ORIGINAL RELAPSED MULTIPLE ARTICLE MYELOMA Clinical Course of Patients With Relapsed Multiple Myeloma SHAJI K. KUMAR, MD; TERRY M. THERNEAU, PHD; MORIE A. GERTZ, MD; MARTHA Q. LACY, MD; ANGELA DISPENZIERI, MD; S. VINCENT RAJKUMAR, MD; RAFAEL FONSECA, MD; THOMAS E. WITZIG, MD; JOHN A. LUST, MD, PHD; DIRK R. LARSON, MS; ROBERT A. KYLE, MD; AND PHILIP R. GREIPP, MD OBJECTIVE: To study the clinical course of patients with multiple myeloma (MM) that relapses after initial therapy. PATIENTS AND METHODS: Patients with MM, seen at the Mayo Clinic in Rochester, Minn, between January 1, 1985, and December 31, 1998, were identified from a prospectively maintained database. Our study population consisted of 578 patients with newly diagnosed MM who were followed up and monitored throughout their clinical course at our institution. RESULTS: The median age of the 578 patients with MM was 65 years (range, 26-92 years); 228 patients (39%) were women. The median follow-up of 71 surviving patients was 55 months (range, 0-202 months). The overall survival (OS) for the 578 patients at 1, 2, and 5 years was 72%, 55%, and 22%, respectively; the median OS from initial therapy was 28.4 months. The median OS of 355 patients who experienced relapse after initial treatment was 17.1 months from initiation of the second therapy, and 84% died within 5 years. The duration of response decreased consistently with each successive regimen. Patients with a high plasma cell labeling index ( 1.0%), low platelet count (<150 10 9 /L), high creatinine level ( 2.0 mg/dl), and low albumin level (<3.0 g/dl) had a poorer prognosis. CONCLUSIONS: Our study revealed decreasing response duration with increasing number of salvage regimens, probably reflecting acquired drug resistance and an increasing proliferative rate of the myeloma cells. Patients who experienced relapse after initial treatment and received salvage therapy had a median survival of nearly 1.5 years. This must be remembered when making treatment decisions for these patients and must be factored in when assessing the efficacy of new therapies. Mayo Clin Proc. 2004;79(7):867-874 CI = confidence interval; MM = multiple myeloma; OS = overall survival; PCLI = plasma cell labeling index; RR = relative risk Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of immunoglobulin-secreting plasma cells. Clinically, MM presents with anemia, renal insufficiency, hypercalcemia, and/or lytic bone lesions. Multiple myeloma accounts for 1% of all malignancies and 10% of hematologic malignancies. 1 The disease predominantly affects older individuals; the median age at diagnosis is 65 years. Multiple myeloma results in considerable morbidity and mortality among affected patients. Based on projections, 15,270 patients will be diagnosed as having MM and 11,070 will die of MM in 2004. 2 Since the introduction of melphalan and prednisone for treatment of myeloma 4 decades ago, multiple other chemotherapy combinations have been tried for the treatment of MM with better response rates but with no improvement in survival. 3 In a review of 1027 patients with newly diagnosed MM seen at the Mayo Clinic in Rochester, Minn, between January 1, 1985, and December 31, 1998, no improvement in overall survival (OS) was observed. 4 However, the OS was higher compared with a group of patients seen during a preceding period. 5 The median survival from diagnosis for the 1027 patients was 33 months. Several randomized trials of high-dose therapy with autologous stem cell transplantation vs standard combination chemotherapy have shown improved OS with transplantation, especially in those younger than 65 years. 6,7 Median survival of 4 to 5 years has been observed in the transplantation trials. Recent trials have suggested a role for additional high-dose regimens or tandem transplantation, which may further improve survival. 8,9 Unfortunately, most patients experience relapse after responding to initial therapies, including high-dose therapy and stem cell transplantation. Long-term remissions are rare. 10 Various salvage therapies have been tried for these patients including combination chemotherapy and allogeneic stem cell transplantation. Several agents are active in MM including alkylating agents and corticosteroids, and it is not unusual for many patients with relapsed disease to receive several treatment regimens of 1 or more of these agents. 11 Unfortunately, the responses obtained from most of these approaches are not durable. The clinical course of patients whose disease relapses after initial therapy has not been studied systematically with respect to the response and survival from each subsequent therapy. The primary reason for this lack of complete data from diagnosis to death is because patients often are treated at various institutions during the course of disease. From the Division of Hematology and Internal Medicine (S.K.K., M.A.G., M.Q.L., A.D., S.V.R., T.E.W., J.A.L., R.A.K., P.R.G.) and Division of Biostatistics (T.M.T., D.R.L.), Mayo Clinic College of Medicine, Rochester, Minn; and Division of Hematology/Oncology, Mayo Clinic College of Medicine, Scottsdale, Ariz (R.F.). Supported in part by Hematological Malignancies Fund, Mayo Foundation, National Cancer Institute (CA62242), and a research grant from Millennium Pharmaceuticals, Cambridge, Mass. Dr Greipp received honoraria for his participation on Millennium Pharmaceuticals advisory board. Individual reprints of this article are not available. Address correspondence to Philip R. Greipp, MD, Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: greipp.philip@mayo.edu). 2004 Mayo Foundation for Medical Education and Research Mayo Clin Proc. July 2004;79(7):867-874 www.mayo.edu/proceedings 867
Once the patient has relapse, even if he or she is participating in a clinical trial, usually only survival data are collected. Understanding the clinical course of relapsed myeloma is important because it forms another benchmark for comparing results from the various clinical trials evaluating new active agents for relapsed disease. This is especially important in the context of MM, for which several new active agents have been introduced in the past 5 years. Our study describes the clinical course of patients with relapsed MM who were followed up and monitored at our institution. PATIENTS AND METHODS STUDY POPULATION Our study population consisted of 578 patients who satisfied the inclusion criteria and were selected from among 1027 patients with newly diagnosed MM; these patients were seen at the Mayo Clinic between January 1, 1985, and December 31, 1998. Patient information pertaining to the time of diagnosis and detailed clinical and laboratory follow-up information were available from a prospectively maintained institutional database approved by the Mayo Foundation Institutional Review Board. The database was searched to identify patients who were seen at least 6 times per year, on average, over the course of their treatment and follow-up. These criteria were used to ensure availability of complete follow-up and treatment details. Also, the search criteria allowed the study of a homogeneous group of patients who were followed up and monitored throughout their entire disease course at our institution. Laboratory values were derived from tests performed within 1 month after the diagnosis of MM. Laboratory and other test results as well as radiographs obtained more than 30 days before or after the patients were diagnosed as having MM were recorded as missing and were not reported. Of the remaining 449 patients excluded from the study, 30 received no treatment, and 419 were seen too infrequently to allow accurate assessment of their disease progression and types of treatment. For each patient, we have a complete treatment history until death or last follow-up. The start date of each subsequent treatment regimen was considered the date of progression from the prior therapy. If patients had relapse and a regimen was initiated to which they responded to earlier, the treatment was considered new. Clinical and laboratory results that were obtained within 30 days before initiation of a new treatment regimen were recorded to be evaluated for their potential prognostic significance. The clinical details of the entire group have been reported previously. 4 The diagnosis of MM was based on (1) an increased number of abnormal, atypical, or immature plasma cells in the bone marrow or histologic proof of plasmacytoma, (2) the presence of an M protein in the serum or urine, or (3) bone lesions consistent with those of MM. 12 Patients with reactive plasmacytosis due to connective tissue disorders, liver disease, metastatic carcinoma, or chronic infections were excluded. Also excluded were those with monoclonal gammopathy of undetermined significance, smoldering MM, solitary plasmacytoma, and plasma cell leukemia. Therapeutic regimens consisted primarily of alkylating agents with or without corticosteroids. STATISTICAL ANALYSES The overall distribution of patients, as a function of time from diagnosis, was completed using the cumulative incidence method. If there was no censoring, this method is equivalent to simple frequency tabulation, at each desired time point, of the current state of each patient: first treatment group, second treatment group, through the sixth treatment group or higher, or death. The cumulative incidence formula can be used in the event of censoring. 13 This analysis used a variant based on the redistribute-to-theright algorithm, which generalizes to multiple transient and absorbing states. 14 For individual treatments, the primary analysis was based on time to treatment failure, ie, the time from initiation of a treatment regimen until death or the start of a new treatment. Both Kaplan-Meier plots and cumulative incidence curves were computed; the latter distinguishes the 2 modes of failure death and next treatment arm from each other. Exploration of covariate effects was based on an Andersen-Gill model of time to treatment failure, which uses all failure episodes for a given patient. The time scale was time from treatment initiation, and the robust grouped variance was used to correct for correlation. 15 For each covariate, the individual Cox model was checked for the presence of outliers and/or large leverage points using the dfbeta residuals, for nonproportional hazards, and for the continuous variables, appropriateness of the functional form of the relationship to survival, eg, use of creatinine vs log(creatinine) vs some other transformation. RESULTS A total of 1027 patients with newly diagnosed MM were seen at the Mayo Clinic between January 1, 1985, and December 31, 1998 (median, November 1992). This group of patients has been reported previously 4 but not from the perspective of relapsed disease, the focus of the current study. Of these patients, 578 were determined to have had complete treatment records, as defined previously. The 578 patients who satisfied the working definition of those re- 868 Mayo Clin Proc. 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ceiving most of their monitoring and follow-up at the Mayo Clinic (as described in the Patients and Methods section) were compared with the 449 patients who were excluded with respect to baseline features (Table 1). The median age of the study population was 65 years (range, 26-92 years), and 228 patients (39%) were women. The patients were monitored for 1638 person-years (median, 8.2 years; range, 0-17 years). The median follow-up for those still alive (n=71) was 55 months (range, 0-202 months with only 4 patients having <1 year of follow-up). The status of the 578 patients, grouped by the number of treatments they received, is shown in Table 2. CLINICAL COURSE FROM INITIAL DIAGNOSIS The median OS for the 578 patients was 28.4 months from diagnosis (Figure 1). At 1 year from diagnosis, 46% of patients still had not received a second therapy, 33% were receiving a second therapy, and 21% had died (Table 3). The percentages of surviving patients, at various times from diagnosis, associated with their current regimen, are shown in Figure 2. For example, at 3 years from diagnosis, 46% of the patients who are still alive (n=237) are still receiving their first treatment regimen. The median duration of first therapy was 9.9 months. Of the 578 patients in this study, 355 (61%) received a second therapy, either after relapse from the first therapy or because of a lack of response to initial treatment. The rest of the patients either had not received another therapy by the last follow-up or had died of progressive disease without receiving a second regimen. At 10 years from diagnosis, nearly all the patients had died of either their disease or other causes (Figure 1). Minor differences in the clinical features were seen between the 2 groups of patients (Table 1), namely those included and not included in the current study. Although some of the differences appear statistically significant, given the study group sizes, the absolute differences appear small, especially for important prognostic factors such as serum albumin, creatinine, and platelet count. Overall, the 2 groups appear to be similar in terms of their biological features, especially for the different prognostic factors. A direct comparison of the survival between the 2 groups, although feasible, would be fraught with the danger of overinterpretation. The differences in survival between the groups likely will be more a reflection of the incomplete follow-up in the excluded patient population. In comparing patients who had a complete follow-up and those with an incomplete follow-up (the basis of the grouping in our study), we did not directly compare survival. Given the selection criteria, we believe that this study group is probably representative of patients with MM who TABLE 1. Comparison of Presenting Features Between the Study Group and Excluded Patients* Study group Excluded Characteristics (n=578) (n=449) P value Median (range) Age at diagnosis (y) 65 (26-92) 67 (20-92).82 M protein level (g/dl) 3.3 (0-12) 3.2 (0-7.9).13 C-reactive protein (mg/dl) 0.47 (0.01-19) 0.4 (0.01-49).80 Albumin (g/dl) 3.4 (1.9-5.1) 3.5 (1.9-4.7) <.01 Bone marrow plasma cell (%) 51 (1-99) 47 (2-100) <.01 Creatinine (mg/dl) 1.3 (0.5-18) 1.2 (0.5-13.4) <.01 No. (%) of patients Preceding plasma cell disorder 236 (40.8) 146 (34.8).06 Female 228 (39.5) 182 (43.4).21 PCLI 1% 203 (37.6) 107 (28) <.01 β 2 -microglobulin >2.7 µg/ml 324 (78) 218 (71).04 Platelet count <150 10 9 /L 95 (16.5) 56 (13.4).17 Lytic bone disease 369 (65) 273 (66.8).56 Monoclonal protein (heavy chain).92 IgG 296 (51.2) 225 (53.7) IgA 128 (22.2) 80 (19.1) Biclonal 10 (1.7) 8 (1.9) *NS = not significant; PCLI = plasma cell labeling index. Percentages based on total number of patients in each group for whom the particular variable was available. are likely to be enrolled in clinical trials and that the results are generalizable. RELAPSED DISEASE There were 355 patients who received a second treatment regimen and were analyzed separately to better understand the course of relapsed disease; their disease progression is shown in Table 3. The response duration, defined as time to death or start of a new therapy, decreased progressively with each successive treatment regimen (Figure 3). The median duration of second therapy (7.3 months) was shorter than the first (9.9 months). The median survival from initiation of the second therapy was 17.1 months, and TABLE 2. Status of Study Patients Grouped by Number of Treatment Regimens Received Patient status No. of regimens No. (%) No. who received who died received regimen 1 211 (95) 223 2 114 (88) 130 3 80 (78) 103 4 46 (79) 58 5 29 (94) 31 6+ 27 (82) 33 Total 507 (88) 578 Mayo Clin Proc. July 2004;79(7):867-874 www.mayo.edu/proceedings 869
Percentage 100 80 60 40 20 0 0 5 10 15 Years from diagnosis FIGURE 1. Overall survival from diagnosis of multiple myeloma for the study group of 578 patients. The overall survival at 1 year was 72%, at 2 years was 55%, and at 5 years was 22%. The median survival for the study group is 28.4 months (95% confidence interval, 25.0-30.6 months). most patients (84%) died within 5 years after initiation of their second treatment (Figure 4). PER-REGIMEN OUTCOME The percentages of patients in each successive treatment regimen who died during that regimen, received another treatment, or are still receiving that regimen are shown in Table 3. For a group of 20 patients receiving the first treatment regimen, at 3 years, 6 will have died without receiving further treatment, about 10 will have received another regimen, and 4 will still be receiving the first regimen. The median event-free survival (in days) for each regimen is shown in Table 3. As seen in Figure 5, the risk of relapse increases and the duration to relapse or disease progression decreases with each successive regimen. Figures 4 and 5 show the overall and event-free survival, respectively, for patients receiving each regimen. These patients received several types of therapy, the most com- mon of which were alkylating agents, corticosteroids, and VAD (vincristine, Adriamycin, dexamethasone) (Table 4); 75 patients received high-dose therapy at some point during their disease course. MULTIVARIATE ANALYSIS FOR PROGNOSTIC FACTORS We examined the following variables: age, regimen number, sex, platelet count, creatinine level, plasma cell labeling index (PCLI), and percent bone marrow plasma cells. Results of the multivariate analysis are limited by the proportion of missing values when all the time points are combined. For example, β 2 -microglobulin was not included in the final analysis because this information was missing for most patients. There was a progressive increase in the risk of relapse with increasing treatment number. Patients with a low platelet count (<150 10 9 /L) (relative risk [RR], 1.9; 95% confidence interval [CI], 1.6-2.2; P<.001), high PCLI ( 1.0%) (RR, 1.4; 95% CI, 1.2-1.7; P<.001), high creatinine level ( 2.0 mg/dl) (RR, 1.3; 95% CI, 1.1-1.5; P=.004), and low albumin level (<3.0 g/dl) (RR, 1.5; 95% CI, 1.3-1.8; P=.01) had a poorer prognosis. These laboratory values retained their prognostic value with successive treatments. DISCUSSION The clinical course of patients with MM that relapses after initial therapy is not well documented. We present the outcome of patients followed up and monitored at our institution throughout their disease course to better understand the clinical course of the relapsed disease. Selection of patients who had most of their monitoring and follow-up at our institution allows for better follow-up data, and the demographic characteristics of the group are basically the same as those generally described for the disease. This study represents a unique description of the clinical course of patients with relapsed myeloma, which to our knowledge has not been previously examined systematically. TABLE 3. Patient Experience With Each Regimen* Time Regimen from diagnosis First Second Third Fourth Fifth Sixth 3 mo 11/10/79 10/16/74 16/16/68 19/20/61 22/22/56 18/27/55 6 mo 17/17/66 18/27/55 22/28/50 26/30/44 39/31/30 25/37/38 1 y 21/33/46 25/40/35 28/40/32 32/44/24 44/44/12 37/41/22 2 y 27/42/31 29/54/17 34/51/15 36/53/11 45/50/5 55/45/0 3 y 31/50/19 31/62/7 35/54/11 40/54/6 45/52/3 55/45/0 Median EFS (d) 302 221 182 137 122 99 *Values represent percentages of patients receiving regimen who died during treatment/received another treatment/are still receiving this regimen. EFS = event-free survival from initiation of regimen. 870 Mayo Clin Proc. July 2004;79(7):867-874 www.mayo.edu/proceedings
Years from initiation of regimen No. (%) of living patients 578 (100) 317 (55) 164 (31) 69 (17) 17 (6) 10 (3) FIGURE 2. Percentage of patients living and receiving their current regimen number at various times from start of initial treatment. The median duration to the initiation of the second therapy was only 9.9 months. The short time to failure of the initial therapy in this study reflects the inclusion of patients irrespective of the response to initial treatment, whether their disease was sensitive or primary refractory. Extremely few patients in this group had undergone stem cell transplantation as initial therapy. This therapy improves survival compared with conventional chemotherapy, and the duration would have been different if more patients had undergone initial transplantation. Maintenance therapy administered after initial response also can delay disease progression but has not improved OS in myeloma. 16 Because extremely few patients in the current study were receiving maintenance therapy, this would not have affected the duration of the initial response. We observed a median OS of 17.1 months from first relapse, consistent with previous observations. 17 As noted previously, relatively few patients in our study received high-dose therapy, either for initial therapy or for salvage therapy after initial relapse. It is unclear whether the median survival from relapse would have been substantially different if more patients in this study initially had received autologous transplantation. In a study of 94 patients who had relapse after autologous transplantation, Tricot et al 18 reported an estimated 59% survival at 18 months, slightly higher compared with the current observation (50% survival at 17 months). Studies investigating early transplantation compared with transplantation at relapse after ini- tial therapy show similar OS. For our study, salvage therapy chosen for patients with relapsing disease included, in decreasing frequency, single-agent alkylating drugs or corticosteroids, combination chemotherapy agents, and autologous stem cell transplantation. Recently, newer agents such as thalidomide, the proteasome inhibitor bortezomib (PS-341), and novel therapies have become available. 19,20 Median response duration (mo) 12 10 8 6 4 2 0 CONCLUSIONS An important consideration when selecting salvage therapies for patients with MM is the median survival of 17.1 First Second Third Fourth Fifth Sixth Treatment regimen FIGURE 3. Gradual decrease in the response duration with increasing order of treatment regimen. Mayo Clin Proc. July 2004;79(7):867-874 www.mayo.edu/proceedings 871
1.0 0.8 Cumulative probability 0.6 0.4 0.2 0.0 Years from initiation of regimen FIGURE 4. Overall survival from initiation of each treatment regimen. months from first relapse. New effective agents would be expected to improve this outcome. Durable responses were seen in a recently concluded clinical trial evaluating thalidomide for relapsed myeloma, with a median response duration of nearly 12 months. 21 In a phase 2 study of the proteasome inhibitor bortezomib in patients with relapsed myeloma refractory to multiple treatments, the median duration of response was 12 months, and the median OS was 16 months. 20 Results of the current study can serve as a reference point when considering the effect of newer therapies. In the bortezomib trial, the median duration of response for patients with multiple relapses (91% with at least 3 therapies) was 12 months compared with 5 months for those receiving their fourth regimen in the current 1.0 0.8 Cumulative probability 0.6 0.4 0.2 0.0 Years from initiation of regimen FIGURE 5. Event-free survival from initiation of each treatment regimen. 872 Mayo Clin Proc. July 2004;79(7):867-874 www.mayo.edu/proceedings
TABLE 4. Type of Therapy by Regimen* Regimen Sixth or Therapy Total First Second Third Fourth Fifth higher Melphalan ± prednisone 396 292 66 18 9 10 1 Combination alkylating agents 386 119 160 56 32 12 7 VAD 188 114 33 22 12 6 1 Corticosteroids 106 2 35 36 19 10 4 Thalidomide 41 0 5 10 7 10 9 Radiation 113 35 27 19 15 9 8 High-dose therapy 75 1 26 29 17 1 1 Other therapies 72 15 3 35 11 6 2 Total 578 355 225 122 64 33 *VAD = vincristine, Adriamycin, dexamethasone. study. Patients, especially those who have had multiple relapses, should be encouraged to participate in clinical trials using the newer agents. In our patient group, successive treatment regimens resulted in progressively shorter response durations. Similar observations have been reported in other studies. 22,23 The decreasing duration of response with consecutive regimens likely reflects acquired drug resistance. Multiple mechanisms have been implicated in acquired drug resistance in myeloma, including overexpression of P-glycoprotein causing reduction in intracellular drug concentration, changes in cellular drug targets, chromosomal aberrations, altered drug metabolism, and enhanced cellular repair processes. 24 Patients who experience relapse after long intervals are likely to respond to the same or similar regimens. For patients who have only brief periods of control, use of drugs with different mechanisms of action may overcome drug resistance to some extent. Also, newer therapies targeting the disease biology and the myeloma microenvironment are likely to result in more durable responses. The decreasing response duration also reflects the disease biology, with more tumor cells expressing a more aggressive phenotype with higher proliferative rates 25 and lower apoptotic rates. Several prognostic factors have been identified for patients with newly diagnosed myeloma. These include, but are not limited to, β 2 -microglobulin, 26,27 PCLI, 26 C-reactive protein, albumin, 28 presence of renal dysfunction, platelet count, cytogenetics, lactate dehydrogenase, 29 and disease stage. 30,31 Whether these factors retain prognostic value at the time of the relapse is unclear. Although limited somewhat by missing data, at least PCLI, platelet count, and albumin appear to have value as prognostic factors, which should be remembered when choosing therapeutic strategies for relapsed disease. Although our study included a selected group of patients treated at a myeloma referral center and most patients were seen before the general use of high-dose therapy, the findings were derived from prospectively acquired data and represent a sophisticated analysis of a hitherto little-studied but important group of patients. These patients are likely the most representative of those entering clinical trials for MM, and our findings may serve as the best available reference for measuring the effect of newer therapies. The median survival of patients with relapsed disease in our study, likely to be longer with new therapies, should encourage clinicians to continue active therapy for patients who can tolerate it. REFERENCES 1. Bataille R, Harousseau JL. Multiple myeloma. N Engl J Med. 1997;336: 1657-1664. 2. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29. 3. 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. 1998; 16:3832-3842. 4. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33. 5. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clin Proc. 1975;50:29-40. 6. Attal M, Harousseau J-L, Stoppa A-M, et al, Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335: 91-97. 7. Child JA, Morgan GJ, Davies FE, et al, Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348: 1875-1883. 8. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93:55-65. 9. Attal M, Harousseau J-L, Facon T, et al. Double autologous transplantation improves survival of multiple myeloma patients: final analysis of a prospective randomized study of the Intergroupe Francophone du Myelome (IFM 94) [abstract]. Blood. 2002;100(pt 1):5a. Abstract 7. 10. Abe R, Ishibashi T, Shichishima T, Maruyama Y. Ten-year survivor with multiple myeloma in first complete remission following treatment with conventional chemotherapy: case report and a review of the literature. Acta Haematol. 2001;105:241-243. Mayo Clin Proc. July 2004;79(7):867-874 www.mayo.edu/proceedings 873
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