Autologous Hematopoietic Cell Transplantation in Patients With Multiple Myeloma: Effect of Age

Accepted Manuscript Autologous Hematopoietic Cell Transplantation in Patients With Multiple Myeloma: Impact of Age Binod Dhakal, Ariel Nelson, Guru Subramanian Guru Murthy, Raphael Fraser, Daniel Eastwood, Mehdi Hamadani, Marcello Pasquini, Anita D’Souza, Parameswaran Hari PII:

S2152-2650(16)30869-2

DOI:

10.1016/j.clml.2016.11.006

Reference:

CLML 858

To appear in:

Clinical Lymphoma, Myeloma and Leukemia

Received Date: 5 September 2016 Revised Date:

4 November 2016

Accepted Date: 8 November 2016

Please cite this article as: Dhakal B, Nelson A, Guru Murthy GS, Fraser R, Eastwood D, Hamadani M, Pasquini M, D’Souza A, Hari P, Autologous Hematopoietic Cell Transplantation in Patients With Multiple Myeloma: Impact of Age, Clinical Lymphoma, Myeloma and Leukemia (2016), doi: 10.1016/ j.clml.2016.11.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH MULTIPLE MYELOMA: IMPACT OF AGE Binod Dhakal1, Ariel Nelson2, Guru Subramanian Guru Murthy1, Raphael Fraser3, Daniel Eastwood3, Mehdi Hamadani1, Marcello Pasquini1, Anita D’Souza1, Parameswaran Hari1

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Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI Division of Hematology/Oncology, Case Western University, Cleveland, OH Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI

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1. 2. 3.

Financial Disclosure and Propriety Statement: Nothing to disclose

Running title: Age and Autologous hematopoietic cell transplantation in multiple myeloma

Corresponding author:

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Key words: MM, AHCT, Age

Parameswaran Hari, MD, MS

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Professor of Medicine

Medical College of Wisconsin

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Milwaukee, WI 53226

Phone: (414) 805-4600 Fax: (414) 805- 6815

Email: [email protected]

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ABSTRACT:

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In both the novel and pre-novel agent era, high dose therapy followed by autologous hematopoietic cell transplant (AHCT) has been shown to prolong survival in multiple myeloma (MM) in randomized trials, but only included patients 65 years and younger. Given the median age at diagnosis is 66 years, it is important to know the

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outcomes of AHCT in older patients. Similarly, the definite outcomes of AHCT in very

young patients (<50 years) is also lacking as they represent a very small proportion in

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clinical trials. We analyzed a consecutive cohort of patients with MM receiving AHCT from 2000-2015 in two different age groups, old (>70 years) and young (≤50 years) and compared the outcomes. The primary objectives were to assess overall survival (OS), progression free survival, (PFS), and non-relapse mortality (NRM) in these two groups.

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Eighty-six patients were young (≤50 years), while 105 patients were old (>70 years). Young patients had better performance status and lower co-morbidity index, while majority of old patients received melphalan dose between 140-180 mg/m2. Median follow up in the young was 33 months (range, 2-164) compared to the 22.5 months (3-133) in

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the old group (p=0.02). The PFS at 1 year was 60% (95%CI 46-72) for young patients and 58 (95%CI, 45-69) for the old ones. The OS at 1 year was 92% (95% CI 84-96) for

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young and 85% (95% CI 76-91) for the older cohorts. On multivariate analysis, age did not have any effect on survival (p =0.82), but the patients with high-risk cytogenetics (HR 2.2, 95% CI 1.06-4.6, p=0.04) had worse overall mortality. High-risk cytogenetics (HR 1.2, 95% CI 1.1-3.5, p=0.004) and those with no response or progressive disease at transplantation (HR, 5.0 95% CI 1.8-13.5, p=0.02) were significantly associated with worse PFS. Age shouldn’t be a limiting factor in considering the modality of AHCT, however at the same time young patients may benefit from other additional novel

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treatment approach in the setting of clinical trials given their similar outcomes with the old patients based on our study.

Mircro-abstract:

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Autologous hematopoietic cell transplantation (AHCT) has been shown to prolong

survival in patients with multiple myeloma (MM), however adequate data is lacking in patients >70 years and less than 50 years of age. We retrospectively analyzed and

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compared the outcome of patients between the two age groups (>70 vs. ≤ 50 yrs.). Our

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study showed comparable outcomes between these two age groups.

Introduction:

Multiple Myeloma (MM) is a hematological malignancy characterized by clonal proliferation of plasma cells in the bone marrow leading to monoclonal paraproteinemia

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and resultant organ dysfunction. The median age of patients with MM is about 70 years with roughly 33% of patients 75 years or older1. Less than 5% of new diagnoses of MM are made in patients under the age of 55. Autologous hematopoietic cell transplantation

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(AHCT) is the standard of care in younger patients and is considered to be the preferred treatment for older eligible patients with MM2,3. Early high dose therapy and AHCT has

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been shown to have benefit when compared with conventional chemotherapy, with improvement in time without symptoms, treatment and treatment related adverse events and thus may be preferred in younger patients 4. However, most prospective clinical trials on AHCT in MM have excluded older MM patients (inclusion criteria <65 years), hence its efficacy and safety in this patient populations is based on retrospective analyses and is influenced by the institution’s protocol. This precludes the ability to extend the results of the trials to almost half of the patients with MM underscoring the

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need for more prospective trials in this age group. Recent large database studies have found that older adults are increasingly receiving AHCT for MM

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with comparable

outcomes with their younger counter parts. In a retrospective study by Kumar et al.

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which included 33 MM patients >70 years old undergoing AHCT, an overall response rate of 98% with a median time to progression of 28.5 months was demonstrated9. On the same note, being a disease of the elderly, there is under representation of patients

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less than 50 years of age in clinical trials, again limiting our ability to extend the results in this age group with confidence. Few retrospective studies have looked at the outcomes

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after AHCT in younger patients with variable results 10,11.

Given the limited evidence of outcomes of AHCT in these two different age groups (one >70 and ≤ 50 years), we report a single center experience of AHCT in this

Methods:

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Patient population

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patient population and compare the outcomes.

All adult MM patients in the age group of more than 70 years and 18-50 years,

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who underwent upfront AHCT from 2000-2015, were included in the study. The Institutional Review Board at the Medical College of Wisconsin approved the study. The study included only those receiving single AHCT, and those with tandem autologous or allogeneic transplantation were excluded from the study. But patients receiving either AHCT or allogeneic transplantation at relapse were included.

Conditioning regimens and prophylaxis:

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Most of the patients received melphalan (100- 280 mg/m2) as the conditioning regimen. Other conditioning regimens that include BCNU, etoposide, cytarabine and melphalan (BEAM), busulfan and cyclophosphamide (BuCy), cyclophosphamide and

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total body irradiation (CyTBI) were used in some of the patients. Growth factors were used uniformly after transplantation to hasten neutrophil recovery. All patients received fungal (fluconazole), herpes zoster/herpes simplex (acyclovir or valacyclovir), and

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bacterial prophylaxis (ciprofloxacin) per institutional guidelines.

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Definition of outcomes:

Response, disease progression and relapse were defined according to the International Myeloma Working Group uniform response criteria (12). For progressionfree survival (PFS), a patient was considered a treatment failure at the time of progression/relapse or death from any cause. Death from any cause other than relapse

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was defined as non-relapse mortality (NRM). Patients alive without evidence of disease relapse or progression were censored at last follow up. Overall survival (OS) was defined as the interval from the date of transplantation to the date of death. Surviving

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patients were censored at last follow up. Neutrophil engraftment was defined as first of 3 successive days with absolute neutrophil count >0.5 x 109/L after post-transplantation

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nadir. Platelet engraftment was considered to have occurred in the first of three consecutive days with platelet count 20 x 109/L or higher, in the absence of platelet transfusion for 7 consecutive days. Engraftment syndrome was defined as the presence of non-infectious fever plus any of the following: skin rash, pulmonary infiltrates or diarrhea in patients during the engraftment period 12. High-risk MM was defined as having high risk chromosomal abnormalities: del 13 or hypodiploidy on conventional

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cytogenetics, chromosome 1 q abnormality (4:14), t (14:16) or del 17p on fluorescence in situ hybridization (FISH) or conventional cytogenetics13,14.

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Statistical methods:

The outcomes of interest included relapse/progression, NRM, PFS and OS

between the two age groups. Continuous and categorical variables between the two

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groups were compared using Wilcoxon rank sum and chi-square test respectively.

Univariate analysis of these outcomes consisted of constructing Kaplan Meier curves of

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OS and PFS and cumulative incidence estimates of NRM and relapse. Death and relapse were treated as competing risk for relapse and NRM respectively. Cox proportional hazards regression was used to assess the factors, which impacted these outcomes and the strength of the effects.

For multivariate analysis, a Cox regression model of each outcome was

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constructed using selection of potential risk factors including cytogenetic risk, time from time diagnosis to transplantation, karnofsky performance score, HCT-CI, and disease status at transplantation with age group as the main effect. A significance level of 0.05

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was used as the criterion for inclusion in the final model. Due to sample size limitations, interactions between predictors in the final models were not tested. All analysis was

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performed in SAS 9.4(SAS institute, Cary, NC).

Results

Baseline characteristics:

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The baseline characteristics of 191 patients included in the analysis are shown in Table 1. Eight-six patients were young (≤50 years), while 105 patients were above 70 years. The 2 groups did not differ significantly at baseline for patient gender, race,

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immunoglobulin subtype, and serum creatinine at diagnosis, the type of induction treatment, disease status at transplant, cytogenetics/FISH, international staging system (ISS) stage and bone marrow plasma cells percentage at diagnosis. Median age in

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young patients was 46 years (range 32-50) and 73 years (range 71-79) for older

patients. Majority of the patients in both the groups had ISS stage II-III. Young patients

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had better performance status and also lower co-morbidity index. There was significant difference in the dose of melphalan dose with majority of old patients received between 140-180 mg/m2. Younger patients had higher likelihood of getting transplantation within 12 months of diagnosis (90% vs. 73 %, p=0.002). Median follow up was slightly longer in the young age group 33 months (range, 2-164) compared to the 22.5 months (3-133) in

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the older group (p=0.02). Majority of the patients received bortezomib based induction with 23% of the patients in the younger group and 35% of the patients in the older group receiving both bortezoimib and lenalidomide based combination. In both the groups, the

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response rates at transplant were comparable with 19% of young patients and 22% of

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the older ones were able to achieve complete response.

Transplantation and Response: The transplantation was performed either outpatient or inpatient in both the groups (based on the patient preference and their home address). As shown in Table 2, the young and old patients did not differ in the number of outpatient transplants (15% vs. 16% p=0.83) and in the rate of engraftment syndrome (17.4% vs. 19%, p=0.85). There

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was also no difference in the median time to platelet engraftment (median 20 days in each group, p=0.9) and neutrophil engraftment (median 12 in young vs. 11 in old, p=0.05) between the two groups. The median cell dose infused was 4.0 x106 cells/kg in

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younger patients compared to 3.8 x 106 cells/kg in older patients. The complete remission (CR) rates were similar between the two groups and older patients had slightly higher very good partial response (VGPR) rates. Lenalidomide was the most common

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maintenance drug used in both the groups (32.5% vs. 29.5%, p=0.18). Other drugs used for maintenance were bortezomib, dexamethasone, pomalidomide, carfilzomib and

Progression free survival

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ixazomib.

The PFS at 1 year was 60% (95%CI 46-72) for young patients and 58 (95%CI,

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45-69) for the old ones (Table 3). There was no difference in the PFS between the two groups, Fig 1. On multivariate analysis, age did not have any effect on PFS (p=0.89). However, the disease risk (HR 1.2, 95% CI 1.1-3.5, p=0.004) and those with no

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response or progressive disease at transplantation (HR, 5.0 95% CI 1.8-13.5, p=0.02)

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were significantly associated with worse PFS. (Table 4)

Overall survival:

The OS at 1 year was 92% (95% CI 84-96) for young and 85% (95% CI 76-91) for the older cohorts (Table 3). There was no difference in the OS between the two groups, Fig 2. On multivariate analysis, age did not have any effect on survival (p =0.82), but the patients with high risk cytogenetic (HR 2.2, 95% CI 1.06-4.6, p=0.04) had worse

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OS. There was trend for worse OS for those who had progressive disease at transplantation, however did not reach its statistical significance. The time from

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diagnosis to transplant, performance status and HCT-CI were not associated with OS.

Risk status:

Of the patients who had tested for cytogenetics/FISH, 14% of the young cohort

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and 19% of old cohort had the high-risk disease as defined above. About half of the

patients in both the groups had standard risk cytogenetics (48.4% in young and 52.3% in

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old). In our study, high-risk disease was consistently associated with worse PFS, OS and the incidence of relapse/progression on adjusted analysis as shown in Table 4.

Relapse and NonNon-relapse mortality:

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The cumulative incidence of NRM at 1 year was 3.8% (95% CI 1-9.8) in the young cohort and 2.1% (95% CI 1.4-9.9) for the old ones (Fig 3). Similarly, there was no difference in the cumulative incidence of relapse/progression between the two groups.

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The 1-year estimates of relapse/progression for the young patients and old were 23% (95%CI 14-33) and 23% (95% CI 15-33) respectively. On multivariate analysis for

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relapse/progression, disease risk (HR 4.1, 95% CI 1.3-13.3, p=0.002) and those with no response or progressive disease at the time of transplant (HR 4.19, 95% CI 1.3-13.3, p=0.01) were associated with increased incidence of relapse.

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Causes of death: Myeloma remains the major cause of death in both the groups (31.3% in young vs. 29.5% in the old ones). The other causes of death included secondary malignancy,

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organ failure and unknown causes.

Discussion:

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Our data suggests that age did not have any effect on the outcomes after AHCT in MM. Patients with high-risk cytogenetics did carry the worse overall outcomes

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regardless of age. Those patients who failed to show any response to induction therapy also had poor outcomes. Age shouldn’t be a limiting factor in considering the modality of ASCT, however at the same time young patients may benefit from other additional novel treatment approach in the setting of clinical trials given their similar outcomes with the

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old patients based on our study.

The impact of age on the prognosis is different for different cancers, for example in acute myeloid leukemia young age is significantly better in the absence of adverse cytogenetics 15. On the other hand, young patients with breast cancer are supposed to

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carry very poor outcomes 16. In MM, the results are inconsistent. In one study, the outcomes were worse when corrected for differences in life expectancy 17. Ludwig et.al

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demonstrated favorable features at presentation in MM patients younger than 50 years and improved survival compared to older patients 18. Chretien et. al in a recent retrospective analysis evaluated outcomes of AHCT in patients <66 years of age and demonstrated that patients younger than 60 years had improved overall survival10. A recent CIBMTR study comparing the outcomes of upfront AHCT in different age groups, showed that the older patients derive similar benefit without any difference in nonrelapse mortality, relapse rate or progression free survival 19. Possibility of underlying

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disease aggressiveness in young group resulting in the similar survival compared with old cohorts cannot be ignored. Based on our findings, it might be reasonable to offer these patients under clinical trial whenever possible. The causes of death are myeloma

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in this patient population and even in older patients and not transplant related as might be speculated. The median PFS in the entire cohort is shorter than usual and is likely due to inclusion of patients with relapsed/refractory disease.

As expected, older patients in our cohort had worse KPS and HCT-CI, and higher

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proportion received reduced dose of melphalan (>70% received less than 180 mg/m2).

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Only 25/105 patients >70 years old received melphalan 200 mg/m2 and we did not see any difference in toxicities when compared to lower dose group. This judicious selection of patients based on KPS and HCT-CI could have likely resulted in the comparable NRM when compared to younger patients. Similarly, significant higher percentage of patients in older group had transplant done after 18 months of diagnosis. This is probably due to

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the referral bias as most of the patients in this age group were referred later in the course and some even at relapse, possibly due to the belief that transplant was not an option due to their age. Time from diagnosis to transplant did not affect the survival in

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our study. As discussed, the NRM was similar in both the groups at different time points. This is due to the careful patient selection (small number of patients with KPS<80 and

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HCT-CI more than 3) and melphalan dose adjustment, both of which were successful at controlling the toxicity, and at the same time without compromising the benefit. Randomized trials, before the era of novel agents have shown that in young

eligible patients, frontline AHCT was associated with improved response rates, diseasefree survival rates and even overall survival in some studies 3,20,21. The benefit persisted in the era of novel agents too 22-25, with AHCT achieving deep molecular- or flowcytometry defined complete response 26-28. Similarly, a number of prospective and retrospective studies have been done to solve the outstanding issue of early versus late

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AHCT 29-31; and the most recent data showed better response rates and progression free survival rates along with no transplant related deaths in those with early AHCT 32. One randomized study of patients between 65-75 years showed that melphalan, prednisone

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(MP) combined with thalidomide was superior in PFS and OS when compared to MP or AHCT33. The patients in the AHCT arm received lower dose of melphalan at 100 mg/m2 and non-novel induction regimens and this emphasizes the importance of novel drugs in

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MM outcomes. In our study, there was no difference in the CR rates and survival rates despite the dose difference in melphalan between the groups. The results of our study

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underscores the fact that chronological age shouldn’t limit a biologically fit elderly MM patients to get the benefit of AHCT and is consistent with other published studies including the large scale CIBMTR study19.

Our study also has its limitations owing to its retrospective nature. There is significant heterogeneity in the study groups, the various induction regimens used over

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the course of years and the treatment of progression as some of the young patients underwent allogeneic stem cell transplant at relapse. The median follow up is also very short for both groups to definitely assess the meaningful differences in the outcomes.

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In conclusion, our study demonstrates comparable outcomes of AHCT in patients older than 70 years when compared to young patients, less than 50 years. Age

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shouldn’t be a limiting factor in considering the modality of AHCT, however at the same time young patients may benefit from other additional novel treatment approach in the setting of clinical trials given their similar outcomes with the old patients based on our study.

Clinical practice points:

1. Autologous hematopoietic cell transplantation is the standard of care in younger and also preferred in older transplant eligible patients.

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2. Randomized trials looking into the effect of AHCT only included patients younger than 65 years of age. 3. Data is also lacking in young patients ≤50 years of age as they represent a small

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proportion in the clinical trials. 4. The PFS at 1 year was 60% (95%CI 46-72) for young patients and 58 (95%CI, 45-69) for the old ones.

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5. The OS at 1 year was 92% (95% CI 84-96) for young and 85% (95% CI 76-91) for the older cohorts.

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6. On multivariate analysis, age did not have any effect on survival (p =0.82), but the patients with high-risk cytogenetics (HR 2.2, 95% CI 1.06-4.6, p=0.04) had worse overall mortality.

7. Age shouldn’t be a limiting factor in considering the modality of autologous

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hematopoietic transplantation in multiple myeloma.

References

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31. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18.

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1. Tuchman SA, Shapiro GR, Ershler WB, Badros A, Cohen HJ, Dispenzieri A, Flores IQ, Kanapuru B, Jurivich D, Longo DL, Nourbakhsh A, Palumbo A, Walston J, Yates JW. Multiple myeloma in the very old: an IASIA conference report. J Natl Cancer Inst. 2014;106:10.1093/jnci/dju067. 2. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-7. 3. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ, Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-83. 4. Costa LJ, Zhang MJ, Zhong X, Dispenzieri A, Lonial S, Krishnan A, Freytes C, Vesole D, Gale RP, Anderson K, Wirk B, Savani BN, Waller EK, Schouten H, Lazarus H, Meehan K, Sharma M, Kamble R, Vij R, Kumar S, Nishihori T, Kindwall-Keller T, Saber W, Hari PN. Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma. Biol Blood Marrow Transplant. 2013;19:1615-24. 5. Bashir Q, Shah N, Parmar S, Wei W, Rondon G, Weber DM, Wang M, Orlowski RZ, Thomas SK, Shah J, Qureshi SR, Dinh YT, Popat U, Anderlini P, Hosing C, Giralt S, Champlin RE, Qazilbash MH. Feasibility of autologous hematopoietic stem cell transplant in patients aged >/=70 years with multiple myeloma. Leuk Lymphoma. 2012;53:118-22. 6. Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P, Group Myelome-Autogreffe. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227-33. 7. Merz M, Neben K, Raab MS, Sauer S, Egerer G, Hundemer M, Hose D, Kunz C, Heiss C, Ho AD, Goldschmidt H, Hillengass J. Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents. Ann Oncol. 2014;25:189-95. 8. McCarthy PL,Jr, Hahn T, Hassebroek A, Bredeson C, Gajewski J, Hale G, Isola L, Lazarus HM, Lee SJ, Lemaistre CF, Loberiza F, Maziarz RT, Rizzo JD, Joffe S, Parsons S, Majhail NS. Trends in use of and survival after autologous hematopoietic cell transplantation in North America, 1995-2005: significant improvement in survival 16

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for lymphoma and myeloma during a period of increasing recipient age. Biol Blood Marrow Transplant. 2013;19:1116-23. 9. Kumar SK, Dingli D, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Rajkumar SV, Litzow MR, Gertz MA. Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: Results from a matched pair analysis. Am J Hematol. 2008;83:614-7. 10. Chretien ML, Hebraud B, Cances-Lauwers V, Hulin C, Marit G, Leleu X, Karlin L, Roussel M, Stoppa AM, Guilhot F, Lamy T, Garderet L, Pegourie B, Dib M, Sebban C, Lenain P, Brechignac S, Royer B, Wetterwald M, Legros L, Orsini-Piocelle F, Voillat L, Delbrel X, Caillot D, Macro M, Facon T, Attal M, Moreau P, Avet-Loiseau H, Corre J. Age is a prognostic factor even among patients with multiple myeloma younger than 66 years treated with high-dose melphalan: the IFM experience on 2316 patients. Haematologica. 2014;99:1236-8. 11. Ludwig H, Durie BG, Bolejack V, Turesson I, Kyle RA, Blade J, Fonseca R, Dimopoulos M, Shimizu K, San Miguel J, Westin J, Harousseau JL, Beksac M, Boccadoro M, Palumbo A, Barlogie B, Shustik C, Cavo M, Greipp PR, Joshua D, Attal M, Sonneveld P, Crowley J. 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;111:4039-47. 12. Maiolino A, Biasoli I, Lima J, Portugal AC, Pulcheri W, Nucci M. Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant. 2003;31:393-7. 13. Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR, Dispenzieri A, Fonseca R, Sher T, Kyle RA, Lin Y, Russell SJ, Kumar S, Bergsagel PL, Zeldenrust SR, Leung N, Drake MT, Kapoor P, Ansell SM, Witzig TE, Lust JA, Dalton RJ, Gertz MA, Stewart AK, Rajkumar SV, Chanan-Khan A, Lacy MQ, Mayo Clinic. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013;88:360-76. 14. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV, International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-73. 15. Bacher U, Kern W, Schnittger S, Hiddemann W, Haferlach T, Schoch C. Population-based age-specific incidences of cytogenetic subgroups of acute myeloid leukemia. Haematologica. 2005;90:1502-10. 16. Gajdos C, Tartter PI, Bleiweiss IJ, Bodian C, Brower ST. Stage 0 to stage III breast cancer in young women. J Am Coll Surg. 2000;190:523-9. 17. Corso A, Klersy C, Lazzarino M, Bernasconi C. Multiple myeloma in younger patients: the role of age as prognostic factor. Ann Hematol. 1998;76:67-72. 18. Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weissmann A, Adam Z. Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014;123:985-91. 17

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19. Sharma M, Zhang MJ, Zhong X, Abidi MH, Akpek G, Bacher U, Callander NS, Dispenzieri A, Freytes CO, Fung HC, Gale RP, Gasparetto C, Gibson J, Holmberg LA, Kindwall-Keller TL, Klumpp TR, Krishnan AY, Landau HJ, Lazarus HM, Lonial S, Maiolino A, Marks DI, Mehta P, Mikhael Med JR, Nishihori T, Olsson R, Ramanathan M, Roy V, Savani BN, Schouten HC, Scott E, Tay J, To LB, Vesole DH, Vogl DT, Hari P. Older patients with myeloma derive similar benefit from autologous transplantation. Biol Blood Marrow Transplant. 2014;20:1796-803. 20. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R, InterGroupe Francophone du Myelome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495-502. 21. Fermand JP, Ravaud P, Chevret S, Divine M, Leblond V, Belanger C, Macro M, Pertuiset E, Dreyfus F, Mariette X, Boccacio C, Brouet JC. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: upfront or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92:3131-6. 22. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M, GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:207585. 23. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pegourie B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traulle C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118:5752,8; quiz 5982. 24. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omede P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895-905. 25. Rosinol L, Oriol A, Teruel AI, Hernandez D, Lopez-Jimenez J, de la Rubia J, Granell M, Besalduch J, Palomera L, Gonzalez Y, Etxebeste MA, Diaz-Mediavilla J, Hernandez MT, de Arriba F, Gutierrez NC, Martin-Ramos ML, Cibeira MT, Mateos MV, Martinez J, Alegre A, Lahuerta JJ, San Miguel J, Blade J, Programa para el Estudio y la Terapeutica de las Hemopatias Malignas/Grupo Espanol de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120:1589-96. 18

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26. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Feyler S, Ross FM, Cook G, Jackson GH, Morgan GJ, Owen RG. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31:2540-7. 27. Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA, Sureda A, Montejano L, Gutierrez NC, Garcia de Coca A, de Las Heras N, Mateos MV, LopezBerges MC, Garcia-Boyero R, Galende J, Hernandez J, Palomera L, Carrera D, Martinez R, de la Rubia J, Martin A, Blade J, Lahuerta JJ, Orfao A, San Miguel JF, GEM (Grupo Espanol de MM)/PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatias Malignas) Cooperative Study Groups. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112:4017-23. 28. Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, Crippa C, De Rosa L, Pregno P, Grasso M, Liberati AM, Caravita T, Pisani F, Guglielmelli T, Callea V, Musto P, Cangialosi C, Passera R, Boccadoro M, Palumbo A. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010;28:2077-84. 29. Gay F, Cavallo F, Caravita T, et al. Maintenance therapy with lenalidomide significantly improved survival of young newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2013;122(21):2089. 30. Palumbo A, Gay F, Spencer A, et al. A phase III study of ASCT vs cyclophosphamide-lenalidomide-dexamethasone and lenalidomide- prednisone maintenance vs lenalidomide alone in newly diagnosed myeloma patients. Blood (ASH Annual Meeting Abstracts). 2013;122(21):763. 31. Siegel D, Jacobus S, Rajkumar SV, et al. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplanta- tion in the ECOG E4A03 randomized clinical trial. Blood (ASH Annual Meeting Abstracts). 2010;116(21):38. 32. Attal et al. Autologous Transplantation for Multiple Myeloma in the Era of new Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome(IFM 2009/DFCI). . ASH 2015. 33. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H, Intergroupe Francophone du Myelome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370:1209-18.

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Table 1. Baseline Characteristics

HCTCI2 score 1 2-3 >3

37(43) 45(52.3) 3(3.4) 1(1.1)

Immunochemical subtype IgG IgA Light chain Others

EP

AC C

<0.001 0.9 <0.001

0.008

63(60) 38(36) 4(4) 0.06

34(39.5) 9(10.4) 26(30.2) 3(3.4)

56(53.3) 21(20) 19(18) 6(5.7)

1.3(0.69-14)

1.2(0.5-4.5)

0.22

20(23.2) 9(10.4) 38(44.1) 8(9.3) 11(12.7)

37(35.2) 13(12.3) 42(40) 5(4.7) 8(7.6)

0.08 0.65 0.65 0.25 0.22 0.23

17(19.7) 16(18.6) 24(28) 10(11.6) 7(8.1) 12(13.9)

23(22) 25(24) 43(41) 5(5) 8(7.6) 1(0.9)

15(17.4) 58(67.4) 2(2.3) 1 1 0 11(12.7)

75(71.4) 23(22) 3(2.8) 1 0 1 4(3.8)

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Serum creatinine, median (range) Induction chemotherapy Lenalidomide+ Bortezomib Thalidomide based Bortezomib based Lenalidomide based Others Disease status at transplant CR/sCR3 VGPR4 PR5 SD6 PROG7 Missing MEL8, median (range), mg/m2 140-180 180-200 >200 BEAM9 CyTBI10 BuCy11 Missing

p-value

6(5.7) 81(77.1) 2(1.9) 16(15.2)

M AN U

68(79) 18(21) 0

Old (>70 years) N=105 73(71-79) 58(55.2)

RI PT

Age, median (range), years Sex, Male KPS 1 >90 80-90 <80 Missing

Young(≤50 years) N=86 46(32-50) 70(81.3)

SC

Variable

<0.001

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Cytogenetic/FISH Standard High Unknown/Untested Time from diagnosis to transplant <12 months 12-18 months >18 months Transplant at first remission induction Transplant at relapse/refractory

0.56 55(52.3) 20(19) 30(28.5)

78(91) 1(1.1) 5(5.8) 69 (80.2%) 17 (19.7%)

77(73.3) 11(10.4) 16(15.2) 91(86.6%) 13 (12.3%)

M AN U

71(83) 13(15) 2(2)

3.7(1.2-38.6)

SC

3.5(0.54-34.5)

RI PT

0.002

Serum beta-2 microglobulin, median (range) Race White African American Others ISS stage13 I II III Missing

EP

AC C

0.91 0.06

0.31 29(27) 22(21) 28(27) 26(25)

40(10-96) 33(2-164)

47(3-90) 22.5(3-133)

KPS: Karnofsky performance score HCTCI: Hematopoietic cell transplantation co-morbidity index CR/sCR: Complete remission/ Stringent complete remission VGPR: very good partial response PR: Partial response SD: Stable disease PROG: Progressive disease MEL: Melphalan BEAM: BCNU, Etoposide, cytarabine, melphalan CyTBI: Cyclophosphamide, Total body irradiation BuCy: busulfan, cyclophosphamide ISS stage: International Staging System

<0.001

97(92) 8(8) 0

15(17.4) 22(26) 20(23) 29(34)

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Bone marrow plasma cells at diagnosis, % Median follow up, in months median (range) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

42(48.8) 12(14) 32(37.2)

0.49 0.02

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Table 2. Transplant Outcomes

43(50) 9(10.4) 18(21) 2(2.3) 1(1.1) 13(15) 12(9-31)

53(50.4) 20(19) 10(9.5) 6(5.7) 10(9.5) 6(5.7) 11(8-30)

20(10-92)

20(11-58)

28(32.5) 7(8.1) 5(5.8) 5(5.8)

p value 0.83 0.85 0.01

RI PT

Old(>70 years) N=105 17(16) 20(19)

SC

Outpatient transplant Engraftment syndrome Response after transplant CR/sCR VGPR PR SD PROG Missing Median time neutrophil engraftment(range) Median platelet engraftment(range) Maintenance -Lenalidomide -Bortezomib -Dexamethasone others

Young(≤50 years) N=86 13(15) 15(17.4)

M AN U

Variable

0.05 0.95 0.18

31(29.5) 9(8.5) 6(5.7) 1(.95)

Outcome

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Table 3. Univariate results:

AC C

EP

Overall survival -at 1 year -at 2 year -at 3 year Progression free survival -at 1 year -at 2 year -at 3 year Non relapse mortality -at 1 year -at 2 year -at 3 year Progression/Relapse -at 1 year -at 2 year -at 3 year

Young(≤50 years) N=86

Old( >70 years) N=105

92(84-96)% 83(73-90%) 66(53-76)%

85(76-91)% 72(61-81)% 64(51-74)%

60(46-72)% 37(24-50)% 25(14-37)%

58(45-69)% 30(19-41)% 16(8-27)%

3.8(1-9.8)% 6.7(2.4-14)% 12(5.5-21)%

2.1(1.4-9.9)% 9.4(3.4-16)% 9.4(3.4-16)%

23(14-33)% 40(28-51)% 46(33-58)%

23(15-33)% 42(31-53)% 61(46-73)%

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Table 4: Multivariate results: Hazard ratio(95% CI)

p-value

For mortality Age group(main effect) -≥70 years vs ≤50 years

0.93(0.50-1.72)

0.82

Cytogenetic/FISH risk -high risk vs. standard risk

RI PT

Risk factors

2.2(1.06-4.6)

0.6(.34-1.26) 0.8(.17-4.0) 2.6(0.81-7.9)

Time from diagnosis to transplant -12-18 months vs <12 months ->18 months vs <12 months

0.58(0.13-2.5) 0.73(0.83-3.5)

M AN U

SC

Disease status at transplantation -VGPR/PR vs CR/sCR -SD vs CR/sCR -NR/PD vs CR/sCR

KPS -80-90 vs >90 -<80 vs >90

0.04 0.09

0.39

0.21

1.4(0.77-2.7) 3.1(0.66-14.7)

HCT-CI -2-3 vs 0-1 -≥3 vs 0-1

AC C

EP

TE D

0.92(0.55-1.56) 4.4(0.56-35.4)

0.34

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Disease status at transplantation -VGPR/PR vs CR/sCR -SD vs CR/sCR -NR/PD vs CR/sCR Time from diagnosis to transplant -12-18 months vs <12 months ->18 months vs <12 months KPS -80-90 vs >90 -<80 vs >90

0.89

1.2(1.1-3.5)

0.004

1.1(0.68-1.9) 0.9(0.23-3.4) 5.0(1.8-13.5)

0.83(0.36- 1.9) 0.94(0.52-1.7)

HCT-CI -2-3 vs 0-1 -≥3 vs 0-1

M AN U

1.4(0.88-2.4) 2(0.57-6.9)

0.82(0.52-1.29) 1.2(0.16-9.0)

1.02(0.60-1.75)

TE D

For Relapse/Progression Age group(main effect) -≥70 years vs ≤50 years

4.1(1.3-13.3)

Disease status at transplantation -VGPR/PR vs CR/sCR -SD vs CR/sCR -NR/PD vs CR/sCR

1.08(0.62-1.37) 1.13(0.53-2.4) 4.19(1.3-13.3)

Time from diagnosis to transplant -12-18 months vs <12 months ->18 months vs <12 months

1.1(0.52-1.29) 1.20(0.16-9.0)

EP

Cytogenetic/FISH risk -high risk vs, standard risk

AC C

RI PT

Cytogenetic/FISH risk -high risk vs. standard risk

1.03(0.63-1.7)

SC

For progression free survival Age group(main effect) -≥70 years vs ≤50 years

0.02

0.90

0.20

0.68

0.92

0.002

0.78 0.73 0.01 0.56

0.23

KPS -80-90 vs >90 -<80 vs >90

1.2(0.68-2.1) 1.3(0.30-6.3)

HCT-CI -2-3 vs 0-1 -≥3 vs 0-1-2-3

0.73(0.43-1.24) 1.51(0.19-11.5)

0.46

TE D

M AN U

SC

RI PT

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Fig 1. Progression free survival between the two age groups, 1: >70 years old and 2: ≤50 years old.

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Fig 2. Overall survival between the two age groups, 1: >70 years old and 2: ≤50 years old.

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Fig 3: Cumulative incidence of non-relapse mortality between the two groups