Evaluation of the Feasibility and Efficacy of Autologous Stem Cell Transplantation in Elderly Patients with Multiple Myeloma

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1 ORIGINAL ARTICLE Evaluation of the Feasibility and Efficacy of Autologous Stem Cell Transplantation in Elderly Patients with Multiple Myeloma Tsuyoshi Muta 1, Toshihiro Miyamoto 1, Tomoaki Fujisaki 2, Yuju Ohno 3, Tomohiko Kamimura 4,KojiKato 1, Katsuto Takenaka 1, Hiromi Iwasaki 1, Tetsuya Eto 5, Yasushi Takamatsu 6, Takanori Teshima 7, Koichi Akashi 1 and Fukuoka Blood and Marrow Transplant Group (FBMTG) Abstract Objective The feasibility and efficacy of high-dose melphalan (HD-MEL) followed by autologous hematopoietic stem cell transplantation (auto-sct) in elderly patients with multiple myeloma (MM) are discussed. Methods We retrospectively analyzed and compared the results of 25 elderly patients (aged years, elderly group) and 63 control patients (aged years, control group). Many patients received a vincristine and doxorubicin combined with dexamethasone (VAD) regimen (elderly group: 92%, control group: 78%) with autologous peripheral blood stem cells being harvested after the administration of chemotherapy with high-dose cyclophosphamide (elderly group: 72%, control group: 87%). Ten elderly patients received MEL at a dose of mg/m 2, while 15 patients received MEL at a dose of mg/m 2. Results Treatment-related deaths occurred in one elderly patient and two younger patients due to infections. The rate of achieving complete response (CR) or very good partial response (VGPR) was 60% in the elderly group and 83% in the control group. Progression-free survival from auto-sct in the elderly group was similar to that observed in the control group (median 17.1 vs months, p=0.26), with the median overall survival (OS) from auto-sct being 40.8 months in the former and 72.5 months in the latter group (p=0.07). When calculated from the beginning of induction treatment, the median OS of the elderly group was 47.0 months and the 3-year OS rate was 81%. Conclusion The current study provides evidence for the efficacy of auto-sct in elderly MM patients. A prospective study of auto-sct in elderly patients using strict eligibility criteria is required to evaluate the prolongation of survival in the era of novel agents. Key words: elderly patients with multiple myeloma, autologous hematopoietic stem cell transplantation, high-dose melphalan (Intern Med 52: 63-70, 2013) () Introduction High-dose melphalan (HD-MEL) (at a dose of 200 mg/ m 2 ) combined with autologous hematopoietic stem cell transplantation (auto-sct) is now established as an essential treatment for patients with symptomatic multiple myeloma (MM) (1). In general, auto-sct is used to treat patients Department of Hematology/Oncology, Kyushu University Hospital, Japan, Department of Internal Medicine, Matsuyama Red-Cross Hospital, Japan, Department of Hematology, Kitakyushu Municipal Medical Center, Japan, Department of Hematology, Hara-Sanshin Hospital, Japan, Department of Hematology, Hamanomachi Hospital, Japan, Division of Medical Oncology, Hematology, and Infectious Disease, Fukuoka University Hospital, Japan and Department of Hematology and Oncology, Hokkaido University Graduate School of Medicine, Japan Received for publication June 15, 2012; Accepted for publication October 1, 2012 Correspondence to Dr. Tsuyoshi Muta, muta-t@intmed1.med.kyushu-u.ac.jp 63

2 with MM aged less than 65 years. However, the mean age at diagnosis of patients has been reported to be 68.3 years (2), with the clinical stages of MM usually increasing with age (3). Therefore, treating the majority of patients with MM older than 65 years with modified doses of MEL represents a challenge with respect to achieving greater efficacy whilst avoiding significant toxicity. Palumbo et al. performed auto-sct successfully in patients aged years by reducing the dose of MEL to 100 mg/m 2 (4), then subsequently verified that the survival rate of auto-sct with 100 mg/m 2 of MEL is superior to that of chemotherapy in terms of event-free survival and overall survival using a randomized study (5). Badros et al. also reported the safety and efficacy of MEL at a dose of 140 mg/m 2 in elderly patients older than 70 years of age (6). In contrast, the IFM randomized trial failed to confirm the existence of a survival advantage of auto-sct and 100 mg/m 2 of MEL over therapy with prednisolone (MP) and thalidomide (7). Consequently, novel agents such as bortezomib, lenalidomide, and thalidomide have become the mainstay of treatment in the majority of patients older than 65 years of age. In Japan, HD-MEL with auto-sct has been used since June 2001, when the Ministry of Health, Labor and Welfare (MHLW) approved the use of intravenous administration of MEL. Although the eligible age for auto-sct is usually limited to less than 65 years, attending physicians sometimes raise the upper age limit when preserving the organ function is judged to outweigh the anticipated treatment-related toxicities associated with HD-MEL and auto-sct. As a result, a substantial number of elderly patients in Japan have undergone auto-sct, although the efficacy and toxicity of this procedure have yet to be evaluated. In order to investigate the feasibility and efficacy of auto-sct, we performed a retrospective analysis of data obtained from elderly patients aged 65 years or older at our institutes. We then compared these results with those of data obtained from patients younger than 65 years of age to assess the toxicity and survival benefit of HD-MEL with auto-sct in elderly patients. Patients Materials and Methods Between October 2001 and August 2011, 103 patients with MM underwent auto-sct at five medical centers in the Fukuoka Blood and Marrow Transplant Group (FBMTG). Informed consent was obtained prior to treatment by each attending physician. Patients with severe renal failure, poor performance status, a compromised cardiac or pulmonary function and uncontrolled psychological problems were not considered for auto-sct. Twenty-five patients 65 years or older at the time of auto-sct were classified into the elderly group. The patients younger than 50 years of age (n= 15) had a more frequent occurrence of limited disease (Durie-Salmon (D-S) staging system I-II) compared to that observed in the elderly group (p=0.02); therefore, the results of the elderly group were compared with those of the patients aged between years, who were classified into the control group (n=63). The subtype of MM, stage at diagnosis, disease status at transplantation, duration (days) from original diagnosis to auto-sct, use of conditioning chemotherapy and clinical data were compared between the two groups. Seattle s hematopoietic cell transplantationspecific comorbidity index (HCT-CI) was used to score the comorbidities (8). Chemotherapy regimens Conventional regimens included continuous infusions of vincristine and doxorubicin combined with dexamethasone (VAD), oral administration of melphalan and MP, and MP combined with methyl chloroethyl nitroso urea (MCNU) and vincristine (ROAD). Regimens with novel agents included oral thalidomide, bortezomib and dexamethasone (BD), and lenalidomide and dexamethasone (LD). Stem cell mobilization and collection In the majority of patients, peripheral blood hematopoietic stem cells were mobilized with granulocyte colonystimulating factor (G-CSF), followed by the administration of cytotoxic chemotherapy with cyclophosphamide (CY) at a dose of 1, 1.5, or 2 g/m 2 for two days (n=73), or etoposide (VP16) at a dose of 500 mg/m 2 for three days (n=6). Nine patients including two with poor mobilization with CY in the control group received G-CSF alone at a daily subcutaneous dose of 10 μg/kg. Conditioning regimen and supportive care The dose of MEL in the conditioning regimen was modified for each recipient as follows: 100 mg/m 2 (elderly group: n=5, control group: n=2), 120 mg/m 2 (elderly group: n=5, control group: n=4), 180 mg/m 2 (elderly group: n=5, control group: n=12), or 200 mg/m 2 (elderly group: n=10, control group: n=45). Supportive care was provided according to each institution s protocol, with each attending physician deciding to perform either single or tandem auto-sct depending on the condition of the patient. All patients without contraindications received bisphosphonates. Assessment of transplant-related toxicity Non-hematological toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. The variables analyzed in the two groups during each patient s first auto-sct included bacterial and viral infections, gastro-enteric, renal (serum creatinine) and hepatic (bilirubin, alanine transaminase, and aspartate transaminase) function, cardiotoxicity, and second malignancies. Treatment-related mortality (TRM) was defined as death within 100 days of auto-sct. Statistical methods We summarized the characteristics of the patients using the medians and ranges for continuous variables, and per- 64

3 Table 1. Baseline Characteristics Table 2. Results of Peripheral Blood Stem Cells Collection Elderly Control (n = 25) (n = 63) p value Age at stem cell transplantation, median (range) 67 (65 76) 60 (51 64) - Male gender 13 (52%) 34 (54%) 0.8 Durie-Salmon stage, n (%) I 0 1 (2%) 0.38 II 4 (16%) 15 (24%) III 21 (84%) 47 (74%) International staging system for multiple myeloma, n (%) I 8 (32%) 13 (21%) 0.5 II 9 (36%) 26 (41%) III 3 (12%) 14 (22%) missing 5 (20%) 10 (16%) ECOG performance status 2 <, n (%) 2 (8%) 10 (16%) 0.3 Laboratory data at diagnosis (median) Alubumin, mg/dl Serum creatinine, mg/dl LDH, IU/L Calucium, mg/dl Hemogulobin, g/dl Plasma cell in bone marrow, % Induction treatment VAD MP, VAD 3 5 ROAD 1 4 VAD, BD 3 8 Dexamethasone, BD 1 4 VAD, Thalidomide 0 1 Dexamethasone, LD 0 1 centages for categorical variables. Patient characteristics and baseline features were assessed using the Chi-square test, Fisher s exact test or the Mann-Whitney U-test, as appropriate. The disease response was classified as a complete response (CR), a very good partial response (VGPR) or a partial response (PR), in addition to progressive disease (PD) and relapse (Rel), according to the International Myeloma Working Group uniform response criteria (9). To compare the results of auto-sct between the two groups, the progression free survival (PFS) and overall survival (OS) were defined as the time from first auto-sct to progression or death, as described previously (6). A comparison of survival end-points between the two groups was made using the logrank test. This study was conducted under the approval of our board. The statistical analyses were performed out using JMP Ver.9. SAS, Institute Inc., Cary, NC, USA. Patient characteristics Results The patient characteristics are shown in Table 1. The majority of patients had advanced and D-S stage III disease (elderly group: 84%, control group: 74%; p=0.38). The international staging system for myeloma (ISS) was distributed symmetrically between the two groups, although it should be noted that 20% of the patients in the elderly Number of CD34+ cells, median (range) 10 6 /kg Elderly Control p value All patients 4.0 ( ) 7.5 (1.0 42) 0.8 (n = 25) (n = 63) Mobilization regimen CY 2 3 g/m ( ) 7.3 (2 18) 0.9 (n = 12) (n = 8) (n = 4) CY 4 g/ m ( ) 10 ( ) 0.9 (n = 61) (n = 10) (n = 51) Etoposide 9 ( ) 32 (1.7 42) 0.6 (n = 6) (n = 3) (n = 3) G-CSF alone 4.2 ( ) 3.7 ( ) 0.3 (n = 9) (n = 4) (n = 5) group and 16% of the patients in the control group had missing data for beta-2 microglobulin. A small number of patients had poor performance status primarily due to the presence of multiple bone diseases (elderly group: 8%, control group: 16%). Laboratory parameters such as the albumin levels, lactate dehydrogenase (LDH) levels, blood counts, bone marrow plasma cell percentage, and the presence of chromosomal metaphase abnormalities were comparable between the two groups, whereas the baseline levels of serum creatinine (0.7 vs. 0.8 mg/dl; p=0.01) and corrected calcium (9.3 vs mg/dl; p=0.01) were significantly higher in the control group. The majority of patients in both groups had an HCT-CI score of 0 (elderly group: 84%, control group: 83%). The majority of patients received a VAD regimen for induction chemotherapy (elderly group: 92%, control group: 78%) (Table 1). Bortezomib was subsequently introduced in four elderly and 12 control patients, while either thalidomide or lenalidomide was administered to two patients in the control group. As a result, a minority of patients underwent conventional induction therapy supplemented with novel agents prior to receiving auto-sct (elderly group: 16%, control group: 22%). The majority of patients also underwent successful harvest of CD34+ cells following stem cell mobilization with high-dose CY (elderly group: 72%, control group: 87%). As shown in Table 2, the dose of CY was lowered in a significant number of elderly patients (eight patients in the elderly group vs. four patients in the control group; p=0.0002). The dose of MEL in the conditioning regimen was also reduced to <120 mg/m 2 in 40% of the patients in the elderly group and only in 10% of the patients in the control group (p=0.0003) (Table 3). Tandem auto-sct was frequently used in the control group (32% in the elderly group vs. 56% in the control group; p=0.046) (Table 3). Clinical outcomes of auto-sct The median yield of CD34+ cells was /kginthe elderly group and /kg in the control group (Table 2). The actual number of CD34+ cells infused during each auto-sct was similar in the two groups (3.4 vs /kg; p=0.2) (Table 3). With the exception of two patients in the 65

4 Table 3. Clinical Outcome of Autologous Stem Cell Transplantation Elderly Control (n = 25) (n = 63) p value Conditioning, n (%) MEL mg/m 2 15 (60%) 57 (90%) MEL mg/m 2 10 (40%) 6 (10%) Tandem auto-sct, n (%) 8 (32%) 35 (56%) Infused CD /kg, median (range) 3.4 ( ) 4.0 (0.1 42) 0.2 Neutrophil count > 500 median days (range) 10 (9 16) 10 (7 16) 0.9 Platelet count > 50,000 median days (range) 16 (10-66) 16 (12-89) 0.23 Hospitalization after SCT, median days (range) 24 (14 152) 28 (14 87) 0.9 Best response, n (%) CR 3 (12%) 15 (24%) 0.06 VGPR 12 (48%) 37 (59%) Disease progression after SCT, n (%) Relapse 2 (8%) 1 (2%) 0.7 Pogressive disease 13 (52%) 41 (65%) Salvage treatment, n (%) Conventional chemotherapy 3 (12%) 4 (6%) 0.6 Novel agents 11 (44%) 33 (52%) Auto-SCT 1 (4%) 3 (5%) Allogeneic-SCT 1 (4%) 3 (5%) A B Probability of progression-free survival Probability of overall survival Progression-free Survival p = Years from transplantation Overall Survival p = Years from transplantation Figure. A log-rank comparison of progression-free survival (A) and overall survival (B) in elderly patients (bold line) vs. younger matched controls (thin line) following autologous stem cell transplantation. control group who died from sepsis before engraftment, the time to engraftment after auto-sct was equal between the two groups (10 days) (Table 3). The CR and VGPR rates were 12% and 48%, respectively, in the elderly group and 24% and 59%, respectively, in the control group. The median follow-up time from auto-sct in the surviving patients was 30 months (range: months). The median PFS was 17.1 months in the elderly group compared to 20.8 months in the control group (p=0.26; Figure A), while the median OS in the elderly group was 40.8 months compared to 72.5 months in the control group (p=0.07; Figure B). When calculated from the beginning of induction treatment, the median PFS and OS in the elderly group were 23.3 months and 47.0 months, respectively, and the 3-year OS rate was 81%. The duration of survival after progression tended to be shorter in the elderly group than in the control group (median 18.6 months vs months; p=0.08). Transplantation-related toxicity The median hospitalization time between the day of auto- SCT and the day of successful discharge was 24 days (range days) in the elderly group compared to 28 days (range days) in the control group (p=0.9) (Table 3). Table 4 summarizes the non-hematological toxicities occurring after auto-sct using data of the first auto-sct in cases of tandem auto-sct. Gastrointestinal toxicities were frequent, while paroxysmal atrial fibrillation occurred in two elderly patients. Febrile episodes were common (elderly group: 76%, control group: 84%; p=0.25). Two patients in the elderly group showed base line abnormal ejection fractions (EF) on echocardiography prior to receiving auto-sct. The CD34+ cells of one 66-year-old man with dilated cardiomyopathy and an EF of 40% was successfully harvested using VP16, and then he revived MEL 180 mg/m 2 followed by auto-sct without grade 3-4 non-hematological toxicity, resulting in PD 17 months after auto-sct. The CD34+ cells of another 71-year-old man with an old myocardial infarction and an EF of 35% was successfully harvested using VP 16 and revived MEL at a dose of 100 mg/m 2. After undergoing auto-sct, that patient developed renal toxicity of grade 3 and suffered from paroxysmal atrial fibrillation. He was discharged on day 69 after auto-sct but was intolerant to 66

5 Table 4. Non-hematological Toxicity Following the First Autologous Stem Cell Transplantation Elderly Control (n = 25) (n = 63) p value Grade 3-4 toxicity 21 (84%) 46 (73%) 0.1 Mucositis 1 (4%) 2 (3%) 0.8 Diarrhea 17 (68%) 29 (46%) 0.06 Arrhythmia 2 (8%) 0 (0%) 0.02 Hypokalemia 3 (12%) 5 (8%) 0.5 Hyperkalemia 1 (4%) 1 (2%) 0.5 Febrile neutropenia 19 (76%) 53 (84%) 0.25 Sepsis 1 (4%) 3 (5%) 0.9 Eenteritis 1 (4%) 3 (5%) 0.5 Cytomegalovirus- reactivation / infections 4 (16%) 9 (14%) 0.8 Pneumocystis pneumonia 1 (4%) 0 (0%) 0.1 2nd malignancy Hematologic 1 (4%) 0 (0%) 0.9 Solid cancer 0 (0%) 2 (3%) Death <100 days 1 (4%) 2 (3%) 0.7 prophylactic use of trimethoprim/sulfamethoxazole and died of acute respiratory failure caused by Pneumocystis jiroveci on day 89. Two patients in the control group died on days 6 and 8 after auto-sct due to sepsis caused by Pseudomonas aeruginosa. Treatment-related mortality (TRM) was therefore documented in one elderly patient (4%) and two controls (3%) (p=0.7). Cytomegalovirus (CMV) reactivation / infections occurred in 16% of the patients in the elderly group and 14% of the patients in the control group (p=0.8). During follow-up after auto-sct, three patients developed second malignancies, including a myelodysplastic syndrome in a 67-year-old man, endometrial cancer in a 62-year-old woman and prostate cancer in a 61-year-old man during two months of salvage therapy with lenalidomide. We also compared the incidence of non-hematological toxicities between two subgroups of elderly patients who received different doses of MEL (Table 5). Ten patients received MEL at a dose of mg/m 2 and 15 patients received MEL at a dose of mg/m 2. The patients receiving mg/m 2 of MEL were older than those receiving mg/m 2 of MEL (median 71 vs. 67 years; p= ). The incidence of grade 2-4 non-hematological toxicities in patients receiving mg/m 2 of MEL was significantly lower than that in the patients receiving mg/m 2 of MEL (60% vs. 93%; p=0.04) (Table 5). As a result, the rate of achieving CR or VGPR with mg/m 2 of MEL was comparable to that observed with mg/ m 2 of MEL (40% vs. 67%; p=0.19) (Table 5). Salvage therapy Table 5. Comparison of Two Groups Received Different Melphalan (MEL) Doses for the Elderly Patients MEL 120>/= MEL >/=180 (n = 10) (n = 15) p value Age, median (range) 71 (67 76) 67 (65 70) Incidence of grade 2-4 toxisities All Grade (60%) 14 (93%) 0.04 Febrile neutropenia, n (%) 4 (40%) 15 (100%) Cardiac, n (%) 0 (0%) 4 (27%) 0.07 Renal, n (%) 1 (10%) 1 (7%) 0.7 Electrolite, n (%) 1 (10%) 3 (20%) 0.5 Diarrhea, n (%) 6 (60%) 14 (93%) 0.04 Anorexia, n (%) 6 (60%) 11 (73%) 0.4 Results Achieving CR or VGPR 4 (40%) 10 (67%) 0.19 We evaluated the fact that the included patients received neither consolidation nor maintenance therapy. During follow-up after auto-sct, 15 patients (60%) in the elderly group and 42 patients (67%) in the control group met the criteria for PD or Rel (Table 3). Three patients in the elderly group and two patients in the control group received salvage therapy with conventional chemotherapy regimens. The majority of patients with disease progression received salvage therapy with novel agents (elderly group: 44%, control group: 52%). Regarding the salvage setting, one elderly patient and three controls received auto-sct, while one elderly patient and three control patients underwent allogeneic SCT. Discussion A recent meta-analysis of randomized studies showed a significant benefit with auto-sct in terms of prolonged PFS (10). In addition, there is evidence of a quality of life (QOL) advantage in patients who receive auto-sct compared to chemotherapy alone (11) or delayed auto-sct (12). The current study demonstrated the occurrence of preferential engraftment in the elderly group, with an incidence of grade 3-4 non-hematological toxicities that did not differ from that observed in the control group. In addition, the rate of achieving CR or VGPR was 60% in the elderly group and 83% in the control group. According to the results of a previous study, the rate of achieving CR or VGPR is 49% in patients receiving single auto-sct and 63% in patients receiving tandem auto-sct (13). Combination therapy with novel agents followed by auto-sct produces a higher rate of achieving CR or VGPR (82%) (14). In the current study, four (16%) patients in the elderly group and 14 (22%) patients in the control group received novel agents before auto-sct. In addition, eight (32%) patients in the elderly group and 35 (56%) patients in the control group received tandem auto-sct. Incidentally, the number of patients receiving both induction treatment with novel agents and tandem auto-sct was only one in the elderly group and six in the control group. Accordingly, a substantial portion of patients received either novel agents containing therapy or tandem auto-sct, which may have contributed to the superior response rate observed in the current study. As a result, PFS in the elderly group was confirmed to be equal to that observed in the control group (17.1 vs months, p=0.26). In the elderly group, the median PFS from the beginning of induction treatment was 23.3 months, which appears to be superior to the median PFS of 17.8 months with MP therapy alone reported in IMF (7). 67

6 Table 6. Summary of Published Data of Autologous Stem Cell Transplantation for Elderly Patients with Multiple Myeloma Auther Age median, (range) Induction PBSC mobolization Conditioning Number TRM n (%) CR (%) Median PFS (months)# Median OS (months)# Siegel [16] 67 (65 78) Not described HD-CY+G or G 1st MEL (8) nd MEL 200/140+TBI 15/13 0 Palumbo [4] 64 (60 75) VAD HD-CY+G MEL 100, 1st/2nd/3rd 71/68/ * Sirohi [17] 67 (66 74) VAMP/CVAMP, MP, CY G MEL (19) Badros [6] 72 (72 83) Not described HD-CY+G 1st MEL (16) nd MEL 200/140 7/4 1 (9) 1st MEL (2) 27 2nd MEL 200/140 7/9 2 (13) Reece [18] 63 (60 73) MP, VAD - MEL130>/ /190-18/45/18 5 (6) Palumbo [5] -(65 70) VAD HD-CY+G MEL * Jantunen [19] 68 (65 73) VAD HD-CY+G MEL * Kumar [20] 71 (70 75) Not described G-CSF MEL 200/140 23/10 1 (3) 42* Bashir [21] 72 (72 80) Various, Thalidomide G-CSF MEL 140, 180, 200 8/21/55 3 (4) Current 67 (65 76) VAD etc. HD-CY or VP16+G, G MEL / /10 1 (4) Abbreviations; VAD: vincristine and doxorubicin combined with dexamethasone, MP: melphalan and prednisolone, VAMP: MP plus vincristine and doxorubisin, CVAMP: VAMP plus cyclophosphamide, CY: cyclophosphamide, HD: high dose, G: granulocyte stimulating factor, VP16: etoposide, TBI: total body irradiation, MEL: Melphalan mg/ m 2, TRM: treatment related mortality, CR: complete response, VGPR: very good response, PFS: progression free survival, OS: overall survival, #Survivals were calculated from the 1st SCT except for reference [4] and [5], both of which from the beginning of initial treatment. *Immunofixation negativity was not used as a criterion for complete response. In the current study, when calculated from the beginning of induction treatment, the median OS was 47.0 months and the 3-year OS rate was 81%. Regarding elderly patients receiving MP therapy alone, the median OS calculated from the time of randomization was 33.2 months in IMF (7). According to the Velcade as Initial Standard Therapy in Multiple Myeloma study (VISTA) study, the median OS was not reached with bortezomib-melphalan-prednisone (VMP) and was 43 months with MP, while the 3-year OS rates were 68.5% vs. 54.0% (15). Because of the limitation of the current analysis being retrospective in nature, it is not appropriate to compare these results directly. At least in part, the results of the current study imply that selected elderly patients can receive benefits from auto-sct, which might be superior to chemotherapy. Several retrospective studies have also reported encouraging data on auto-sct in elderly patients with MM (summarized in Table 6) (4-6, 16-21). In the current study, 88% of the elderly patients received conventional chemotherapy without novel induction agents. The results of four studies (summarized in Table 6) that used conventional induction regimens without novel agents (2, 17-19), showed a TRM ranging between 0% and 19% and a median PFS ranging between 15 and 34 months. These results compare favorably with those of the current study (4% and 17 months, respectively). The eligibility criteria for selecting elderly myeloma patients to receive auto-sct should be discussed. In the IFM trial, 83% of the patients in the high-dose MEL arm received cyclophosphamide, while only 70% underwent auto-sct; however, there were no treatment-related deaths after auto-sct (7). The patients who maintained good performance status without experiencing severe adverse events during induction treatment and high-dose cyclophosphamide therapy were selected to receive auto-sct (7). In this report, we concretely described the conditions of 25 elderly patients prior to undergoing auto-sct. All patients had successfully harvested a CD34+ cell count of greater than /kg. Before the initiation of conditioning MEL, 96% of the patients had the Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 and 88% had Hematopoietic cell transplantation specific comorbidity index (HCTC) score of 0 with no signs of active infections. All patients (92%) except two exhibited an ejection fraction of >50% on echocardiography. Laboratory investigations showed a median hemoglobin level of 9.8 (range ) g/dl, a median platelet count of 216 ( ) 10 3 /μl, and a median serum creatinine level of 0.7 ( ) mg/dl. One of two patients with an impaired cardiac function suffered treatment-related death, as mentioned above; therefore, an assessment of the basal cardiac function should be included in the eligibility criteria for auto-sct. In the future, the prognostic factors in elderly patients undergoing auto-sct should be investigated. An alternative procedure has been proposed to delay auto- 68

7 SCT at the time of relapse, although it should be noted that elderly patients would age if the procedure of auto-sct was delayed. In fact, auto-sct should be performed as early as possible in elderly patients in order to attain improved QOL, if it has been determined that a patient will definitely receive this treatment. Regarding tandem auto-sct in the era of novel agents, a meta-analysis of data pooled from controlled prospective trials failed to show any survival benefits compared to single SCT (22). This finding indicates that tandem auto-sct may no longer have a significant impact on survival in the era of novel agents. In general, tandem auto-sct is associated with a statistically significant increase in TRM (18); therefore, single transplantation should be suitable for elderly patients eligible for auto-sct. The standard regimen for stem cell mobilization in younger patients with MM consists of CY followed by granulocyte colony-stimulating factor (G-CSF) administration. Compared to the intermediate dose of CY at 3-4 g/m 2, a dose reduction to CY to 1.5 g/m 2 may reduce the incidence of febrile neutropenia, although the yield of CD34+ cells harvested would be lower (23). In the current study, 10 elderly patients (one patient older than 70 years) received 4 g/m 2 of CY for stem cell mobilization, while eight elderly patients (five patients older than 70 years) received a decreased dose of CY of 2-3 g/m 2 (Table 2). The incidence of febrile neutropenia (78% vs. 68%; p=0.7) and the harvested yield of CD34+ cells (median 4.3 vs /kg; p=0.09) did not differ significantly between these patient groups. A reduced dose of CY can be administered safely to elderly patients, especially those older than 70 years. A previous study of patients with MM aged 70 years or older showed that G-CSF alone can safely mobilize CD34+ cells (24). In the current study, a sufficient number of CD34+ cells ( /kg) was collected using G-CSF alone in four elderly patients (aged years) without significant toxicity. Accordingly, G-CSF alone may be an alternative method to collect autologous peripheral blood stem cells for elderly patients. On the other hand, a recent retrospective study (25) suggested that the CY regimen exhibits an anti-myeloma effect; therefore, the selection of mobilization methods should be balanced with regard to efficacy and toxicity, especially in elderly patients. We also evaluated the dose of MEL in the conditioning regimen used in the elderly patients. The dose of MEL was reduced from 200 mg/m 2 to less than 120 mg/m 2 in 10 of the 25 elderly patients, primarily because of the patients advanced age and fragility, as judged by each physician. As shown in Table 5, our results demonstrated a lower rate of grade 2-4 non-hematological toxicities in the elderly patients who received mg/m 2 of MEL compared to that observed in the patients who received the full dose of 200 mg/ m 2 (60% vs. 93%, p=0.04), while the rate of achieving CR or VGPR did not differ significantly. Table 6 highlights the association between the dose of MEL and the TRM reported in previous studies. The TRM for 200 mg/m 2 of MEL is either 19% (17) or 16% (6), while that for 100 mg/m 2 of MEL is 0% (2) and that for 140 mg/m 2 of MEL is 2% (6). In addition, the survival outcomes of patients undergoing auto-sct with 140 mg/m 2 of MEL were not inferior to those of patients receiving 200 mg/m 2 of MEL when compared in a study by Badros et al. (6). Taken together, these results support a dose reduction of MEL to mg/m 2 in elderly patients in order to avoid significant toxicities. Finally, we should discuss the duration of survival after disease progression, which tended to be shorter in the elderly group than in the control group (median 18.6 months vs months, p=0.08). The utilization rates of novel agents as salvage therapy were similar between the two groups. However, the number of administered salvage therapy lines was fewer in the elderly group than in the control group (mean 1.6 vs. 2.3 lines, p=0.038). In addition, 24% of the PD and relapsed patients in the control group received bortezomib combined with chemotherapeutic agents, while only 13% of similar patients in the elderly group receiving this therapy. Accordingly, the tendency toward shorter survival after PD in elderly patients may indicate the necessity for innovative treatment modalities after SCT, rather than being related to the negative impact of auto-sct itself. The current study provides preliminary evidence for the efficacy of auto-sct in elderly patients with MM. In general, achieving complete remission is an important target for prolonged survival irrespective of age (26); however, it is also important to consider the substantial toxicity associated with high-dose therapy in frail patients. In addition, prolonged therapy with novel agents can induce the accumulation of toxicities and may often impair QOL. As for elderly patients with a preserved organ function, the development of auto-sct using an adjusted dose of conditioning MEL combined with novel agents for enhanced safety is desirable in order to achieve a better response and prolonged survival. A prospective study using strict eligibility criteria in elderly patients is required to evaluate the outcomes of this treatment regime and to clarify the prolongation of treatmentfree intervals without impaired QOL in the era of novel agents. The authors state that they have no Conflict of Interest (COI). References 1. 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