapy. The use of autologous stem-cell transplantation either at the time of the initial diagnosis or at progression improved the median overall survival from approximately 36 months to 50 to 55 months.
During the past 10 years, thalidomide, bortezomib, and lenalidomide have been introduced to the regimen for treatment of multiple myeloma. These agents show promise for improving the rate of complete remission both before and after autologous stem-cell transplantation without increasing toxicity. However, it is not clear whether such therapies are superior if they are used as an alternative to transplantation or whether they may reduce the need for and use of transplantation in patients in whom treatment is indicated.
Clinical Use
Treatment of multiple myeloma is not indicated in all patients with the disease. Those with "smoldering" myeloma, who have no symptoms or specific laboratory abnormalities (Table 1),24 should be observed without therapy, since their condition may remain stable without progression to active disease for years25 and since there is no clear evidence that treating asymptomatic patients improves the prognosis.26
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Autologous hematopoietic stem-cell transplantation is recommended for patients with active myeloma who are relatively young and do not have serious coexisting illnesses. Patients who were enrolled in the above-mentioned randomized trials were all under 70 years of age, and there were conflicting results regarding the effect of high-dose therapy in patients over the age of 65 years.20,27 In Europe, transplantation is generally considered only in patients 65 years of age or younger, whereas in the United States, a formal age limit is not imposed. Trial participants were also free of significant renal dysfunction (usually with a creatinine level of <2.3> per liter]). Although transplantation is feasible in patients with renal failure, it is more toxic than in those with normal renal function, and its benefit has not been shown in randomized studies. Other coexisting illnesses that may be of concern include serious cardiac, hepatic, neurologic, or pulmonary disease. Good functional status is also regarded as necessary for transplantation (a performance status of less than grade 2, according to the Eastern Cooperative Oncology Group scale) (Table 2).
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The procedure of autologous stem-cell transplantation has been clearly defined during the past 20 years and should be fully explained to the patient initially. It includes induction treatment, stem-cell collection, and high-dose chemotherapy, followed by infusion of the transplanted cells. The entire duration of treatment is 4 to 6 months.
Induction treatment consists of 3 to 6 cycles of chemotherapy in order to reduce the tumor burden and plasma-cell infiltration in bone marrow. Since melphalan is toxic for hematopoietic stem cells, induction treatment is dexamethasone-based, and melphalan is not used so that efficient stem-cell collection is ensured. Dexamethasone alone or combined with vincristine and doxorubicin (VAD) has long been the standard induction regimen. However, this approach is being replaced by the use of dexamethasone in combination with thalidomide, bortezomib, or lenalidomide. Induction treatment is performed on an outpatient basis. Blood counts are monitored weekly or, in the case of intravenous agents, before treatment. Patients are seen in the hospital only for intravenous treatments, for monthly assessments, or in case of complications. The response to induction treatment is evaluated by measuring the M component in blood and urine.
The next step consists of collection of hematopoietic stem cells from the patient. Peripheral-blood progenitors have completely replaced bone marrow as the source of stem cells because of easier availability, faster hematopoietic recovery after transplantation, and possibly reduced contamination by tumor cells.28 Peripheral-blood progenitors are collected during apheresis procedures after stem-cell mobilization with the use of granulocyte colony-stimulating factor (G-CSF), either alone or with cyclophosphamide. The particular goal of stem-cell mobilization is to increase the number of cells collected that are positive for the cell-surface protein marker CD34, because there is a significant correlation between the number of CD34+ cells infused and the speed of engraftment, especially in platelet recovery. The minimal dose of CD34+ cells necessary for safe engraftment is 2x106 per kilogram of body weight. Mobilization is more efficient with the use of cyclophosphamide combined with G-CSF than with G-CSF alone, but the combination carries the risk of transient myelotoxicity. Administration of G-CSF may cause bone pain, which responds to narcotic analgesics. After collection, stem cells are usually cryopreserved in dimethyl sulfoxide until transplantation.
The standard preparative regimen before autologous stem-cell transplantation is high-dose melphalan (200 mg per square meter of body-surface area). This agent is administered either as a single intravenous infusion lasting 30 to 60 minutes or as two infusions of 100 mg per square meter during a 2-day period, with forced diuresis. Melphalan alone is currently preferred to the combination of melphalan (at a dose of 140 mg per square meter) plus total-body irradiation because of easier administration and a better ratio of efficacy to toxicity.29
The hematopoietic stem cells are infused 48 hours after melphalan administration through a central venous catheter at a rate ranging from 5 to 20 ml per minute. The patient may be premedicated with an antihistamine, an antiemetic agent, an antipyretic agent, and corticosteroids to mitigate infusion reactions.30 The infusion is usually performed in a reverse-isolation room. The use of a room with a laminar airflow system is unnecessary, since the duration of severe neutropenia is usually less than 10 days with infusion of peripheral-blood stem cells and the administration of G-CSF after transplantation.
During the hospital stay, temperature and vital signs are checked several times a day, physical examination is performed at least daily, blood counts and routine biochemical measurements of renal function are performed at least every other day, and hepatic function is checked weekly, except in the event of clinical symptoms. Patients are discharged after resolution of any adverse effects and when the polymorphonuclear leukocyte count is greater than 5x108 per liter. The typical duration of hospitalization is 2 to 3 weeks.
After discharge, blood counts are initially checked three times a week, especially in the case of delayed platelet recovery, which may require additional platelet transfusions. Patients are seen in the hospital for the evaluation of disease status 1 month after transplantation and every 3 to 4 months thereafter. Monitoring includes measurement of the M component in blood and urine; for patients with no detectable monoclonal protein, monitoring includes immunofixation, serum free light-chain assay, and a bone marrow examination.
The cost of autologous stem-cell transplantation, including stem-cell collection and cryopreservation, varies greatly according to the country and the duration of hospitalization but is not less than $10,000 to $15,000 and can be substantially higher. In an analysis of the U.S. Nationwide Inpatient Sample, the mean total hospital cost for the procedure was approximately $43,000 and was markedly influenced by whether complications such as bacteremia occurred during the course of treatment.31
Adverse Effects
The toxicity of induction treatment includes side effects of high-dose dexamethasone therapy (e.g., infection, diabetes, and psychiatric disturbances). The adverse effects of the VAD regimen are those related to the use of a central venous line (infection and thrombosis) as well as adverse effects of vincristine (neurotoxicity) and doxorubicin (neutropenia and infection). The use of thalidomide or lenalidomide plus dexamethasone increases the risk of deep-vein thrombosis and may justify prophylactic treatment.32,33 The major adverse event that is associated with the use of bortezomib plus dexamethasone is peripheral neuropathy.34
Severe and prolonged myelosuppression is the major side effect of high-dose melphalan, which is the reason that autologous stem-cell transplantation is performed to reduce the duration of cytopenia. With the use of peripheral-blood stem cells as the autograft, the median duration of severe neutropenia and thrombocytopenia is 7 days.28 During neutropenia, fever is common (occurring in 40% of patients), although bacteremia occurs less often (in 17%), according to one analysis.31 Gastrointestinal toxic effects occur frequently, with grade 3 or 4 mucositis in 30% of patients.29 Transient alopecia and gonadal toxic effects are common. Unpredictable toxic effects on the lungs or heart (atrial fibrillation) and veno-occlusive hepatic disease have been reported infrequently. The rate of death associated with transplantation is less than 2% at most centers.11 When used as part of initial therapy, high-dose melphalan does not seem to increase the incidence of secondary neoplasms, and the 10-year probability of myelodysplasia or secondary acute myelogenous leukemia is less than 5%.35
The infusion of autologous stem cells itself is associated with a variety of adverse effects, including nausea and vomiting, headache, and chills and fever.30 These effects are caused by the release of cytokines from lysed cellular elements in the stem-cell infusate and by the effects of dimethyl sulfoxide used as the cryopreservative. In most patients, such effects are mild and transient, although anaphylaxis and cardiac arrest have been reported infrequently.
Areas of Uncertainty
Despite a better outcome with high-dose therapy than with conventional-dose treatment, almost all patients ultimately have a relapse. Double, or tandem, autologous stem-cell transplantation has been proposed with the objective of further increasing the rate of complete remission. This procedure involves the administration of a second cycle of high-dose melphalan and a second stem-cell infusion within a few months after the first procedure.36 Three randomized studies have shown that this approach may increase progression-free survival.37,38,39 However, only patients who were not in remission after receiving the first transplant appeared to benefit from the second transplantation.37,38 Moreover, although some patients had long-term remission, those with high-risk initial characteristics, such as a high β2-microglobulin level or unfavorable cytogenetic results, still had a poor outcome, despite undergoing two autologous stem-cell transplantations.40
As previously noted, the introduction of thalidomide, bortezomib, and lenalidomide to myeloma regimens shows promise in improving the results of autologous stem-cell transplantation. With the use of such agents in induction treatment, very high rates of complete remission or very good partial remission (up to 70%) are now achieved.34,41 Another possible improvement is to use novel agents as maintenance therapy after transplantation. Two randomized studies have shown that maintenance with thalidomide significantly improved rates of remission, progression-free survival, and overall survival.42,43 The addition of novel agents both before and after transplantation44,45 yielded impressive rates of complete remission and appeared to improve the outcome, particularly among patients with poor prognostic features. However, the optimal approach to the use of such modifications of standard therapy has not been established.
Whether the use of novel agents might mitigate the need for autologous stem-cell transplantation is another area of active interest. European groups have prospectively compared the classic regimen of melphalan plus prednisone with the same combination plus thalidomide, bortezomib, or lenalidomide in elderly patients.27,46,47,48 The investigators have shown that these combinations are associated with rates of remission and median progression-free survival that are similar to those achieved in younger patients with transplantation. U.S. groups have evaluated lenalidomide plus dexamethasone as initial treatment with or without transplantation.33,49,50,51 Prolonged treatment with lenalidomide plus dexamethasone or the addition of bortezomib to this combination has resulted in remission rates of up to 70%.49,51 Therefore, randomized trials comparing novel agents with or without transplantation as initial therapy are warranted.
Guidelines
Current guidelines from Europe52,53 and the United States54 state that high-dose therapy and autologous hematopoietic stem-cell transplantation should be part of the initial therapy in patients with newly diagnosed multiple myeloma who are 65 years of age or younger and who have adequate performance status. Conditioning with melphalan at a dose of 200 mg per square meter is recommended.29 There is no consensus regarding double transplantation. The addition of novel agents before or after transplantation improves the results, but the optimal use of these agents has not yet been defined.55 Moreover, such drugs have not yet been approved for this indication by regulatory authorities in any country.
Recommendations
For the patient described in the vignette, autologous stem-cell transplantation would be appropriate, given his active disease and relatively young age, as well as the absence of coexisting illnesses. Some experts (especially in the United States) might propose initial therapy with a combination of dexamethasone and lenalidomide or a triple-agent combination with bortezomib, without early transplantation. This recommendation is reasonable, given the excellent short-term results, easy administration, and good tolerability of these newer regimens. However, we would still recommend transplantation for three reasons. First, lenalidomide is not yet available for patients with newly diagnosed disease in many countries. Second, given the lack of long-term data, the durability of the response and the efficacy of salvage treatment after the use of novel agents remain unknown, whereas data regarding autologous stem-cell transplantation are more mature. Third, this patient has no adverse prognostic factors, and his life expectancy with transplantation is more than 80% at 5 years,56 with a 30% chance of long-term remission.57
Dr. Harousseau reports receiving consulting and lecture fees from Celgene, Janssen Cilag, and Pharmion and consulting fees from Millennium; and Dr. Moreau, consulting fees from Janssen Cilag and Celgene and lecture fees from Pharmion and Schering-Plough. No other potential conflict of interest relevant to this article was reported.
Source Information
From the René Gauducheau Cancer Center, Nantes–Saint Herblain (J.-L.H.), and University Hospital Hôtel Dieu, Nantes (P.M.) — both in France.
Address reprint requests to Dr. Harousseau at the René Gauducheau Cancer Center, Blvd. J. Monod, 44805 Nantes–Saint Herblain, France, or at jl-harousseau@nantes.fnclcc.fr.
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