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AHCPR Health Technology Reviews. Rockville (MD): Agency for Health Care Policy and Research (US); 1992-1995. 

                        - This publication is provided for historical reference only and the information may be out of date.

**This publication is provided for historical reference only and the information may be out of date.**

## AHCPR Health Technology Reviews.

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#  12Hematopoietic Stem-Cell Transplantation in Multiple Myeloma

DO Handelsman, DO.

Published: August 1995.

## 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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AHCPR Pub. No. 95-0072

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