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Activation and expansion of T helper (Th) cells followed by regulation of activation are essential to the generation of immune responses while limiting concomitant autoreactivity. In order to characterize T cells reactive towards myeloma-derived monoclonal immunoglobulin (mIg), an autologous coculture assay for single-cell analysis of mIg-responding cells was developed. When cultured with dendritic cells loaded with mIg, CD4+ Th cells from patients with progressing multiple myeloma (MM) showed a proliferative MHC class II–dependent response. CD8+ T-cell reactivity and Th1 activation were consistently low or absent, and Th2 and regulatory cytokines were expressed. The presence of such non-Th1 CD4+ T cells in peripheral blood was independent of treatment status, while the frequencies of responding cells varied between patients and reached the same order of magnitude as those measured for tetanus toxoid–specific Th memory cells. Furthermore, investigations of T-cell subpopulations indicated a possible regulatory role on the mIg responsiveness mediated by suppressive CD25highFOXP3+CD4+ T cells. It is proposed from the present results that a predominant in vivo activation of non-Th1 mIg-reactive CD4+ T cells constitute an Ig-dependent autoregulatory mechanism in human MM, with possible tumor growth supporting or permissive effects.

Recently, the derepressed expression of the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), the enzyme that elongates telomeres, has been implicated as an important step in the immortalization process. The exact regulation of hTERT expression, which is the rate-limiting factor for telomerase activity, is at present unclear. As transformed cells seem to be dependent on a constitutive telomerase activity, the availability of inhibitors would potentially be of great value in antineoplastic therapy. Interferons (IFNs) have been successfully used in the treatment of several forms of malignancies, but the underlying molecular mechanisms responsible for the antitumor activity are poorly defined. In this study we have investigated the effects of IFNs on hTERT expression and telomerase activity. We found that IFN-α rapidly (commonly within 4 hours) and significantly down-regulates the expression of hTERT and telomerase activity in a number of human malignant hematopoietic cell lines, primary leukemic cells from patients with acute leukemia as well as T-lymphocytes from healthy donors. This effect of IFN-α did not seem to depend on IFN-α–mediated cell growth arrest or alterations in c-myc expression. The finding that IFN induces a repression of hTERT and a decrease in telomerase activity suggests a novel mechanism that may play a significant role in the antitumor action of IFN.

Background Ixazomib is the first orally administered PI to be studied in the clinic. The feasibility of combining a PI with cyclophosphamide and dexamethasone has been demonstrated with the PI bortezomib (Reeder et al Leukemia 2009; Mai et al Leukemia 2015). This open-label, multicenter, phase 2 study is evaluating the all-oral triplet combination of ICd, with two different doses of cyclophosphamide, as a 12-month induction therapy in previously untreated, transplant-ineligible pts with NDMM, and is the first study to assess ICd for the frontline treatment of MM. Methods Adult pts with previously untreated, symptomatic NDMM who were ineligible for stem cell transplantation due to age and/or comorbidities, had ECOG PS 0-2, and adequate hematologic, hepatic, and renal function, were included. Pts were randomized 1:1 to receive up to 13 x 28-day cycles of induction therapy with ixazomib 4.0 mg PO on days 1, 8, and 15, plus cyclophosphamide 300 mg/m2 (ICd-300 arm) or 400 mg/m2 (ICd-400 arm) PO on days 1, 8, and 15, plus dexamethasone 40 mg PO (20 mg in pts aged >75 years) on days 1, 8, 15, and 22. A safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable pts in each arm after cycle 1. The primary endpoint was the combined rate of complete response plus very good partial response (CR+VGPR). Secondary endpoints included overall response rate (ORR; CR+VGPR+ partial response [PR]) and safety (adverse events [AEs]). Response was investigator-assessed at the end of every cycle per IMWG criteria. Sample size (n=70) was determined to provide 80% power for the primary endpoint of CR+VGPR rate (1-sided alpha=0.10). Here we present a preliminary analysis of data post-induction (data cut-off: July 1, 2015). Results 70 pts were randomized (36 to ICd-300, 34 to ICd-400): median age 72.5 and 75.5 years; 42% and 53% male; 64% and 59% ISS stage II/III (92% and 79% Durie-Salmon stage II/III), respectively. Mean duration of follow-up was 7.0 months in both arms. Response data are summarized in the Table. Best unconfirmed CR+VGPR rates across all 13 cycles were 27% (ICd-300) and 23% (ICd-400); ORRs were 80% and 73%. Best M-protein reductions are shown in the Figure. Twelve pts (6 ICd-300; 6 ICd-400) were DLT-evaluable; no DLTs were observed in either arm. Pts received a median of 6.0 (1-13) and 6.5 (1-13) cycles in the ICd-300 and ICd-400 arms, respectively. Mean ixazomib relative dose intensity was 90.7% in the ICd-300 arm and 89.8% in the ICd-400 arm. Across all 13 cycles of treatment (ICd-300 and ICd-400, respectively), rates of Gr ≥3 AEs were 53% and 62%, serious AEs 33% and 53%, AEs leading to dose reduction in any study drug 17% and 21%, discontinuation of all study drugs due to AEs 14% and 12%, and on-treatment deaths 2 pts (cardiac arrest; upper gastrointestinal hemorrhage) and 1 pt (pneumonia) which were not deemed as treatment-related. In the ICd-300 and ICd-400 arms, respectively, rates of anti-emetic use were 36% and 44% (8% and 18% for AEs) and G-CSF use 11% and 50% (11% and 35% for AEs); erythropoietin was used in only 1 pt (ICd-300 arm). Thrombocytopenia events occurred in 5 pts (no Gr ≥3) in the ICd-300 arm and 4 pts (3 Gr ≥3) in the ICd-400 arm. Most common AEs (>15% all pts) were anemia (19% and 29%), neutropenia (17% and 32%), nausea (14% and 24%), peripheral neuropathy (PN; 17% and 21%), diarrhea (19% and 15%), vomiting (14% and 21%), constipation (17% and 15%), and fatigue (14% and 18%). Most common Gr ≥3 AEs were neutropenia (14% and 32%), anemia (11% and 15%), and pneumonia (8% and 9%); no Gr ≥3 PN was observed. Conclusion These preliminary data suggest that the all-oral triplet combination of ICd is tolerable in transplant-ineligible pts with NDMM, with a manageable toxicity profile in line with that previously seen with ixazomib and with manageable myelosuppression. Comparably high response rates were reported in both the ICd-300 and ICd-400 arms. Toxicity rates appeared higher with ICd-400, suggesting that ICd-300 may be a more preferable regimen for elderly NDMM pts. Updated data, including long-term outcomes after additional follow-up will be presented at the meeting. Table. Best unconfirmed response by IMWG criteria during cycles 1-13 (response-evaluable pts) Response, n (%) ICd-300(n=30) ICd-400(n=30) CR 3 (10) 3 (10) PR 21 (70) 19 (63) VGPR 5 (17) 4 (13) CR+VGPR 8 (27) 7 (23) ORR (CR+VGPR+PR) 24 (80) 22 (73) SD 6 (20) 8 (27) SD, stable disease Disclosures Dimopoulos: Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with cyclophosphamide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are transplant-ineligible.. Nahi:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Byrne:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Background The indication for use of lenalidomide in second line of therapy has been based upon two phase III studies comparing lenalidomide and dexamethasone vs. placebo and dexamethasone (Weber 2007, Dimopoulos 2007) showing a TTP of 11.1 and 11.3 months respectively. In 2009 Stadtmauer et al showed that patients with only one prior therapy had significantly longer median TTP compared with those treated in later lines (17.1 months vs. 10.6 months). Here we report outcomes from the REVII trial in 2nd line treatment of MM, a two part study with first an observational part with standard treatment of lenalidomide combined with corticosteroids and then, a randomized part, where patients that had responded in the first part, were randomized to lenalidomide combined with dexamethasone or lenalidomide as a single drug. Methods 132 patients with multiple myeloma in first relapse were included in the first, observational part of the study, and treated with up to 9 cycles of lenalidomide combined with betamethasone or dexamethasone according to local routines. Patients that had achieved at least partial response and had consolidation treatment with at least two additional cycles were offered to take part in the second part of the study. In the second part 63 patients were randomized to be treated with either lenalidomide combined with dexamethasone (LenDex) or lenalidomide as a single drug (Len) for a maximum of 24 cycles. In the first part of the study the primary endpoint was time to response and secondary endpoints were quality of life, safety and cytogenetic markers as gain 1q21, t(4;14), t(11;14) and del17p. In the second part, primary endpoint was time to progression and secondary endpoint was safety. In the second part we also performed detailed NK/T-cells phenotype analyses. Survival data were calculated from first entry in the observational study. Data cutoff was 1st of July 2015, with a median follow-up of 21.4 months. Results A very high proportion of patients achieved PR or better (≥PR 84%). Of the patients 3% were primary refractory and 12% achieved a minor response or stable disease. Very good partial response or better (≥VGPR) was achieved in 44% of the patients. First response, at least PR, was achieved after a median of 7 weeks and best response after a median of 10 weeks. After randomizations no differences in responses between the Len and the LenDex group were found. Late responses were common and 7 of the patients received their best response after more than one year of treatment. Median overall survival (OS) was not reached. 61% of the participants were still alive at the data cut off. OS in the first part was 32 months and 78% of the patients in the second part were still alive at data cut off. Median time to progression (TTP) for the whole study was 16 months and for the first and second part 10 and 30 months respectively. After randomization TTP in the Len-group was 25 months and in the LenDex median TTP was not reached, 54% of the participants were still alive after 36 months of treatment. The difference between the two groups was not significant (p=0,48). Patients with gain1q21 had median OS of 31 months while 77% of patients with no gain 1q21 where still alive at the same time (p=0.054). TTP for patients with or without gain of 1q21 was 11 months vs. 28 months respectively (p=0.014). Patients with either gain 1q21, t(4;14) and/or del17p had a TTP of 11 months while patients with none of these chromosomal aberrations had a TTP of 30 months (p=0.0058). NK/T-cells phenotype data will be presented at the congress. Discussion Len/Dex was associated with a very high response rate at 2nd line treatment of MM. On achieving at least PR, continuing with dexamethasone in addition to len does not add any benefit for the patients regarding responses, TTP or OS. As expected, chromosomal abnormalities had a negative impact on TTP and OS. Disclosures Waage: Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Gimsing:Amgen: Honoraria. Mellqvist:Celgene, Amgen, Mundipharma and Novartis: Honoraria. Nahi:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract 2970 Evaluating real life outcomes in Multiple Myeloma (MM) pts in order to understand treatment outcome in clinical practice is very important. The introduction of novel agents (Bortezomib, Thalidomide, Lenalidomide) has been shown to increase overall survival (OS). Can MM be regarded as a chronic disease, defined as a similar OS as a matched normal population at diagnosis, after the introduction of novel agents? All pts diagnosed with MM since earliest Jan 2000 until latest Jun 2011 from 6 university clinics, 3 regional centers and 4 local hospitals in Sweden were included. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis. Partial response (PR) was defined as a 50% reduction in M-protein, no response (NR) as less than 50% reduction and progress was considered when the increase was ≥ 25%. The Swedish population (n = 9 340 682 in 2009) was used to select a gender and 5-yrs age strata matched cohort based on 2008–2010 observed death rates. In the total MM population n=1 843, 201 (11%) pts were excluded due to non treatment demanding disease setting the study population to n=1 642. The median follow up of pts still alive was 30 months. The median age was 70 yrs and 45% women. The most common subtype was IgG (59%) followed by IgA (22%), BJ (15%) and Other (4%). High dose treatment (HDT) was given to 517 (32%) pts. The median number of given treatment lines in both the HDT and the non-HDT population was two but the number of pts receiving more treatment lines were declining rapidly. The response distribution for the HDT population nCR/PR/NR was 47/41/12% in 1st line (induction and high-dose melphalan) and 25/42/33% in 2nd line. In the non-HDT population the response distribution was 14/42/44% in 1st line and 11/31/58% in 2nd line. Non-HDT pts receiving novel agents in 1st line had significantly higher nCR rates compared to pts receiving older drugs, 22% vs. 12% as well as pts receiving novel agents in 2nd line with nCR rates of 16% vs. 6%. In the HDT population the median time to progression/time to next treatment (TTP/TTNT) was 21.0/29.7 months in 1st line and 8.1/12.7 in 2nd line. In the non-HDT population the median TTP/TTNT was 11.0/16.8 months in 1st line and 7.3/11.4 in 2nd line. There was a significantly increased TTP/TTNT in 1st and 2nd line depending on the increased depth of the response for both the HDT and non-HDT populations. The median OS for HDT pts was 6.7 yrs 95% CI[6.1;7.6] and correlated with 1st line response (nCR 7.6, PR 6.1 and NR 6.2 yrs). When comparing HDT pts to the matched normal population the 1-year survival was 97% vs. 99%, 3-year survival 86% vs. 98% and 5-year survival 66% vs. 95%. The median OS for non-HDT pts (n=1080) was 2.7 yrs 95% CI[2.5;3.0] and increased with better response in 1st line; nCR 3.4, PR 3.0 and NR 1.9 yrs. Kaplan-Mayer analysis showed that the use of novel agents in 1st line (n=316, median age 72.1 yrs) predicted a significantly longer OS compared to conventional treatment (n=764, median age 75.4), median 4.9 vs 2.3 yrs. When comparing pts that received at least two lines of treatment, pts treated with novel agents in 1st line followed by novel agents in 2nd had not reached the median survival but had a lower CI of 6.3 yrs, novel agents in 1st line followed by old agents in 2nd line had a median OS of 4.3 yrs old agents in 1st line followed by novel agents in 2nd line had a median of OS 3.3 yrs and old agents in 1st line followed by old agents in 2nd line had a median of OS 3.0 yrs. Compared to the matched normal population non-HDT pts receiving novel agents in both 1st and 2nd line the 1-year survival was 90 % vs. 96%, 3-year survival 71% vs. 86% and 5-year survival 67% vs. 77%. The number of pts receiving 2nd and 3rd line treatment declined rapidly. Non-HDT pts treated with novel agents in 1st line had a superior response and OS compared to the group treated with standard chemotherapy. Pts treated with novel agents in 2nd line as well seem to have a further improved survival compared to other alternatives. In comparison to a normal population, matched for gender and age at diagnosis, the survival is still shorter. However, if novel agents were used in an optimal treatment sequence the survival could potentially be higher. There is still a need for further development in MM treatment before one can call it a chronic disease. Figure 1: HDT treated pts compared to a matched normal population Figure 1:. HDT treated pts compared to a matched normal population Figure 2: Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Figure 2:. Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Mellqvist:Janssen, Celgene: Honoraria. Näsman:Janssen-Cilag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

Abstract 3937 Treatment results in clinical practice and in real life can be different from each other. Therefore, evaluating real life outcomes in Multiple Myeloma (MM) patients in order to understand treatment outcome in clinical practice is very important. All patients diagnosed with MM and treated between Jan 2000 and Jul 2010 at Karolinska University Hospital, Huddinge and Södersjukhuset were included. Furthermore, all diagnosed patients between Jan 2005 and Jul 2010 at Karlolinska University Hopital, Solna were included. At diagnosis data regarding age, gender, type of myeloma and skeleton destruction as well as Ca, Hb, β2-microglobelin, albumin and creatinine were collected. For each treatment line, drugs given and specific start and stop dates for each drug were collected. Serum and urine M-protein was collected at baseline and each time the measurement differed from the previous. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis but not always confirmed by immunofixation since it was not required in clinical practice. Partial response (PR) was defined as a 50% reduction in M-protein. No response (NR) was defined as less than 50% reduction of M-protein. Progress was considered when M-protein increased with ≥ 25%. Novel agents were defined as bortezomib, lenalidomide and thalidomide. In the total population n=674, 89 (13%) patients were excluded due to non treatment demanding disease or plasmacytoma without MM diagnosis setting the study population to n=585. The median follow up of the study population was 815 days. The median age in the study population was 68 years and 45% were women. High dose treatment (HDT) was given to 214 (37%) patients. The median age in the HDT population was 58 years and 34% were women. The median age in the non-HDT population was 75 years and 51% was women. The median number of given treatment lines was 2. The proportion of patients receiving more treatment lines were declining rapidly with the number of received lines of therapy. The response distribution for the entire population nCR/PR/NR was 27/41/32 in 1st line, 18/34/48 in 2nd line. In the HDT population the same response distribution was 50/38/12 in 1st line and 28/38/34 in 2nd line. In the non-HDT population the response distribution was 14/43/43 in 1st line and 12/33/55 in 2nd line. The depth of the responses was significantly dependent on the line of therapy. Responses were significantly better in the HDT population vs. the non-HDT population in the first two treatment lines. There seems to be a correlation between the responses in 1st and 2nd line in the entire population. Improving the responses in 2nd line compared to 1st line seems not very likely. Statistical analysis shows that the non-HDT patients receiving novel agents in 1st line had a significantly higher probability of achieving nCR, 25% vs 9%.The same statistical difference was seen in the HDT patients with nCR rates of 65% vs 47%. The median TTP/TTNT for the study population was 309/381 days in the 1st line and 182/210 in 2nd line. In the HDT population the TTP/TTNT was 538/639 days in 1st line and 199/257 in 2nd line. In the non-HDT population the TTP/TTNT was 244/295 days in 1st line and 177/193 in 2nd line. In the HDT population both the TTP and the TTNT in the 1st line were significantly better than in the non-HDT population with no difference in the 2nd line. There was a significant trend of increasing TTP/TTNT in 1st line depending on the increased depth of the response. Statistical analysis showed that the use of novel agents in 1st line predicted a longer TTP for the non-HDT population. Median OS was 4.3 years 95% CI [3.9;5.0] with 53% censored. HDT patients had a significant longer median OS 6.3 years 95% CI [5.4;8.5] than the non-HDT patients OS 3.0 years 95% CI [2.2;3.6]. The median OS for non-HDT patients with 1st line best response nCR was 4.9 years, PR 3.3 years and NR 1.5 years. Kaplan-Mayer analysis shows that use of novel agents in the 1st line predicted a longer OS, median 5.1 years vs. 4.1 years. Patients receiving 2nd and 3rd line treatment were declining rapidly. To get a good response in 1st line increases the likelihood of having a good response in 2nd line. Receiving an nCR in 1st line seems to be very important and this study confirms the prognostic impact of achieving at least nCR. The use of novel agents improves the outcome for patients in clinical practice. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Näsman:Janssen-CIlag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

Abstract 530 An open, multi-center, randomized phase III trial performed by the Nordic Myeloma Study Group (NMSG) was designed to explore the effect of a 21-week consolidation period of single agent bortezomib, given during months 3-8 after ASCT. Primary end-point was event free survival and secondary end-points were response rate, toxicity, overall survival, quality of life and cost utility. Between November 2005 and April 2009 404 patients were included, 372 of whom were randomized. This report comprises preliminary data concerning feasibility, toxicity and response rate for the initial 299 randomized patients. Patients were randomized 3 months post ASCT to either no consolidation therapy (current standard in Scandinavia), or to a period of bortezomib consolidation. Initial treatment before ASCT was optional. Patients were stratified for single or double ASCT. Bortezomib was given in a dose of 1.3 mg/m2 twice weekly (days 1, 4, 8 and 11) in a 3 week schedule for the first 2 cycles. In the following four cycles, bortezomib was given once weekly (days 1, 8 and 15) in a 4 week schedule, in total 20 injections over 21 weeks. Before each dose of study drug, the patients were evaluated for possible toxicities. Baseline characteristics were well balanced between the 149 patients in the bortezomib group and the 150 in the control group. All analyses were performed on an intention to treat basis. The mean number of bortezomib injections was 15, median 19 of optimal 20. The mean total dose given was 82 %, median 90 %, of the planned dose. Thirty-one patients (21 %) had to reduce the dose to zero for one cycle or more, mainly due to neuropathy, 11 patients, or progression, 8 patients. Hematological toxicity according to CTC included neutropenia grade ≥ III in 33 patients (22 %), thrombocytopenia grade ≥ III in 14 patients (9 %). Neurological pain grade ≥ III was seen in 7 patients (5 %). Sensory neuropathy grade ' III was seen in 5 patients (3 %). A significant difference in improvement of response was noted between the two arms. At the time of randomization the proportion of CR/nCR was 23 % for patients in the bortezomib arm and 21 % in the control arm. However, when measured six months after randomization (9 months after ASCT), the proportion of CR/nCR was 54 % in the bortezomib group versus 35 % for the controls, p < 0.005. The proportion of patients improving their response from PR to CR/nCR was 20 % and 12 % for the bortezomib and control groups respectively, p = 0.06 NS. The proportion of patients who relapsed during the initial 6 month observation period did differ significantly, 1 % versus 6 %, p Our results indicate that consolidation with bortezomib given as a single agent is feasible and does improve treatment response after ASCT. Disclosures: Mellqvist: Jansen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Johnson and Johnson: Research Funding. Off Label Use: Bortezomib. Consolidation therapy after high dose melphalan.. Westin:Celgene: Membership on an entity's Board of Directors or advisory committees. Gimsing:Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Schering-Plough: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Laane:Schering-Plough: Membership on an entity's Board of Directors or advisory committees. Remes:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Waage:Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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.