Report

Multiple myeloma (MM) is a malignancy of unknown etiology in which a monoclonal proliferation of B-lymphocyte-derived plasma cells, producing immunoglobulins (M-Proteins), replace the normal bone marrow and are associated with a variety of abnormal hormonal, immunologic, and physiochemical effects (e.g., lytic bone lesions, hypercalcemia, immunodeficiency, and renal failure).(1-4).

Mutiple myeloma has an approximate annual incidence of 4/100,000, representing 1 percent of all malignancies and causing approximately 10,000 deaths/year in the United States, with blacks affected twice as frequently as whites.(5-8). The peak incidence occurs in the 7th decade at a median age of 69 years. (6). Although MM remains a uniformly fatal malignancy, it has a highly variable clinical course and a 5-year survival rate of approximately 28 percent. Survival durations range from a few months to several years, albeit the latter is true in less than 5 percent of patients. (3,6,9-11).

Patient outcome in MM generally depends on stage of disease, histologic subtype, and a number of heterogeneous prognostic factors that account for its variable clinical course.(9,12). Histologic evaluation, the current varied staging systems, biologic assays, and methods for measuring bone disease have all failed consistently to identify subsets of patients who might benefit from various aggressive therapies and achieve possible long-term survival.(3,12,13). The clinical staging system of Durie and Salmon (Which clinically correlates presenting features of MM patients with measured myeloma cell mass) is the most widely used staging system applied to evaluate survival.(1). This system divides MM into three tumor burden groups: Stages I (low), II (intermediate), and III (high). Subclassifications A and B refer to relatively normal or abnormal renal function (defined as serum creatinine less than 2 mg/dL, and equal to or over 2 mg/dL respectively) as an additional prognostic factor. (14). In contrast to malignancies such as Hodgkin's disease where sophisticated staging is used as a basis for treatment, the prognostic value of staging in MM continues to be questioned.(9,15,16).

Among the prognostic factors sought to help identify patients for whom more aggressive therapy might be indicated are the plasma-cell labeling index (percent of cells in S-phase) and beta 2-microglobulin (beta(2)-M) levels.(3,16,17). beta(2)-M has been found to be highly predictive for survival during the first 2 years of treatment followup. However, it is unreliable as a guide for long-term survival.(18-20).

Response rates in MM have been variably defined by percent reductions in serum myeloma protein and marrow plasma cells. A partial response (PR) is commonly defined as a 75 percent or greater reduction of serum myeloma protein synthesis with disappearance of Bence Jones proteinuria and reduction of bone marrow plasmacytosis to less than 5 percent for a minimum of 2 months. (21). A complete response (CR) had been defined as the disappearance of serum monoclonal protein on immunofixation and less than 1 percent monoclonal plasma cells in the marrow for at least 2 months; but more recently, a "true CR" has been defined as absent monoclonal gammopathy (in both urine and serum) on immunofixation analysis, normalization of bone marrow, and absent monoclonal plasma cells on DNA/cytoplasmic immunoglobulin flow cytometry.(22-27).

Before the advent of chemotherapy for MM, the median survival was approximately 6 months.(28). Since 1968, the use of melphalan plus prednisone as standard treatment has resulted in a response rate of approximately 40-50 percent and a median survival for responders of approximately 24-36 months.(4,9,22,29). However, these results do not reflect the highly variable clinical course of MM and represent groups of patients with an admixture of prognostic factors subsequently found to influence survival significantly.(3,9,16,30).

The fact that both nonresponders and patients who initially respond to melphalan plus prednisone eventually succumb to this disease has been primarily attributed to the development of drug resistance which commonly manifests within 2-3 years.(1,6). This fact, in addition to examples of improved survival suggested in clinical trials with multidrug combinations or high-dose chemotherapy (HDCT) regimens in malignancies such as lymphomas and leukemias, has prompted such trials in MM.(31-35). These trials, including other conventional dosage chemotherapy combinations or HDCT with or without total-body irradiation (TBI) and stem-cell support, have resulted in higher response rates, albeit with no appreciable change in prognosis and minimal extension of median survival beyond 36 months.(8,22,36,37).

The initial attempt in overcoming primary resistance in MM using HDCT (without stem-cell support) was reported by McElwain and Powles in 1983.(38). That preliminary report demonstrated a CR in three of five patients and led to subsequent studies of further dose-intensification regimens including combinations with TBI, and hematopoietic support with autologous or allogeneic stem cells, and cytokines.(39). The rationale for HDCT with stem-cell support is predicated on the premise that intensive therapy would yield both improved responses and increased survival times resulting in an improved quality of life and possibly prolonged survival or cure, and that stem-cell support would circumvent the hematologic toxicity associated with HDCT.(38,40,41). Limitations of these treatment regimens include the profound myelo-and gastrointestinal toxicity associated with high-dose therapies, the difficulty in totally eliminating myeloma cells with the current preparatory regimens, and the limited feasibility of such regimens in the elderly population of myeloma patients.(1). Measurements of the effectiveness of HDCT regimens with stem-cell support ideally include time to hematologic reconstitution, incidence of nonhematologic toxicity, overall response rates, duration of response, and survival time. Current reported CR rates (defined as the absence of M-proteins and the restoration of normal marrow) with such high-dose regimens are in the range of 30-50 percent.(1,7,42,43). Published reports including a metaanalysis of 18 trials, suggest that chemotherapy combinations are superior to standard treatment only for the category of poor prognosis myeloma patients. However, this issue remains unresolved.(5,44-46). Multiple myeloma continues to be an example of a malignancy in which substantial responses are achieved with single agent chemotherapy, but intensive treatment with combination chemotherapy fails to result in improved survival.(47).

A compilation of results of current treatments of MM can be seen in Table 1.

Table

Table 1. Commonly reported results of the current treatment of MM.

The efficacy of current therapies in prolonging survival in myeloma patients continues to be problematic, because the majority of trials involved limited numbers of patients, had varied prognostic factors and nonuniform treatment regimens, and failed to use intention-to-treat analyses in evaluating results.

To date, no published series has demonstrated evidence of a plateau in the survivals curve, and the similar median survivals seen after any form of current treatment makes the identification of optimal therapy difficult.(54,55).

Compared with many younger leukemia and lymphoma patients, the advanced age and poor performance status of many MM patients has, until recently, precluded consideration of HDCT regimens.(56). However, the advent of the use of stem cells and cytokines to mitigate the morbidity and mortality associated with HDCT has led to the increased use of such treatment, albeit in the absence of data from randomized clinical trials (RCT) comparing HDCT with standard regimens.(29,39,40,56). HDCT is frequently being applied in patients with refractory or relapsing disease or with high-risk features related to high tumor mass. High response rates and relatively long-term survival using HDCT has been reported in a trial using allogeneic bone marrow transplantation (BMT), which resulted in a 58 percent CR for patients achieving engraftment (20 percent died before engraftment) and an actuarial survival of 40 percent at 76 months.(51). However, approximately 40 percent of patients died from treatment-related complications, primarily graft-vs.-host disease and interstitial pneumonia, which is commonly seen in the first months posttransplant.(39). This was a nonrandomized trial involving 90 patients in 26 separate centers. Patient selection criteria were not described, and pretransplant variables included different stages of disease, number of courses of treatment, and varied responses to pretransplant treatment. This heterogeneity of patients made it impossible to draw conclusions on the relative efficacy of allogeneic vs. autologous transplants, but patients who did not respond to conventional therapy appeared to have an improved actuarial survival. Unrelated donor transplants continue to be an option for allogeneic transplant patients without a suitably matched sibling.

Potential advantages of using allogeneic stem cells include absence of tumor cells in the graft, and possible graft-vs. -tumor effect.(8,57). A recent update of this data, from the multi-institutional study of the European Group for Bone Marrow Transplantation, and results from studies in 35 patients at a single center (again, with a heterogeneous patient population), indicated projected overall survival at 7 years of 28 and 30 percent, respectively.(52,58). These results have appeared only in abstracts making it impossible to evaluate the quality of the evidence properly. Because of the limited availability of suitable sibling donors, BMT can only be offered to approximately 10 percent of stem-cell transplantation candidates. (22). The reported CR and survival duration for BMT are better than almost all reports of autologous stem-cell transplants, but the much higher mortality and morbidity related to the use of allogeneic cells remains a significant handicap and has led to the increased use of ABMT, which is associated with a mortality of approximately 5-10 percent.(29,59-61).

Since 1989, interest has been generated in the use of peripheral blood stem cells (PSC) for hematopoietic reconstitution after HDCT in MM.(62). This interest derives from the fact that bone marrow in MM always contains myeloma cells. Despite these cells often being detected in the peripheral blood, the volume of contamination in the peripheral blood is likely lower than that in marrow, which theoretically lowers the risk of tumor cell reinfusion.(63,64). In addition, the clonogenic potential of such circulating cells remains unclear.(65). However, this issue, as well as the issue of the need for purging stem-cell harvests, has not been subjected to RCTs.(56,62,66).

The only RCTs of HDCT with autologous stem-cell support vs. conventional dosage chemotherapy regimens were performed in France. Results of these trials and reported in abstract form at a 1994 international conference on MM in Mulhouse, France,(48,49). are preliminary and have relatively short median followup times of 26 and 28 months. The trial involving PSC rescue (167 previously untreated patients, median age 46, 88 percent stage III) failed to demonstrate a statistically significant difference in 2-year survival (82 percent PSC vs. 67 percent chemotherapy).(49). The trial using ABMT (200 previously untreated patients, median age 57, 75 percent stage III) demonstrated a statistically significant higher response rate in the HDCT arm (87 vs. 73 percent) and a higher 3-year postdiagnosis probability of survival (64 vs. 15 percent).(48). This 15 percent survival is significantly lower than that commonly reported after conventional chemotherapy.

Current HDCT regimens with autologous stem-cell support achieve CR in approximately 20-30 percent of patients, with the best results seen in good-risk patients, who are defined as young patients (less than age 50) with good performance status, a low tumor burden (beta(2)-M 2.5 mg/L or less) and responsive to chemotherapy. (40). Treatment-related mortality in such patients at experienced centers is less than 5 percent and the reported 4-year progression-free and overall survival ranges from 50-70 percent.(29,40,59).

Some reports of achieving CR in the range of 70-75 percent have not been verified with immunofixation techniques to identify M proteins.(24,36,67).

A recent abstract on allogeneic and HLA-identical twin transplants for MM in 257 patients indicated that 72 allograft recipients survived a median of 30 months (range 3 months to 10 years).(53). For the 72 survivors, the probabilities of survival (95 percent confidence intervals) were 53 +/-7 percent at 6 months, 37 +/-7 percent at 2 years, 27 +/-7 percent at 4 years, and 24 +/-7 percent at 5 years.

Data obtained from the Statistical Center of the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicated that the 2-year probability of survival (95 percent confidence interval) for 509 recipients of autotransplants posted in these registries between 1989 and 1994 was 47 +/-8 percent.(50). Data on the source of the stem cells were available for only 96 patients. Of these, 57 received bone marrow alone, 34 received PSC alone, and 5 received both PSC and marrow.

The feasibility of HDCT with stem-cell support has been documented in hundreds of MM patients in all stages of disease (including resistant or relapsed myeloma), and proponents suggest that it is currently the only regimen that offers the potential for cure or long-term survival in selected patients.(22,24,29,39,68,69).

Although high-risk MM has been considered an indication for HDCT regimens, comparative trials with standard chemotherapy will be required to determine whether its use in early and more responsive disease will yield significant prolongation of disease-free and overall survival.(6,46,56,62). In addition, determination of the relative advantages and disadvantages of the type of stem cell used for treatment on eventual outcome will require further study.

Attempts to extend remission and survival times by therapies achieving further tumor mass reductions now include tandem (double) transplants within 6 months of each other and repetitive autologous transplants until the patient dies, withdraws from the study, or achieves a prolonged remission.(25,60,70).

Questions concerning the need and efficacy of purging techniques remain unanswered and are not likely to be resolved without large RCTs.(29,54). Purging can indeed remove malignant plasma cells, but it remains unclear whether myeloma stem cells are also selectively removed.(10,67). Available data from ABMT trials without purging indicate no influence on survival related to the number of myeloma cells contained in the autograft.(6,59).

The costs of hematopoietic stem-cell transplantation vary significantly depending on both the source of the stem cells and variations in the cell yield among individual patients. There are very few published data on the relative costs of ABMT vs. the use of autologous PSC. However, a few reports suggested that the use of PSC was associated with more rapid hematopoietic reconstitution, reduced hospital stay and need for transfusion support, and total costs 25-50 percent less than those of ABMT (average reported cost of ABMT was approximately $100,000). (14,71,72).

Despite newer treatment strategies that yield improved response rates in MM, curative therapy is not available, and survival benefits are minimal.(5,54). A number of single and multi-institutional trials to determine the relative effectiveness of HDCT and stem-cell support with conventional treatment are planned or ongoing, and a 4-to 5-year followup is required to evaluate these current trials.(4). The available data continue to be insufficient to make specific recommendations as to which patients are optimally treated with hematopoietic stem-cell transplantation regimens.(29,51).

Until such time as the use of prognostic factors and the results of trials of current therapies are unequivocally clear, the use of stem-cell transplantation will, at best, be regarded as a halfway technology that requires further clinical study to determine its role in the treatment of MM.

Whether specific treatments can overcome the unfavorable influence of specific prognostic factors such as high tumor mass, or whether high-risk patients are the best candidates for HDCT, remains unproven.(3). The available data from some clinical trials suggest that HDCT regimens are associated with both improved responses and survival; however, the limited data from RCTs are conflicting. In addition, patients selected for intensive treatment regimens because of high-risk factors may also be at increased risk for treatment-related morbidity and mortality.(12). Rather than applying high doses or combinations of active agents in a myriad of possible sequences, solutions to the problem of achieving maximal disease control or cure may derive from a better understanding of the origin and proliferation of the malignant plasma cell.(29,73).

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