Age 40 Years and Under Does Not Confer Superior Prognosis in Patients with Multiple Myeloma Undergoing Upfront Autologous Stem Cell Transmplant

Age 40 Years and Under Does Not Confer Superior Prognosis in Patients with Multiple Myeloma Undergoing Upfront Autologous Stem Cell Transmplant Parneet K. Cheema, Sahar Zadeh, Vishal Kukreti, Donna Reece, Christine Chen, Suzanne Trudel, Joseph Mikhael Multiple myeloma (MM) rarely occurs in patients 40 years of age and younger. This young age has been reported to correlate with improved survival in patients with MM. The objective of this study is to describe presenting features and outcomes of patients #40 years of age with MM who undergo autologous stem cell transplantation (ASCT) as first-line treatment, and compare overall survival (OS) and progression free survival (PFS) to patients aged 41-65 years. We performed a retrospective institutional review of all patients #40 years of age and 41-65 years of age at the time of diagnosis of MM who had undergone upfront ASCT from January 1, 1990, to July 31, 2007. Thirty-eight patients #40 years of age and 608 patients aged 41-65 were identified. There was a high rate of plasma cell leukemia (PCL) in young patients at 11% compared to the reported rate of 2%-4%. At diagnosis, there was an increased rate of renal failure in the young cohort compared to patients aged 41-65 years at 25% versus 16% and Bence Jones proteinuria at 81% versus 51%. The rate of complete or partial response was similar between the groups at 79% and 83% in the young and older cohorts, respectively. Median PFS post-asct was 22.0 months (95% confidence interval [CI]: 16.1, 28.0), versus 26.9 months (95% CI: 24.0, 29.8) for patients aged 41-65 years (P 5.66). Median OS from date of ASCT was also similar to those over 40 years: 68.1 months (95% CI: 39.0, 97.2) versus 80.7 months (95% CI: 68.1, 93.4); P 5.90. Treatment-related mortality (TRM) was low at 2.6% and 2.3% in the young and older cohorts, respectively. Despite previous reports that young age is a positive prognostic marker, our study found OS post-asct is equivalent to those aged 41-65 years. This study emphasizes the importance of developing strategies to better the outcomes of young patients with MM. Biol Blood Marrow Transplant 15: 686-693 (2009) Ó 2009 American Society for Blood and Marrow Transplantation KEY WORDS: Autologous stem cell transplantation, Young patients, Multiple myeloma INTRODUCTION Multiple myeloma (MM) is a malignant plasma cell disorder primarily of the elderly, with a peak incidence between 60 and 70 years of age [1,2]. It is uncommon in persons younger than 40 years, representing only 2% of all patients diagnosed with MM [2,3]. Younger age has been reported to correlate with improved survival, and has been recognized as an important prognostic factor From the Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, Arizona. Financial disclosure: See Acknowledgments on page 691. Correspondence and reprint requests: Joseph Mikhael, MD, Division of Hematology/Oncology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259 (email: mikhael.joseph@ mayo.edu). Received August 13, 2008; accepted February 21, 2009 Ó 2009 American Society for Blood and Marrow Transplantation 1083-8791/09/156-0001$36.00/0 doi:10.1016/j.bbmt.2009.02.013 [2,4-7]. Chromosomal patterns have been analyzed in patients \45 years of age and compared to older cohorts, and no significant difference between the groups have been found, suggesting that MM in young patients does not represent a distinct biologic entity and does not explain the positive prognostic factor [8]. MM in young patients was initially thought to have a more indolent course with atypical presentations such as multiple solitary or extramedullary plasmacytomas, increased osteolytic lesions, lower serum or urinary monoclonal proteins, and few or no plasma cells in the bone marrow [9-11]. However, Blade and colleagues [3] disputed this by publishing a series of 72 patients younger than 40 years of age with MM who had presenting features and response to therapy similar to those reported in series of MM with older patients. Despite the similarities, a median survival of 54 months was observed, which suggested improved survival compared to the general MM population, which had an overall survival (OS) of 2-3 years at that time [12-14]. In that cohort, only 9 patients 686

Biol Blood Marrow Transplant 15:686-693, 2009 Age Does Not Confer Superior Prognosis in Patients with MM 687 underwent autologous stem cell transplantation (ASCT), of which only 3 had upfront ASCT. As ASCT remains the standard of care in eligible patients as upfront therapy, this may not reflect the true prognosis of these patients undergoing this modality of treatment. Indeed, 2 randomized controlled trials comparing conventional chemotherapy to high-dose chemotherapy with ASCT rescue as initial therapy in MM have shown improvement in event free survival (EFS) and OS in patients under the age of 65 years [15,16]. More recently, patients younger than 50 years of age with MM were compared to patients 50 years and older who underwent treatment with either conventional chemotherapy or upfront ASCT and found that young patients had a significantly longer survival with either treatment modality [4]. The standard of care at our institution is to offer upfront ASCT for all suitable patients under the age of 65 years diagnosed with MM. Given that young patients rarely have contraindications to ASCT and may be able to better tolerate high-dose therapy, almost all patients #40 years of age undergo ASCT. The objective of this study is to describe presenting features and outcomes of patients #40 years of age with MM who undergo ASCT as first-line treatment and compare OS and PFS to an older cohort. METHODS Patients Patients were identified from the Princess Margaret Hospital (PMH) ASCT database. All patients aged 40 years or less at the time of diagnosis of MM that underwent ASCT from January 1, 1990, to August 1, 2007, were included in the study. PMH is a referral center for peripheral hospitals, and presenting data was used from the referring centers when available. Only patients who underwent upfront ASCT for the diagnosis of MM were included. Patients who had undergone ASCT as salvage therapy and patients who had received chemotherapy for smoldering myeloma or solitary plasmacytoma were excluded from the study. This patient group was compared to patients aged 41-65 years who were identified by the PMH ASCT database, and had also underwent upfront ASCT. Criteria for a Response and Study Definitions Response to treatment and progression were assessed using the European Blood and Bone Marrow Transplantation (EBMT) criteria [17]. Response to transplantation was taken at the closest follow up visit to 100 days post-asct. Anemia was defined as a hemoglobin \12 g/dl; hypercalcemia defined as a corrected calcium $2.75 mmol/l; and renal failure as a creatinine $177 mmol/l. Plasma cell leukemia (PCL) was defined as the presence of.20% plasma cells in peripheral blood and an absolute plasma cell count more than 2 10 9 /L [18]. Time of neutrophil engraftment was defined as first of 2 consecutive days with an absolute neutrophil count (ANC).0.5 10 9 /L. Time of platelet engraftment was defined as first of 3 consecutive days with platelets.20 10 9 /L and platelet transfusion independent for 7 days. Statistical Analysis OS was measured from date of diagnosis and from date of ASCT to date of last follow-up or death. PFS was calculated for all patients from date of ASCT to time of relapse, death, or date the patient was last known to be in remission. Curves for OS and PFS were plotted according to the method of Kaplan and Meier, and were compared to patients 41-65 years of age by the log-rank test. For all tests, a 2-sided P-value of #.05 was considered statistically significant. Calculations were performed using SPSS/PC (SPSS Inc., Chicago IL). RESULTS Clinical and Laboratory Data Forty-three patients aged #40 years at time of diagnosis of MM were identified. Five patients were excluded for undergoing salvage ASCT or ASCT.18 months from diagnosis. Thirty-eight patients were included in the analysis. All patients identified through the ASCT database had presented with MM requiring treatment; none of the young patients in this study presented with monoclonal protein of undetermined significance (MGUS), smoldering myeloma, or solitary plasmacytomas that had progressed to MM. The median age was 37.2 years (range: 29.3-40.1 years), and 23 (61%) were males. Six hundred eight patients in the comparator group were identified with a median age of 56.4 years (range: 41.1-65.5 years), and 365 (60%) were males. Table 1 shows the distribution according to the M-protein type in young patients. A majority had IgG MM (53%), followed by light chain (LC) MM at 21%. The remainder of patients had IgA or IgD MM at 18% and 8%, respectively. Four patients (11%) had evidence of PCL at diagnosis. A majority of patients had k LC type (74%). No patients had evidence of systemic amyloidosis (AL). Laboratory features at presentation of patients #40 years of age are shown in Table 2. Sixty-seven percent of young patients were anemic. Twenty-five percent of young patients had renal failure at time of diagnosis compared to 16% in the older cohort. The rate of hypercalcemia was similar in the young and older cohorts at 23% and 22%, respectively. The

688 P. K. Cheema et al. Biol Blood Marrow Transplant 15:686-693, 2009 Table 1. Characteristics of Patients #40 Years of Agewith MM Characteristic Age year Median 37.2 Range 29.3-40.1 Males no. of patients (%) 23 (61) Monoclonal protein no.of pts (%) Light chains IgG 20 (53) 17 3 Light chain 8 (21) 4 4 IgA 7 (18) 6 1 IgD 3 (8) 1 2 Plasma cell leukemia no. of patients (%) 4 (11) MM indicates multiple myeloma. rate of $30% plasma cells in bone marrow was comparable at 72% in the young cohort and 74% in the older cohort. Bence Jones proteinuria was more common in the younger cohort at a rate of 81% compared to 51% in the older cohort. A majority of young patients (76%) and older patients (74%) had radiologic evidence of bone disease at diagnosis. In patients #40 years of age, 3 patients (8%) presented with spinal cord compression, and 16 (42%) patients underwent palliative radiation for bone disease prior to ASCT. Of the 21 patients in the young cohort that staging according to the International Staging System (ISS) could be obtained, 48% of patients were stage 1 at diagnosis. Ten young patients had cytogenetics reported, of which 9 had abnormal cytogenetics. Three patients had deletion of chromosome 13, 3 had t(11;14), and 1 patient had both. k l Table 3. ASCT Parameters of Patients #40 Years of age Factor No. of Patients (%) Median Range First line induction therapy (n 5 38) VAD 25 (66) 4 cycles 2-7 Dexamethasone on a VAD schedule 5 (13) Melphalan and Prednisone 5 (13) Patients receiving $2 lines of 16 (42) induction therapy (n 5 38) Patients that progressed while waiting 5 (13) for ASCT (n 5 38) Cyclophosphamide and 33 (87) G-CSF mobilization (n 5 36) Conditioning Regimen (n 5 38) Melphalan 200 mg/m 2 24 (63) Melphalan, VP16, ±TBI 10 (26) Busulfan and cyclophosphamide 4 (11) Type of SCT (n 5 38) Peripheral blood 37 (97) Peripheral blood + bone marrow 1 (3) CD34 + 10 6 cells/kg (n 5 29) 7.52 3.0-73.3 Time to ASCT from diagnosis, months (n 5 38) 8.5 4.8-17.9 VAD indicates vincristine, adriamycin, and dexamethasone; ASCT, autologous stem cell transplantation; SCT, stem cell transplantation; G-CSF, granulocyte-colony stimulating factor; TBI, total body irradiation. *2 pts had planned Melphalan and Prednisone followed by VAD. Transplantation Details of the transplantation for patients aged #40 years of age are summarized in Table 3. As induction chemotherapy, 66% of patients received vincristine, adriamycin, and dexamethasone (VAD), with a median of 4 cycles (range: 2-7), 13% received highdose dexamethasone alone on a VAD schedule, and 13% received melphalan and prednisone (MP). Two patients received both MP and VAD as initial therapy. Eighty-seven percent of patients received cyclophosphamide (Cy) and granulocyte-colony stimulating factor (G-CSF) as mobilizing agents. Sixty-three percent of patients were conditioned with melphalan (Mel) 200 mg/m 2 in either 1 dose or 2 doses of 100 mg/m 2. Twenty-six percent of patients received Mel 160 mg/m 2, VP16 60 mg/kg, 6 total body irradiation (TBI), and 11% received busulfan (Bu) and Cy at a total dose of 14 mg/m 2 and 120 mg/kg, respectively, as part of the Cell Pro Study [19]. All patients received peripheral blood stem cells (PBSCs), with 1 patient receiving bone marrow stem cells in addition to their PBSCs. Median infused CD34 1 cell dose was 7.52 10 6 cells/kg (range: 3-73.3). Median time to ASCT from date of diagnosis was 8.5 months (range: 4.8-17.9 months). Eleven percent of patients had a complete remission (CR) after first-line induction that increased to 13% at the time of ASCT, and 55% had a partial remission (PR) following induction, which also increased to 63% at the time of ASCT Table 4. Table 4. Response Rates in Patients with MM Undergoing Upfront ASCT Table 2. Laboratory Data at Time of Diagnosis of MM in Patients #40 Years of Age # 40 Years, n 5 38 (%) 41-65 Years, n 5 192 (%) Factor No. of Patients Median Range Limit Response Following First Induction Treatment Status Prior to ASCT Post-ASCT Post-ASCT Hemoglobin (g/dl) 33 10.4 39-147 <12, 67% Calcium (mmol/l) 31 2.45 1.99-3.67 $2.75, 23% Creatinine (mmol/l) 32 93 53-894 $177, 25% Bone marrow plasma cells (%) 32 65 4-100 $30%, 72% Albumin (g/l) 24 39.5 22-48 <38, 38% b-2-microglobulin (mmol/l) 20 172 31-1100 >300, 20% Bence Jones protein 31 Present, 81% MM indicates multiple myeloma. CR 4 (11) 5 (13) 11 (29) 33 (17) PR 21 (55) 24 (63) 19 (50) 126 (66) MR 7 (18) 7 (18) 2 (5) 4 (2) SD 3 (8) 2 (5) 3 (8) 15 (8) PD 3 (8) 0 2 (5) 8 (4) MM indicates multiple myeloma, ASCT, autologous stem cell transplantation; CR, complete response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease.

Biol Blood Marrow Transplant 15:686-693, 2009 Age Does Not Confer Superior Prognosis in Patients with MM 689 Table 5 illustrates safety endpoints following ASCT. Median time to neutrophil engraftment was 11 days (range: 9-18 days), and median time to platelet engraftment was 11 days (range: 6-15 days). One patient failed to engraft platelets, and 2 patients platelets never fell below 20 10 9 /L. Of the 22 patients in which transfusion data was available, 41% and 55% required packed red blood cells (PRBC) and platelet transfusions, respectively. Median PRBC transfusions was 2 units (range: 2-4), and median platelet transfusions was 5 units (range: 5-15). The rate of febrile neutropenia was 82% (28 of 34 patients). Median length of hospital admission from date of ASCT was 15 days (range: 11-43 days). Post-ASCT, 49% of patients received maintenance therapy. Regimens varied from combinations of interferon, prednisone, dexamethasone, and thalidomide. Five (13%) of the patients went on to tandem ASCT. Relapse and Survival The median time to best response following ASCT was recorded at 3 months post-asct (range: 31-152). Table 4 illustrates response rates post ASCT. In the young cohort, 29% achieved a CR, 50% a PR, 5% a minimal response (MR), 8% had stable disease (SD), and 5% had progressive disease (PD). Following tandem ASCT, 1 patient with MR and 1 patient with PR obtained a CR. Seventeen percent of patients aged 41-65 achieved a CR, 66% a PR, 2% an MR, 8% had SD, and 4% had PD. The median duration of follow-up among survivors was 53 months (range: 12-198 months). Table 6 displays study outcomes. Median OS from date of diagnosis in patients #40 years of age was 81.4 months (95% CI: 49.0, 113.1). Although there was a trend to shortened survival, there was no difference in median OS from date of ASCT when patients #40 years of age were compared to the cohort of patients 41-65 years of age (68.1 months [95% CI: 39.0, 97.2] versus 80.7 months [95% CI: 68.1, 93.4], P 5.90), nor was there a difference in median PFS from date of ASCT (22.0 months [95% CI: 16.1, 28.0] versus 26.9 months [95% CI: 24.0, 29.8]; P 5.66) (Figures 1 and 2). The actuarial survival of patients #40 years of age at 5 and 10 years from date of ASCT was 60% and 43%, respectively, and PFS at 5 and 10 years was 31% and 25%, respectively. Subgroup analysis, revealed that, although not statistically significant, there was a trend to improved median OS of patients #40 years of age with ISS stage 1 at diagnosis compared those.1 (85.6 versus 33.4 months; P 5.22). There was no statistically significant difference in median OS from date of ASCT if young patients were either in CR or PR post-asct compared to MR, SD, and PD (79.0 versus 42.6 months; P 5.20), whereas those young Figure 1. Kaplan-Meier estimates of OS in patients with MM #40 years of age compared to patients aged 41-65 years who underwent upfront ASCT. patients that achieved CR or PR post-asct appreciated a statistically significant longer PFS (30.9 versus 8.0 months, P 5.02). One patient #40 years of age died from sepsis within 100 days of ASCT, yielding a treatment-related mortality (TRM) of 2.6%. The older cohort experienced a similar TRM, with 14 deaths within 100 days of ASCT (2.3%). Main causes of death in the young cohort were from PD and infection (Table 7). DISCUSSION This is the first series to report that very young patients with MM undergoing upfront ASCT do not have superior prognosis compared to an older cohort. All patients in this study presented with MM without Figure 2. Kaplan-Meier estimates of PFS in patients with MM #40 years of age compared to patients aged 41-65 years who underwent upfront ASCT.

690 P. K. Cheema et al. Biol Blood Marrow Transplant 15:686-693, 2009 Table 5. Safety Endpoints in Patients #40 years of Age with MM Undergoing Upfront ASCT Endpoint No. of Patients (%) Median Range Neutrophil engraftment (n 5 32) 32 (100) 11 days 9-18 Platelet engraftment (n 5 31) 30 (97) 11 days 6-15 PRBC transfusions (n 5 22) 9 (41) 2 units 2-4 Platelet transfusions (n 5 22) 12 (55) 5 units 5-15 Febrile Neutropenia (n 5 34) 28 (82) Days of hospitalization (n 5 35) 15 11-43 MM indicates multiple myeloma; PRBC, packed red blood cells; ASCT, autologous stem cell transplantation. a prior plasma cell disorder. Presenting features of anemia and hypercalcemia in this patient population were comparable to the general population with MM [2] and to reported rates in patients \40 years of age [3]. In our study, IgG MM was found in more than half the patients, which again, is consistent with the general MM population; however, as previously reported in young patients, LC MM occurred at a higher rate than IgA MM, unlike the older population, and there was an increase in IgD MM at 8% compared to reported rate of 2% [20,21]. IgD MM has been commonly associated with renal failure, and a majority have Bence Jones proteinuria [22]; only 1 of the 3 patients with IgD MM had renal failure at diagnosis, but all had Bence Jones proteinuria. Chromosome 13 deletion, a common chromosomal abnormality in MM that has been associated with shortened PFS following ASCT [23], was found in one-third of our patients, again similar to the reported rate in various age groups [8]. Despite the similarities to the general MM population, a few clinical parameters suggest that MM in young patient may present more aggressively. There was a high rate of Bence Jones proteinuria at 81%, and a high rate of renal failure with 25% of patients having a creatinine $177 mmol/l. The rate of renal failure was similar to the report by Blade and colleagues in Table 6. Study Outcomes Endpoint #40 Years Months (95% CI) n 5 38 41-65 Years Months (95% CI) n 5 608 P-Value Median OS from 81.4 (49.0, 113.1) date of diagnosis Median OS from ASCT 68.1 (39.0, 97.2) 80.7 (68.1, 93.4).9 Median PFS from ASCT 22.0 (16.1, 28.0) 26.9 (24.0, 29.8).66 Median OS from ASCT CR + PR (n 5 30) 79.0 (51.4, 106.6).2 MR, SD, PD (n 5 7) 42.6 (0, 88.6) Median PFS from ASCT CR+PR (n 5 30) 30.9 (5.2, 56.5).02 MR, SD, PD (n 5 7) 8.0 (5.2, 10.9) ASCT indicates autologous stem cell transplantation; OS, overall survival; PFS, progression free survival; CR, complete response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease; CI, confidence interval. Table 7. Causes of Death in 38 Patients #40 Years of Age with MM Cause No. of Patients Myeloma progression 7 Infection 5 Aspiration pneumonia 1 Hemorrhagic cystitis/renal failure 1 Pulmonary and brain hemorrhages 1 Unknown 2 MM indicates multiple myeloma. patients \40 years of age [3], but higher than those aged 41-65 years in our series at 16% and previously reported in patients younger than 50 years of age at 15% [4]. There was also an increased risk of PCL at 11% compared to the reported incidence of 2%-4% [24-26]. Although 76% of our young patients had radiologic evidence of bone disease at diagnosis, which is comparable to the rate of 79% found in the general MM population [2], there was a high rate of spinal cord compression at presentation at 8%. These differences may simply suggest a delay in diagnosis of young patients with MM or highlights the aggressive nature of this disease in young patients. We report a 79% combined CR and PR rate following ASCT in young patients. This appears to be similar to response rates reported in the literature following ASCT in patients \65 years of age with MM (81%-86.6%) [15,16], and similar to patients in this series aged 41-65 years. However, in our study there did appear to be a slightly higher rate of CR in the younger cohort. Although clinical response is desirable and is commonly considered an important prognostic indicator for survival [15], neither the rapidity nor degree of response have reliably predicted survival [27,28]. Our study found that although young patients with CR and PR appreciated a statistically significant longer PFS, a statistically significant OS difference was not found. However, there was a trend toward improved survival in patients achieving a CR and PR, which is in keeping with previous reports. Following ASCT in patients with MM\65 years of age the median OS from date of diagnosis has been reported at 54.1 to 56 months [15,16]. We report a median OS of 81 months in patients #40 years of age; although this OS may suggest that patients #40 years of age have improved survival, when compared to the patients 41-65 years of age in our study, there was no significant difference between the 2 groups. In a recent study of outcomes in patients \50 years of age compared to patients $50 years of age undergoing upfront ASCT for MM, a significantly longer survival of 90 months in the young cohort opposed to 68.4 months in the $50 age group was found [4]. When they specifically looked at patients\40 years of age, the relative survival was similar to that of patients \50 years of age at 87.6 months. This discrepancy with our study may be explained by worse outcomes in our

Biol Blood Marrow Transplant 15:686-693, 2009 Age Does Not Confer Superior Prognosis in Patients with MM 691 young population compared to their cohort. Our study did include patients with de novo PCL, which has been associated with worse prediction of survival and poor response rates [22,29]; the rate of PCL in the aforementioned study was not reported. Alternatively, given that the 10 year actuarial survival in the young cohort undergoing upfront ASCT was identical in both studies at 43%, may indicate that our older cohort aged 41-65 years had improved outcomes compared to their comparator group. The lack of increased OS in younger patients in our study was also seen in PFS. The patients in our study experienced less than 2 years of PFS post-asct. EFS from diagnosis of MM has been reported at 27 to 32 months in patients\65 years of age that undergo upfront ASCT [15,16]. Unfortunately, despite their young age, PFS was no different to those patients 41-65 years of age transplanted or followed at our institution. It is possible that with the introduction of upfront ASCT it has eliminated the OS and PFS advantage between the 2 groups. Modalities to lengthen OS and PFS are required in this young patient population. Maintenance therapy was used in only half the patients following ASCT. Although, the role of maintenance therapy is controversial because it has not consistently shown improvement in PFS or OS [30-34], it may be an option for those that did not achieve a good response following ASCT. Several randomized trials investigating tandem ASCT have shown to improve OS and EFS [35-38], andonly 5 patients in this study had received this treatment. Also, autologous transplantation followed by dose-reduced allogeneic stem cell transplantation has shown to be safe and increase CR rates [39-41]; however,improvement in EFS and OS compared to tandem autologous transplantation has shown contradictory results in randomized controlled trials [41-43]. Finally, promising newer agents such as thalidomide, lenalidomide, and bortezomib are changing frontline therapy in the context of ASCT. Thalidomide, in combination with dexamethasone, yielded superior response and very good PR (VGPR) rates compared to dexamethasone-based regimens [44-48]. Compared to VAD, bortezomib plus dexamethasone also significantly improved the rate of CR/VGPR before ASCT at 47%, and after ASCT at 62% [49]. There is limited data with the use of lenalidomide as front-line therapy in ASCT eligible patients; a small pilot study of lenalidomide plus dexamethasone in newly diagnosed patients showed an overall response rate of 91% with 56% obtaining CR/VGPR [50]. However, it is too early to determine whether this better tumor reduction after induction treatment with novel agents will translate into longer PFS and OS, particularly in this very young population that appears to present with aggressive features. Subgroup analysis or new studies to establish the role and benefit of these novel agents in very young patients is needed. Our study confirmed that upfront ASCT in patients #40 years of age is safe, with a low TRM at 2.6%, which is comparable to the older cohort in this study and to the reported rate of 2%-4% [15,16]. Results of ASCT have improved largely through reduction of TRM using modern supportive care, including mobilized PBSCs in place of marrow and preparation with Mel rather than radiation-containing regimens [51-53]. Other safety parameters such as days to engraftment, number of transfusions required, and febrile neutropenia rates did not differ from those reported in the literature for the general MM population undergoing ASCT. ISS for MM has been validated to provide useful prognostic groupings in variety of situations including those patients \65 years [54]. Younger patients are more likely to have ISS stage 1 at diagnosis compared to the older cohorts [4], and in our study, almost half of our young patients were found to be in this stage. Also, it has been reported that patients\40 years of age with MM that have b2-microglobulin levels\2.7 mg/l that would fall in either ISS stage I or II based on albumin levels have a significantly longer survival than those with higher levels [3]. Our study reports a strong trend toward improved OS in patients #40 years of age with stage 1 disease at 86 months versus 33 months in those with stages 2 or 3 disease. Although not statistical significance, this may have been a reflection of the small numbers in this study, or may indeed indicate uniqueness of very young patients with this disease. A limitation to this study is that all patients identified by the ASCT database presented with MM requiring treatment and went on to ASCT. This may represent patients with more aggressive disease at presentation. This study is also somewhat limited by the number of patients included, although MM under the age of 40 years is very uncommon, and very few series in this age group have been reported. This study found that patients aged 40 years and under with MM present with advanced disease, as evidenced by a high rate of PCL, renal failure, and proteinuria. Upfront ASCT is safe, and yields high response rates in young patients; however, despite reports that young age is a positive prognostic marker, PFS post-asct is \2 years, and the median OS is only 5.7 years, which is equivalent to those aged 41-65 years. It is possible that upfront ASCT in the older cohort has eliminated this prognostic advantage for those 40 years of age or younger. Although these findings need to be confirmed by large randomized controlled trials, we conclude that the need for more aggressive and safe treatments are warranted to improve survival in this young patient population. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose.

692 P. K. Cheema et al. Biol Blood Marrow Transplant 15:686-693, 2009 REFERENCES 1. Kyle RA. Long term survival in multiple myeloma. N Engl J Med. 1983;30:314-316. 2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1072 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003; 78:21-33. 3. Blade J, Kyle RA, Griepp PR. Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years. Br J Haematol. 1996;93:345-351. 4. Ludwig H, Durie BGM, Bolejack V, et al. Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group. Blood. 2008;111: 4039-4047. 5. Mileshkin L, Biagi JJ, Mitchell P, et al. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood. 2003;102:69-77. 6. Garcia-Sanz R, Gonzalez-Fraile MI, Mateo G, et al. Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients. Int J Cancer. 2004;112: 884-889. 7. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520. 8. Sagaster V, Kaufmann H, Odelga V, et al. Chromosomal abnormalities of young multiple myeloma patients (\45 yr) are not different from those of other age groups and are independent of stage according to the international staging system. Eur J Haematol. 2007;78:227-234. 9. Hewell GM, Alexanian R. Multiple myeloma in young persons. Ann Intern Med. 1976;84:441-443. 10. Lazarus HM, Kellermeyer RW, Aikawa M, Herzig RH. Multiple myeloma in young men: clinical course and electron microscopic studies of bone marrow plasma cells. Cancer. 1980;46: 1397-1400. 11. Geetha N, Jayaprakash M, Rekhanair A, Ramachandran K. Plama cell neoplasms in young. Br J Radiol. 1999;72:1012-1015. 12. Blade J, San Miguel JF, Alcala A, et al. Alternating combination VCMP/VBAP chemotherapy versus melphalan/prednisone in the treatment of multiple myeloma: a randomized multicentric study of 487 patients. J Clin Oncol. 1993;11:1165-1171. 13. Greipp PR, Lust JA. O Fallon WM, Katzmann JA, Witzig TE, Kyle RA. Plasma cell labeling index and beta 2 microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood. 1993;81:3382-3387. 14. Salmon SE, Tesh D, Crowley J, et al. Chemotherapy is superior to sequential hemibody irradiation for remission consolidation in multiple myeloma: a Southwest Oncology Group study. J Clin Oncol. 1990;8:1575-1584. 15. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996; 335:91-97. 16. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883. 17. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Br J Haematol. 1998;102:1115-1123. 18. Grogan TM, Muller-Hermelink HK, Van CB, Harris NL, Kyle RA. World Health Organization classification tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2001. 142-156. 19. Vescio R, Schiller G, Stewart AK, et al. Multicenter phase III trial to evaluate CD341 selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma. Blood. 1999;93:1858-1868. 20. Ameis A, Ko HS, Pruzanski W. M components-a review of 1242 cases. Can Med Assoc J. 1976;114:889-895. 21. Hobbs JR. Immunochemical classes of myelomatosis. Including data from a therapeutic trial conducted by a Medical Research Council working party. Br J Haematol. 1969;16:599-606. 22. Blade J, Kyle RA. Nonsecretory myeloma, immunoglobulin D myeloma, and plasma cell leukemia. Hematol Oncol Clin North Am. 1999;13:1259-1272. 23. Desikan R, Barlogie B, Sawyer J, et al. Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood. 2000;95:4008-4010. 24. Dimopoulos MA, Palumbo A, Delasalle KB, et al. Primary plasma cell leukaemia. Br J Haematol. 1994;88:754-759. 25. Garcia-Sanz R, Orfao A, Gonzalez M, et al. Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetics characteristics. Blood. 1999;93:1032-1037. 26. Noel P, Kyle RA. Plasma cell leukemia: an evaluation of response to therapy. Am J Med. 1987;83:1062-1068. 27. Blade J, Lopez-Guillermo A, Bosch F, et al. Impact of response to treatment on survival in multiple myeloma: results in a series of 243 patients. Br J Haematol. 1994;88:117-121. 28. Durie BG, Jacobson J, Barlogie B, Crowley J. Magnitude of response with myeloma frontline therapy does not predict outcome: importance of time to progression in southwest oncology group chemotherapy trials. J Clin Oncol. 2004;22: 1857-1863. 29. Witzig TE, Gertz MA, Lust JA, Kyle RA. O Fallon WM, Greipp PR. Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma. Blood. 1996;88:1780-1787. 30. Cunningham D, Powles R, Malpas J, et al. A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol. 1998;102:495-502. 31. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030. 32. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 33. Goldschimidt H, Sonneveld P, Cremer FW, et al. Joint HOVON-50/GMMG-HD3 randomized trial on the effect of thalidomide as part of a high-dose therapy regimen and as maintenance treatment for newly diagnosed myeloma patients. Ann Hematol. 2003;82:654-659. 34. Berenson JR, Crowley JJ, Grogan TM, et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002;99:3163-3168. 35. Goldschmidt H. Single vs double high-dose therapy in multiple myeloma: second analysis of the GMMG-HD2 Trial. Haematologica. 2005;90. PL8.02. 36. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495-2502. 37. Cavo MCC, Zamagni E, Tosi P, et al. Superiority of double over single autologous stem cell transplantation as first-line therapy for multiple myeloma. Blood. 2004;104:536. 38. Sonneveld P, van der Holt B, Segeren CM, Vellenga E, et al. Intensive versus double intensive therapy in untreated multiple myeloma: update analysis of the randomized phase III HOVON 24 study. Haematologica. 2005;90. PL 8.01. 39. Kroger N, Schwerdtfeger R, Kiehl M, et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood. 2002;100:755-760. 40. Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood. 2003; 102:3447-3454. 41. Rosinol L, Perez-Simon JA, Sureda A, et al. A prospective PE- THEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic

Biol Blood Marrow Transplant 15:686-693, 2009 Age Does Not Confer Superior Prognosis in Patients with MM 693 transplantation in newly diagnosed multiple myeloma. Blood. 2008;112:3591-3593. 42. Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356:1110-1120. 43. Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dosereduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006;107:3474-3480. 44. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431-436. 45. Cavo M, Zamagni Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005; 106:35-39. 46. Macro M, Divine M, Uzunban Y, et al. Dexamethasone 1 thalidomide compared to VAD as pre-transplant treatment in newly diagnosed multiple myeloma: a randomized trial [abstract]. Blood. 2006;108 (Abstract #22). 47. Lokhorst HM, Schidt-Wolf I, Sonneveld P, et al. Thalidomide in induction treatment increases the very good partial remission rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica. 2008;93: 124-127. 48. Morgan GJ, Davies FE, Owen RG. Thalidomide combinations improves response rate: results of the MRC IX study [abstract]. Blood. 2007;110 (Abstract #1051). 49. Harousseau JL, Mathiot C, Attal M, et al. Velcade/dexamethasone versus VAD as induction treatment prior to autologous stem cell transplantation in newly diagnosed patients: updated results of the IFM 2005/01 trial [abstract]. Blood. 2007;110 (Abstract #139). 50. Lacy MQ, Gertz MA, Dispenzieri A, et al. Long-term results of response to therapy, time to progression and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc. 2007;82:1179-1184. 51. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone due Myelome 9502 randomized trial. Blood. 2002;99:731-735. 52. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93:55-65. 53. Lahuerta JJ, Martinez-Lopez J, Grande C, et al. Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish registry for transplantation in multiple myeloma. Br J Haematol. 2000;109:138-147. 54. Griepp PR, San Miguel J, Durie BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23: 3412-3420.