ALBERT

Description: Background Despite the advances in the treatment of multiple myeloma using new targeted therapies and autologous hematopoietic stem cell transplant (HSCT) the disease remains largely incurable. Recent efforts in using reduced intensity allogeneic HSCT have been hampered by increased allograft-related morbidity and mortality. Several prospective studies comparing single or tandem autologous HSCT with planned tandem autologous-reduced intensity allogeneic HSCT (auto-allo) have shown no overall survival advantage despite improvements in progression-free survival (PFS) and lower relapse rates with reduced intensity allograft, mainly due to increased non-relapse related mortality (NRM) rates. However, two of these prospective studies; the European Group for Blood and Marrow Transplantation NMAM 2000 and the Italian group study with long term follow-up reported PFS and overall survival (OS) benefits in favor of the auto-allo arm. Currently allogeneic HSCT is recommended within the context of clinical trials and only in high risk multiple myeloma patients who continue to have a very poor outcome with autologous HSCT. While such clinical trials are ongoing there remains a need to address the role of autologous HSCT prior to reduced intensity allogeneic HSCT. The objective of this retrospective study is to evaluate the role of upfront cytoreductive autologous HSCT prior to allograft in the outcomes of patients who have undergone allograft following induction therapy. Study We performed a retrospective analysis of the EBMT database comparing the outcomes of patients who were planned to receive auto-allograft to those who underwent reduced intensity allograft (early RIC) without a prior autologous HSCT within one year from diagnosis. The data in 504 patients were previously reported at the ASH meeting 2010 (abstract 3512). We subsequently included additional patients and requested more information from the participating EBMT centers and updated the study. From 1996 to 2013 a total of 689 patients were registered as reduced intensity allograft. 517 patients were registered as planned auto-allograft; however, 73 did not receive the planned allograft. A total of 172 patients received reduced intensity allograft after induction treatment without prior auto-HSCT. Median age at first transplant was 53 years (range 20-72) in the auto-allo and 51 years (range 31-77) in the early RIC group. Median time from diagnosis was 6.6 months (range 2-156 months) in the auto-allo and 7.7 months (2.8-12.0) in the early RIC group. The disease status at the time of first transplant for the auto-allo group was CR - 8%, PR - 67%, other or missing - 25%; and for the RIC group was CR - 15%, PR - 62%, other or missing - 23%. Donors were HLA matched siblings in 88% and matched unrelated in 12% for the auto-allo group, and 84% siblings and 16% matched unrelated in the RIC group with no significant differences between the two groups. Results With a median follow-up of 93 months in the auto-allo and 84 months in RIC groups, PFS rates were significantly better at 3 and 5 years in the auto-allo group (45.6% and 34.2%) as compared to the RIC group (33.9% and 22.0%, p

Description: Abstract 2008 We have previously reported a dismal outcome for patients with Plasma Cell Leukaemia (PCL) undergoing autologous transplantation, although such patients represent the younger and fittest with this condition and show superior survival to reports of non transplant patients. In this study we report two analyses of 85 eligible patients with PCL who received an allogeneic transplantation (Allo) between 1984 and 2009 and 411 patients receiving autologous transplantation (Auto) in the same period and a further comparison with 850 (Allo) myeloma MM.The first analysis was restricted to the years 1998 to 2009 allowing the identification of a large Myeloablative (MAC) population (n=45) and a smaller reduced intensity (n=17) conditioning (RIC) group. On account of the number of comparisons in the study and the size of the sub populations, only statistically highly significant differences are reported; less significantly powerful differences are viewed as a trend. Patients treated with MAC and RIC were essentially similar although significantly younger (45.9 and 52.9 yrs respectively) than the Auto patients (55.9 yrs) at the time of diagnosis, with similar differences at the time of transplant. RIC patients had a longer time (10.2 months) to transplant than the MAC (6.0m) and Auto (5.8m) groups. No difference was seen in rates of engraftment, acute or chronic graft versus host disease. MAC patients had a higher Complete Response (CR) than Auto. Progression Free Survival (PFS) at 12 and 60 months respectively (with Confidence Intervals) was as follows: Auto; 0.51 (0.45 – 0.57) and 0.10 (0.06 – 0.15), MAC; 0.39 (0.26 – 0.57) and 0.19 (0.09 – 0.39), RIC; 0.43 (0.23 – 0.80) and 0.11 (0.02 – 0.67) with the MAC and RIC curves possibly crossing the Auto curve between 2 and 4 years. These differences are due to highly significant differences in Non Relapse Mortality (Auto better) and Progression (Auto worse) This translates into Overall Survival (OS) at similar times (12 and 60 months) to PFS as follows: Auto; 0.73 (0.68 – 0.78) and 0.25 (0.19 – 0.33), MAC; 0.46 (0.33 – 0.65) and 0.27 (0.16 – 0.47), RIC; 0.59 (0.38 – 0.91) and 0.19 (0.04 – 0.93). The differences between MAC and RIC were not statistically significant. It was noted that whereas Auto patients continue to relapse with time there is a (small) plateau of survivors in both MAC and RIC. These findings are confirmed in the larger non selected analysis of all Auto and Allo patients Although age is seen as a strong prognostic factor favouring the Allo patients appropriate adjustment was made in the analysis. In the comparison of Allo in PCL v. MM the PFS and OS for PCL was inferior to MM: Data at 48 months for PFS and OS respectively: MM 0.22 (0.19 – 0.26) and 0.44 (0.40 – 0.48), PCL 0.20 (0.10 – 0.41) and 0.32 (0.19 – 0.53). In all three analyses the PCL Allo group shows a clear plateau at about 0.2 (20%) similar that seen in a number of recent studies of Allo transplantation in MM, but at a lower level. This contrasts with the ongoing attrition of patients experiencing progression in Auto transplantation. This study presents the first major analysis of Allo transplantation in PCL, confirms the poor prognosis with all types of transplant therapy while indicating it remains the best option for patients with PCL. Further improvements in the management of NRM can improve the outcome for these patients. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3043 Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29–76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Description: Introduction. The impact of therapy in the management of disease relapse in patients with myeloma (MM) needs to be balanced with the impact on quality of life (QoL). The benefit of a salvage autologous stem cell transplant (ASCT2) has been demonstrated in terms of durability of response over non-transplant consolidation (NTC) (G Cook, et al., Lancet Oncology, 2013 Vol. 15, No. 8, p874-885). However, the impact of ASCT2 on patient reported outcomes (PRO) has not been reported to date. Therefore, patients' experience of pain and global measures of QoL, as part of a systematic assessment of PRO were measured at key points before, during and after randomisation in this multi-centre national phase III trial. Methods. 174 patients were randomised and data are presented on 171 who completed self-rated QoL assessments using EORTC QLQ-C30 and the EORTC myeloma module (MY-20). Pain assessments using BPI-SF were also incorporated. Genomic DNA was prepared from PBMNC using standardised GLP methods. Results. Completion rates for EORTC QoL and BPI-SF assessments were 83.3% and 77.1% at registration, and 59.6% and 53.8% at randomisation, respectively. Over half of patients reaching 1 year post-randomisation completed both assessments. EORTC QoL and BPI-SF forms had average 6% and 10% missing data, respectively. These completion rates are commensurate with previous longitudinal studies. EORTC QLQ-C30 Global health status/QoL subscale scores were significantly higher (better) in the NTC arm at 100 days and 6 month post-randomisation (P=0.0496), but not at later time points. BPI-SF pain scores showed significantly higher pain severity in the NTC (4.3/10) than the ASCT2 (2.9/10) patients only at 2 years post-randomisation. However, for pain interference with aspects of daily living, NTC patients reported significantly lower scores at 6 months (P=0.0155), 1 year post-randomisation (P=0.0466) and 2 years post-randomisation (P=0.0348). The MY-20 assessment showed that at 100 days and 6 months post-randomisation, the subscale scores for Side-effects of treatment were significantly higher in the ASCT2 arm than in the NTC arm, but not at later time points up to 2 years. Kaplan-Meier estimate of time-to-progression (TTP) by randomised allocation suggested that patients with an EORTC global QoL score greater than median (ie better QoL) at randomisation and who received ASCT2 had a significant TTP advantage over those receiving NTC (HR 0.3 (95% CI 0.15-0.61), p=0.006). However, with multivariate Cox regression analysis accounting for stratification factors this difference was not significant. Patients who reported a lower (ie better) than median level of concern on the Side-effects of treatment subscale and who received ASCT2 had a significant TTP advantage over those receiving NTC (Kaplan-Meier HR 0.24 (95% CI (0.10-0.55), p=0.003). This survival difference was still observed after multivariate Cox regression analysis (HR 5.02 (95% CI 1.00-25.20), p= 0.0499). We tested for genomic associations of SNPs from key genes reported to be involved in pain perception and analgesic responsiveness, and subjective outcomes. There were no significant associations for the opioid mu-receptor (OPRM1) and pain or QoL. However, the rs2236861 SNP in the opioid delta-receptor (OPRD1) showed nominally significant associations with worst pain (p=0.022), average pain (p=0.03) and pain interference (p=0.02) at baseline. The rs1045642 SNP in the ABCB1 drug transporter gene was nominally associated with worst pain (p=0.047) and average pain (p=0.019) after bortezomib-based induction therapy. A SNP rs13361160 in the chaperonin CCT5 gene was associated with worst pain (p=0.033), least pain (p=0.006) and pain interference (p=0.03). It was also associated with self-reported global QoL (P=0.014). Conclusions. We report the first PROs using self-reported QoL and pain assessments in myeloma patients having salvage ASCT or NTC. Global QoL was worse and side-effects of treatment higher after ASCT2 for up to 6 months post-randomisation but then equalised. Pain caused less interference with daily living after NTC but became more severe at 2 years, possibly associated with relapse. Patients who reported lower concerns about side-effects of treatment after ASCT2 had a significant TTP advantage. The genomic analyses suggest a potential inherited predisposition that influences both pain and quality of life and warrants further exploration. Disclosures Ahmedzai: Mundipharma: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Grunenthal: Consultancy, Research Funding, Speakers Bureau. Snowden:Sanofi: Consultancy; MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau. Williams:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Cavenagh:Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Parrish:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:Amgen: Honoraria; Novartis: Consultancy; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Autolous: Consultancy. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Celgene: Speakers Bureau; Janssen: Other: Educational support; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ashcroft:Janssen: Consultancy, Other: Educational support. Brown:Bayer: Research Funding; Roche: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Morris:Celgene: Other: Meeting support; Janssen: Other: Meeting support. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Description: Introduction Polyneuropathy, organomegaly, endocrinopathy, dermopathy associated with a paraproteinaemia (POEMS syndrome) is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment of the underlying plasma cell dyscrasia, including ASCT, can control the disease and often dramatically control symptoms though limited data is available for ASCT in POEMS. Specific Aim The aim of this study was to describe the clinical outcome of ASCT for patients with POEMS syndrome. We wish to determine the impact of patient and disease-specific factors on prognosis and effectively measure the extent of systemic disease involvement and organ-specific responsiveness of ASCT. Methodology Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database, including tracking incomplete data entries from participating centers. Systemic involvement and organ-specific response to ASCT was detailed utilizing an organ involvement tool pre- and post-ASCT. Results 127 patients underwent an ASCT between 1997-2010 and satisfied the entry criteria. The median age was 50 years (range 26-69) with 51.2% ≤50 years of age. The extent of systematic disease involvement was: peripheral neuropathy in 58.6%, volume overload in 66.2%, organomegaly in 48.3%, papilledema in 19.8%, dermopathy in 46.6% and 34.5% had sclerotic bone lesions at presentation. The median time from diagnosis to ASCT was 7.5 months (range 1-346) with 31.5% of patients receiving an ASCT 〉12 months from diagnosis. The graft source was PBSC in 100% of patients. Disease status at ASCT was: 47.5% CR/PR, 34% SD/MR/untreated and 18.4% in PD (missing information in 19% of patients). The conditioning regimen was Melphalan ≥200mg/m2 in 52.5%, Melphalan

Description: Background: Bortezomib (formerly PS-341) has demonstrated significant activity in patients with relapsed multiple myeloma. Numerous Phase I/II studies have also shown that it has activity in untreated patients, and we have previously reported results of the combination of standard dose bortezomib (1.3mg/m2), adriamycin and dexamethasone (PAD) in this setting where a response rate of 95% was seen. The CREST study has demonstrated that responses still do occur at a reduced dose of bortezomib, and so here a dose of 1.0mg/m2 was used in order to minimise toxicity. Aims: The primary objective of this Phase II study was to assess the feasibility of harvesting peripheral blood stem cells (PBSCs) after PAD, with secondary objectives being response rate, progression free survival, overall survival and safety, toxicity. Methods: Patients with previously untreated multiple myeloma were elligible. The received 4x21 day cycles of PAD comprising of bortezomib 1.0mg/m2 on days 1,4,8,and 11; 9mg/m2 of adriamycin given by iv infusion on days 1–4 and dexamethasone 40mg on days 1–4, 8–11 and 15–18 on cycle 1 and days 1–4 during cycles 2–4. Following PBSC harvesting, they received high dose melphalan (MEL200) with PBSC rescue. Results: At present 19 patients have been enrolled with a median age of 61 (range 34–65), 8 were male and 11 female and 16 were of Durie-Salmon Stage III disease. Out of the 18 evaluable the PR/CR rate was 89% (2 CR. 1 nCR, 4 VGPR, 9 PR). 15 patients completed all 4 cycles and all successfully mobilised PBSC (median 5 x 106 CD34+ cells/kg, range 2.4–16). Of those not completing therapy, one was withdrawn because of primary progressive disease; one died of pneumonia and severe bone disease having achieved a PR after 1 cycle, and the other developed line sepsis requiring cessation of intravenous therapy prior to completion of cycle 1 (response thus unevaluable). 11 patients have received MEL200 so far with adequate haematological recovery - median neutrophil (〉0.5 x 109/L) and platelet (〉20 x 109/L) engraftment of 14 (range 6–28) and 16 (range 11–40) days respectively. Of those who are assessable at 3 months following MEL200, 7 out of 7 have achieved at least a PR (3CR, 1nCR, 1VGPR, 2PR). One patient was refractory to PAD, but has now successfully received MEL200 following re-induction with cyclophosphamide, thalidomide and dexamethasone combination. Toxicities have been modest, with 1 serious adverse event (hospitalisation with pneumonia) and 6 Grade 3 events (abnormal liver function test; thrombocytopaenia, neutropaenia, hyperglycaemia, sepsis and anxiety). Grade 3–4 neuropathy was not seen and the incidence of Grade 1–2 neuropathy was 16%. Summary: This preliminary data suggests that reduced dose PAD is well tolerated, efficacious (89% ≥ PR) and does not prejudice subsequent PBSC collection. Due to the small numbers in the study, a meaningful comparison with PAD (bortezomib 1.3mg/m2) is not possible, however toxicities appear improved especially with regards to neuropathy. This data therefore supports the continued use of dose adjusted bortezomib in PAD if patients develop toxicity. This reduced dose regime may also be of use in patients with pre-existing neuropathy or those with a poorer performance status.

Description: Abstract 52 Introduction: Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning (RIC) is a controversial treatment in multiple myeloma. There are only few prospective studies and results are contradictory. The EBMT initiated a prospective study in the year 2000 comparing ASCT followed by RIC to ASCT. Patients and Method: 358 myeloma patients from 26 European centres were included in a prospective study comparing ASCT-RIC versus ASCT based on the availability of an HLA identical sibling donor. Patients with an HLA-identical sibling were allocated to the ASCT-RIC-arm (n=107) and patients without a matched sibling donor to the ASCT (n=251). Study inclusion was at the time of conditioning for the first autologous transplant at the achievement of a response status of at least stable disease after VAD ( vincristine, doxorubicine, dexamethasone)-like induction treatment of previously untreated patients. Single or tandem (n=122) autografting was optional in the ASCT arm. Conditioning for ASCT was melphalan 200 mg/m2, and for RIC fludarabine 30 mg/m2 × 3 plus TBI 2 Gy. The accrual period was from February 2001 to February 2005, and median follow-up time is 60 months. The two treatment groups were well matched for the standard prognostic parameters, karyotype (del(13) or not), and response status at ASCT. Results: On an intention to treat basis the cumulative 24 months non-relapse-mortality (NRM) was 13 % in the ASCT-RIC- and 5 % in the ASCT arm (p=0.014) and the CR rate was 43 % (CI:35-54%) and 38% (CI:32-45%) respectively. At 60 months after transplantation Relapse/Progression rate was 49% (CI: 40-60%) and 75% (CI: 69-80%) (significant at 5% level), PFS 35% (CI: 27-45%) and 18% (CI:14-24%) (significant at 5% level) and OS 65% (CI:56-74 %) and 57% (CI:51-64%) (at 84 months 60% and 22%) for the ASCT-RIC- and ASCT -arms, respectively. A comparison between those patients who received a second allo (n=88) versus a second auto (n= 104) the corresponding figures were for CR rate 51 % in the ASCT-RIC-arm and 43 % in the ASCT-arm, Relapse/Progession rate 45% and 77%, PFS 39% and 19% and OS 63% and 60% respectively. Information about the chromosome 13 deletion (del(13q14)) was present in 214 patients. In those with the deletion (n= 92) OS at 60 months was 70% and 53%, and PFS 30% and 11% for the ASCT-RIC- and ASCT-arms, respectively. The corresponding figures for patients without the deletion ( n=122) was for OS 70% vs 61% and PFS 44% vs 19%. Relapse rates were lower in the ASCT-RIC in both subgroups. Conclusion: The risk of myeloma relapse was significantly lower in the ASCT-RIC group as compared to ASCT group, both on an intention to treat analysis and when only those patients that received the correct treatment were analysed. NRM was significantly lower in the ASCT group, but still on an acceptable level in the ASCT-RIC group considering the significantly lower relapse/progression rate, improved PFS and a tendency for better long term OS. An improvement or tendency for improvement were seen in both poor (deletion 13) and good (no deletion 13) prognosis subgroups. Disclosures: Bjorkstrand: Roche: Employment, Karolinska Institutet employee until the closing of the study.

Description: Abstract 4115 Introduction: Polyneuropathy, organomegaly, endocrinopathy, skin changes associated with a paraproteinaemia (POEMS syndrome) is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment, including ASCT, of the underlying plasma cell dyscrasia can control the disease and often dramatically control symptoms. Limited data is available for ASCT in POEMS. Specific Aim: The aim of this study was to describe the clinical outcome of ASCT for patients with POEMS syndrome, determining the impact of patient and disease-specific factors on prognosis. The incidence of engraftment syndrome and the presentation of relapse were examined. Methodology: Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database, including tracking incomplete data entries from participating centers. Results: 116 patients underwent an ASCT between 1997–2009 and satisfied the entry criteria. The median age was 50 yrs (range 26–69) with 56.8% of patients '50 year of age. 58.6% had peripheral neuropathy, 66.2% volume overload, 48.3% had organomegaly, 19.8% had papiloedema, 46.6% had dermopathies and 34.5% had sclerotic bone lesions at presentation. The median time from diagnosis to ASCT was 7.8 mns (range 1–346) with 34.5% of patients receiving an ASCT 〉12 months from diagnosis. The graft source was PBSC in 100% of patients. Disease status at ASCT was: 32% CR/PR, 30% SD/MR/untreated and 5 in PD. Missing information on stage in 33% of the cases. The conditioning regimen was Melphalan ≥200mg/m2 in 52.5%, Melphalan

Description: Key Points Tandem autologous/reduced-intensity allogeneic transplantation is superior to autologous transplantation alone in multiple myeloma.

Description: Introduction: The impact of biological variables on treatment outcomes for patients with multiple myeloma (MM) are key to a stratified medicine approach. Whether to re-start therapy at relapse on serological vs symptomatic progression is an important clinical question. Though salvage autologous transplantation (ASCT2) in MM has been shown to induce superior durability of responses over low-dose alkylating consolidation therapy in the relapsed setting (ISRCTN601231201), who benefits most from this strategy remains to be defined. An important subgroup comparison in Myeloma X was to evaluate the impact of age & disease stage on outcomes after ASCT2 vs non-transplant consolidation (NTC). Patients and Methods: Eligible patients with MM relapsing after prior ASCT were enrolled. All patients received Bortezomib, Doxorubicin & Dexamethasone (PAD) prior to 1:1 randomization between ASCT2 or NTC with weekly cyclophosphamide for 12 weeks. Response was assessed (by IMWG criteria) after re-induction & 100 days post-randomization. Patients were stratified by β2M at trial entry & ASCT1 time-to-progression (TTP). The 10 endpoint was TTP. Overall survival (OS) was a key 20 endpoint with subgroup analysis of stage, age, symptomatic status & cytogenetic risk. Results: 297 patients were entered & 174 randomized: ASCT2 n=89, NTC n=85. Median age was 61 (range 38-75) with 22% of patients 〉65 years. The median TTP from ASCT1 was 31 months (range 8-149) with no impact in terms of age at trial entry. 43% of patients were deemed to have symptomatic relapse (sRel) at trial entry based on CRAB criteria (anaemia 30%, renal disease 16% and hypercalcaemia 5%). There was no significant difference in the median ASCT1 TTP between trial entrants with sRel compared to asymptomatic relapse (aRel: 35 months [95%CI 32,38] vs sRel: 36 months [95%CI 32,40]; Mann-Whitney p=0.657). Post-randomization, sCR/CR rate was significantly higher after ASCT2 (odds ratio (OR) = 0.42 [95%CI 0.21,0.85]; p=0á012), with no significant age effect identified (likelihood ratio test (LRT) p=0.131). The impact of aRel compared to SRel demonstrated a non-significant trend towards benefit in sCR/CR rate for aRel patients (aRel: OR=0.28 [95%CI 0.11,0.76] vs sRel: OR=0.66 [95%CI 0.23,1.93]; LRT p=0.343). The median follow-up is 52 months (IQR 41, 62) & updated TTP demonstrates continued advantage of ASCT2 over NTC (hazard ratio (HR)=0.45 [95%CI 0.31,0.64]; p65 yrs: HR=1.02 [95%CI 0.30,3.52]; LRT p=0.827) & symptomatic status (aRel: HR=0.34 [95%CI 0.18,0.64]; sRel: HR=0.36 [95%CI 0.18,0.71]; LRT p=0.697) on PFS2 showed non-significant trends towards benefit. In particular, older patients appearing to derive less benefit from ASCT2 in terms of PFS2. When OS by randomized treatment is considered in relation to age (²65 yrs: HR=0.53 [95%CI 0.32,0.90]; 〉65 yrs: HR=2.34 [95%CI 0.59,9.35]; LRT p=0.635) & symptomatic status (aRel: HR=0.44 [95%CI 0.22,0.90]; sRel: HR=0.68 [95%CI 0.34,1.36]; LRT p=0.347) non-significant trends towards further benefit can be observed (Fig 1b), reflected by the 4-year survival (ASCT2 - aRel: 75.5% vs sRel: 60.2%; logrank p=0.080 & NTC - aRel: 55.1% vs sRel: 49.0; logrank p=0.707) & age at trial entry (ASCT2 - ²65 yrs: 71.2% vs 〉65 yrs: 58.9; logrank p=0.726 & NTC - ²65 yrs: 47.9% vs 〉65 yrs: 68.2; logrank p=0.653). Conclusion: These results show both a clear OS advantage to ASCT2 post bortezomib based re-induction therapy & that this advantage may well be improved in younger patients with biochemical, rather than symptomatic relapse. This data is key for patient-centered clinical decision-making & adds to previous analysis demonstrating a clear advantage to ASCT2 in terms of TTP and PFS in patients with MM at first relapse1. 1. G Cook, et al. The Lancet Oncology, Vol. 15, No. 8, p874-885. Figure 1. Forest plot showing impact of age & symptomatic status at retreatment on (a) TTP and (b) OS of randomised treatment. To the left favors ASCT2 and to the right NTC. (a) TTP (b) OS Figure 1. Forest plot showing impact of age & symptomatic status at retreatment on (a) TTP and (b) OS of randomised treatment. To the left favors ASCT2 and to the right NTC. / (a) TTP. / (b) OS Disclosures Ashcroft: janssen: Consultancy, Research Funding; celgene: Consultancy, Honoraria; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Williams:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Cavenagh:janssen: Consultancy, Speakers Bureau; novartis: Consultancy, Speakers Bureau; celgene: Consultancy, Speakers Bureau; amgen: Consultancy, Speakers Bureau. Snowden:Sanofi: Consultancy; MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau. Parrish:Celgene: Speakers Bureau; Janssen: Speakers Bureau. Yong:Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Novartis: Consultancy; Autolous: Consultancy; Amgen: Honoraria. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Pfizer: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Celgene: Speakers Bureau; Janssen: Other: Educational support. Heartin:Janssen: Consultancy; Celgene: Speakers Bureau. O'Connor:Celgene: Research Funding. Brown:Janssen: Research Funding; Celgene: Research Funding; Roche: Research Funding; Bayer: Research Funding. Morris:Celgene: Other: Meeting support; Janssen: Other: Meeting support. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau.