The role of autologous stem cell transplantation (AuSCT) in older multiple myeloma patients is unclear. Using data from the Autologous Blood and Marrow Transplant Registry, we compared the outcome of 110 patients ⩾the age of 60 (median 63; range 60–73) years, undergoing AuSCT with that of 382 patients <60 (median 52; range 30–59) years. The two groups were similar except that older patients had a higher β2-microglobulin level at diagnosis (P=0.016) and fewer had lytic lesions (P=0.007). Day 100 mortality was 6% (95% confidence interval 4–9) and 1-year treatment-related mortality (TRM) was 9% (6–13) in patients <60 years, compared with 5% (2–10) and 8% (4–14), respectively, in patients ⩾60 years. The relapse rate, progression-free survival (PFS) and overall survival (OS) in the two groups were also similar. Multivariate analysis of all patients identified only an interval from diagnosis to AuSCT >12 months and the use of two prior chemotherapy regimens within 6 months of AuSCT as adverse prognostic factors. Our results indicate that AuSCT can be safely performed in selected older patients: the best results were observed in patients undergoing AuSCT relatively early in their disease course.
Intensive therapy and autologous stem cell transplantation (AuSCT) has been shown, in a randomized trial, to produce superior outcomes in younger patients (<60 years) with Stage II/III multiple myeloma (MM) when compared with standard therapy.1 In addition, phase II studies, largely performed in younger myeloma patients, have demonstrated the ability of this modality to induce remission rates in the majority of patients, with median progression-free survival (PFS) of 2 to 4 years and median overall survival (OS) of 4–6 years.2,3,4 The role of AuSCT in older individuals remains less clear.5,6 Several centers have described encouraging results of AuSCT in older myeloma patients.7,8,9,10 One center, however, found that the PFS after AuSCT was decreased in patients over the age of 60.11 We report the outcome of 110 myeloma patients ⩾60 years, who underwent AuSCT and were reported to the Autologous Blood and Marrow Transplant Registry (ABMTR). The results are compared to younger patients undergoing AuSCT during the same period of time.
Patients and methods
The ABMTR is a voluntary working group of more than 250 transplantation centers primarily in North and South America, that contribute detailed data on autologous stem cell transplants to the Statistical Center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee. Based on data collected in the Centers for Disease Control Hospital Surveys and the US Government Accounting Office and worldwide surveys of transplant activity, slightly more than 50% of autotransplants in North and South America are registered with the ABMTR. Participating centers are required to report all transplants consecutively; compliance is monitored by on-site audits. Patients are followed longitudinally, with yearly follow-up. Computerized checks for errors, physicians' review of submitted data and on-site audits of participating centers ensure the quality of the data.
The ABMTR collects data at two levels: Registration and Research. Registration data include disease type, age, sex, pretransplant disease stage, and chemotherapy responsiveness, date of diagnosis, graft type (bone marrow- and/or blood-derived stem cells), high-dose conditioning regimen, post-transplant disease progression and survival, development of a new malignancy and cause of death. Requests for data on progression or death for registered patients are at 6-month intervals. All ABMTR teams contribute Registration data. Research data are collected on subsets of registered patients, including comprehensive pre- and post transplant clinical information.
This study included patients who underwent a single AuSCT for multiple myeloma between 1994 and 1998 reported to the ABMTR by 88 centers (Table 1). Patients were required to have received hematopoietic stem cell grafts (blood with or without bone marrow). Eight patients were excluded from analysis because they received bone marrow grafts only, 119 because they received two transplants and three because AuSCT was performed for primary systemic amyloidosis. To assure that the Research patients were representative of all reported patients, relapse and survival rates between Research and Registered patients were compared and no differences were noted. In all, 492 patients met the on-study criteria: 382 patients were <60 years and 110 patients ⩾60 years of age. Median follow-up of survivors was 39 (3–111) months for patients <60 years and 39 (3–64) months for those ⩾60 years of age.
For this analysis, the number of chemotherapy regimens prior to transplant did not include chemotherapy given for mobilization of the peripheral blood progenitor cells, as this was considered part of the AuSCT procedure. Patients were considered to be responsive to pretransplant chemotherapy if a ⩾50% reduction in serum paraprotein level, or, in light-chain only myeloma, a ⩾90% reduction in 24 h light chain excretion was documented; patients with nonsecretory myeloma were required to have a ⩾50% reduction in marrow plasma cells. Patients were deemed resistant if these criteria were not met. Post-transplant complete remission (CR) was defined as the absence of a monoclonal protein in the serum and urine by immunofixation for a minimum of 6 weeks and less than 5% plasma cells on bone marrow aspirate (and biopsies, if performed); a confirmatory bone marrow was required only in the case of nonsecretory myeloma. Partial response (PR) required a ⩾50% decrease in paraprotein level and/or ⩾90% decrease in light chain excretion or a level less than 200 mg/day in the absence of other signs of disease progression, which was also maintained for a minimum of 6 weeks. Minimal response (MR) included a 25–49% decrease in monoclonal protein level and/or decrease in 24-h urine light chain excretion by at least 50% for at least 6 weeks. Patients were considered to have stable disease if they did not meet the criteria for MR or disease progression. Progressive disease required a ⩾25% increase in serum paraprotein or urine paraprotein confirmed on a second determination, while relapse from CR was defined as the confirmed reappearance of the original monoclonal protein by electrophoresis or immunofixation, hypercalcemia, new bone lesions or new plasmacytomas.12
Characteristics of patients in the younger and older cohorts were compared using the χ2-test for categorical variables and the Kruskal–Wallis test for continuous variables (Table 1). The primary end points of this study were transplant-related mortality (TRM), relapse/progression rate, PFS, and OS. Probabilities of TRM and relapse were calculated using cumulative incidence estimates to accommodate competing risks.13 Survival and PFS were calculated using Kaplan–Meier estimates. TRM was defined as deaths occurring in continuous CR, PR, MR or stable disease; data were censored at the time of relapse/progression or, among patients in continuous remission, PR, MR or stable disease, at the time of last follow-up. Relapse was defined as the laboratory recurrence or progression of myeloma according to the standard IBMTR/EBMT criteria.12 For analyses of PFS, treatment was considered a failure at the time of relapse or progression of myeloma or at the time of death from any cause; data on patients who were alive and in CR, PR, MR or stable disease were censored at the time of the last follow-up. For analyses of OS, the event was death from any cause; surviving patients were censored at the date of last contact. Univariate comparisons used the log-rank test14 (Table 2).
Comparison of primary outcomes between the younger and the older patients was done using multivariate Cox proportional hazards regression to adjust for potentially confounding effects of other risk factors. The variables considered in multivariate analysis are outlined in Table 3. For each outcome, we compared the likelihood from a model stratified on age at transplant to the likelihood from a model with different risk coefficients for each age group using the likelihood ratio test to determine if there was a statistically significant interaction between age at transplant and the factor being examined. When the likelihood ratio test was significant (P<0.05), an interaction term was added to the model to account for the interaction between the significant factor and the main effect (age at transplant). After determining the interaction terms, we tested the proportional hazards assumption for each factor in the Cox model using time-dependent covariates. When this indicated differential effects over time (nonproportional hazards), models were constructed breaking the post transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. After modeling time-varying effects, the final multivariate model was built using a forward stepwise model selection approach. Each model contained the main effect (age at transplant: <60 vs ⩾60 years). Factors significantly associated with the outcome variable at a 5% level were kept in the final model. Examination for center effects used a random effects or frailty model.15 We found no evidence of correlation between center and any of the outcomes. All P-values are two-sided.
Patient characteristics by age at transplant are listed in Table 1. The median age of the older transplant recipients was 63 vs 52 years in the younger patients. In all, 75% of the older patients were 60–64 years of age, while 25% were ⩾65 years of age, including three patients ⩾70 years. The characteristics between groups were similar, with the exception that older patients had a significantly higher median β2-microglobulin level at diagnosis, while lytic bone lesions were identified more frequently in younger patients. The proportion of patients with a β2-microglobulin >3.5 was similar in the two groups. Post-transplant maintenance therapy with alpha-interferon was administered to approximately one-third of all patients.
The response rates assessed at day 100 were comparable in both groups of patients (Table 2). Specifically, the CR rate was 34% in patients <60 years of age, compared with 33% in the older age group. The rates of PR and MR were 35 and 4%, respectively, in the younger patients, and 34 and 6% in the patients ⩾60 years. The 100-day mortality was 6 vs 5% in the younger and older age groups, respectively. None of these differences were statistically significant.
The cumulative incidence of relapse/progression at 3 years was 39% (95% CI 33–45%) in younger patients and 46% (95% CI 35–56%) in older patients (P=0.262) (Figure 1). In multivariate analysis, relapse did not differ significantly between the two groups (Table 4). Time from diagnosis to transplant >12 months was identified as an adverse prognostic factor (RR=1.63, 95% CI 1.16–2.28, P=0.005).
The cumulative incidence of TRM at day 100 was 4% (95% CI 3–7%) in the younger patients compared with 3% (95% CI 1–7%) in patients ⩾60 years of age (P=0.466). At 1 year post-AuSCT, the TRM in the younger and older groups was 9% (95% CI 6–13%) vs 8% (95% CI 4–14%), respectively (P=0.684) (Figure 2). In multivariate analysis, TRM did not differ significantly between the two groups (Table 4). The only factor associated with an increased risk of TRM among all patients was the use of two chemotherapy regimens (excluding any utilized for stem cell mobilization) within the 6 months preceding AuSCT (RR=3.23, 95% CI 1.13–9.22, P=0.028).
Among patients <60 years of age, the median PFS was 27 (23–35) months, compared with 24 (18–32) months in the older group of patients. PFS did not differ significantly between the two groups (Figure 3). At 3 years, PFS was 44% (95% CI 38–50%) for younger patients and 35% (95% CI 25–46%) for older patients (P=0.157) (Table 2). Patients with >12 months from diagnosis to AuSCT had a significantly higher risk of death or relapse/progression (RR=1.50, 95% CI 1.13–2.00, P=0.005) (Table 4).
Both patients <60 and those ⩾60 years had a median OS of 39 months. The 3-year survival was 55% (95% CI 50–61%) for younger patients and 58% (95% CI 47–67%) for older patients (P=0.696) (Table 2; Figure 4). Factors associated with poorer OS were the use of two chemotherapy regimens within 6 months of AuSCT (RR=2.70, 95% CI 1.31–5.57, P=0.007) and a time from diagnosis to transplant >12 months (RR=1.41, 95% CI 1.03–1.95) (Table 4).
Progressive myeloma was the most frequent cause of death in both age groups. Among the 179 evaluable patients <60 years of age, 140 (78%) succumbed to their primary disease, while two (1%) died of a second malignancy, one (1%) from graft-versus-host disease after subsequent allogeneic transplantation for disease recurrence, eight (4%) from interstitial pneumonitis, 11 (6%) from infection, 10 (6%) from organ failure, and seven (4%) from other causes. The causes of death in older patients were as follows: primary disease in 40 (80%), infection in three (6%), organ failure in three (6%) and other causes in four (8%).
AuSCT has become the standard of care for newly diagnosed younger myeloma patients. However, the median age of patients with this disease is approximately 65 years, and there is considerable interest in the outcome of older patients who undergo AuSCT. Our multicenter analysis demonstrates the feasibility and safety of AuSCT in patients ⩾60 years of age. Patients autografted <12 months from initial diagnosis had an improved PFS and OS, as in other studies of AuSCT in this disease.2,16 There are two caveats, however, related to our findings. First, as in other transplant studies, the older patients undergoing AuSCT represent a select group of individuals with satisfactory organ function and performance status; no data are available on the proportion of older myeloma patients ineligible for this procedure. Another consideration relates to the sample size available for analysis. This study had >80% power to detect a 15% difference in these outcomes; it cannot exclude smaller differences.
Several smaller single-institution studies have also addressed the effect of age at transplant on results for multiple myeloma patients (Table 5). The group at the University of Arkansas has performed a retrospective analysis of autografted myeloma patients ⩾65 of age, the majority of whom received tandem transplants.8 Patients were matched with younger recipients according to cytogenetics, β2-microglobulin level, and C reactive protein level. Day 100 TRM was 8% in patients ⩾65 years vs 2% in those <65 years. The median PFS and OS survival, although somewhat lower in the older recipients, did not differ significantly. As in our analysis, they identified ⩾12 months of prior therapy as an adverse prognostic factor in multivariate analysis. In addition, an elevated β2-microglobulin level and unfavorable cytogenetics (abnormalities of chromosome 11 or 13 or any translocations) predicted a poorer outcome. While our study was designed to look at outcomes based on age < or ⩾60 years, the outcomes for the subset of patients ⩾65 years (n=27) were similar to those 60–64 years (data not shown).
More recently, this group has extended their analysis to 70 recipients of AuSCT, who were ⩾70 years of age (range 72–82.6). Slightly over 50% of these patients had disease refractory to chemotherapy, and 44% received tandem transplants.9 The TRM differed according to the dose of melphalan used for pre-AuSCT conditioning; the TRM rate was only 2% for patients receiving 140 mg/m2 of melphalan compared with 16% for those given 200 mg/m2. Patients receiving tandem AuSCT with ⩽12 months duration of prior therapy had the best outcomes.
Palumbo et al have described a somewhat different strategy for patients 55–75 years of age. After two cycles of vincristine, doxorubicin and dexamethasone, and stem cell mobilization, patients received up to three courses of melphalan 100 mg/m2 with AuSCT support, as a part of initial therapy. The response rates were very high, and no patient died as a result of therapy. The median PFS and OS were 34 months and 56+ months, respectively, with a 4-year PFS of 33% and OS of 71%. When these patients were matched with similar patients treated with nontransplant therapies, the use of the melphalan 100 mg/m2 with AuSCT protocol and a lower β2-microglobulin level were identified as favorable prognostic factors.7
Our study was not able to confirm the prognostic utility of the pre-AuSCT β2-microglobulin level or cytogenetics due to the constraints of a registry analysis, as this information was available for only 52 and 15% of patients, respectively. However, our outcomes were similar to those seen in the studies from Arkansas in which a significant proportion of older patients were treated with two transplants, even though our analysis excluded recipients of tandem AuSCT. Patient selection likely accounts for this observation, as a much higher percentage of patients with refractory disease were included in the Arkansas series, and these patients may have benefited from a double procedure. Similarly, the excellent results in the Italian series were also probably related in large part to the patient population, as all patients were transplanted as part of first-line therapy.
As noted above, several studies have suggested that doses of melphalan ranging from 100 to 140 mg/m2 are better tolerated in older patients than the regimen of 200 mg/m2 often used in younger patients. In addition, there are data indicating that TBI-containing regimens, administered to 31% of our older patients, are associated with additional toxicity, without an improvement in the antitumor effect in multiple myeloma.17,18 Given the heterogeneity of conditioning regimens in our analysis, we were not able to discern differences in TRM or antimyeloma effects based on regimen. Currently, melphalan alone at a dose of 200 mg/m2 has become the preferred conditioning regimen for the majority of myeloma patients, while lower doses are generally reserved for patients over the age of 70 years.
The use of post-AuSCT maintenance therapy has been studied as a means to reduce relapse rates, although an optimal regimen has not yet been defined.18,19,20,21 A beneficial effect of alpha-interferon has been reported by two groups.18,19,20 We were not able to evaluate the use of this agent after AuSCT, as it was given to a minority of patients in this study and the details of administration were unavailable.
In summary, our analysis demonstrates that selected older myeloma patients can experience the same benefit with AuSCT as younger ones without an increase in TRM. Age is not an absolute exclusion criteria for AuSCT. Rather, medical cormorbidities, similar to those which would also potentially exclude younger myeloma patients from this procedure, likely play an important role. However, only a randomized trial analyzed on an intention-to-treat basis could establish the full impact of ASCT in elderly patients. Unfortunately, as in younger patients, recurrence rates are far too high. Additional strategies to decrease or forestall relapse will require the ability to overcome adverse biological features of this disease, such as unfavorable cytogenetic abnormalities and a high β2-microglobulin level. Improved post-AuSCT approaches involving newer targeted therapies,22 immunotherapy23 or perhaps reduced intensity allogeneic transplants may help in this regard.24
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This work was supported by Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute, and grants from Abgenix, Inc.; AmCell Corporation; American Cancer Society; American Society of Clinical Oncology; Amgen, Inc.; Anonymous; Aventis Pharmaceuticals; Berlex Laboratories; BioTransplant, Incorporated; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Oncology; CelMed Biosciences; Center for Advanced Studies in Leukemia; Cerus Corporation; Chimeric Therapies; Chiron Therapeutics; Eleanor Naylor Dana Charitable Trust; Deborah J Dearholt Memorial Fund; Edwards Lifesciences RMI; Empire Blue Cross Blue Shield; Fujisawa Healthcare, Inc.; Gambro BCT, Inc.; Genentech, Inc.; GlaxoSmithKline, Inc.; Human Genome Sciences; ICN Pharmaceuticals, Inc.; IDEC Pharmaceuticals Corporation; IntraBiotics Pharmaceuticals; Kettering Family Foundation; Kirin Brewery Company; Robert J Kleberg, Jr and Helen C Kleberg Foundation; LifeTrac/Allianz; Eli Lilly and Company; The Liposome Company; Nada and Herbert P Mahler Charities; Market Certitude, LLC; Mayer Ventures; MedImmune, Inc.; Merck & Co., Inc.; Milliman & Robertson, Inc.; Milstein Family Foundation; The Greater Milwaukee Foundation/Elsa Schoeneich Research Fund; NeoRx; Nexell Therapeutics; Novartis Pharmaceuticals; Orphan Medical; Ortho Biotech, Inc.; John Oster Family Foundation; Osiris Therapeutics, Inc.; Pfizer US Pharmaceuticals; Pharmacia Corporation; Pharmametrics GmbH; Principal Life Insurance Company; Protein Design Labs, Inc.; Response Oncology, Inc.; RGK Foundation; Roche Laboratories, Inc.; SangStat; Schering AG; Schering Oncology/Biotech; Stackner Family Foundation; The Starr Foundation; SuperGen, Inc.; TheraTechnologies, Inc.; Unicare Life & Health Insurance; Wyeth/Genetics Institute and ZymoGenetics, Inc. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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Reece, D., Bredeson, C., Pérez, W. et al. Autologous stem cell transplantation in multiple myeloma patients <60 vs ⩾60 years of age. Bone Marrow Transplant 32, 1135–1143 (2003). https://doi.org/10.1038/sj.bmt.1704288
- autologous transplantation
- older patients
- multiple myeloma
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