ALBERT

Description: Background:Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors.Cytogenetic abnormalities (CA) has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. In the relapse setting, the combinations including proteasome inhibitors and immunomodulatory drugs have shown to improve, and some of them to overcome, the outcome of patients with high-risk CA. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting of 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the IV administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). The rates of CA was similar in both treatment arms. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 51 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 33 months, p=0.03) and this also translated into a significantly shorter OS (38.4m vs not reached, p=0.002). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (29.5 months vs 31.5 months, p=0.9) and OS (46m vs 63m, p=0.1). This beneficial effect observed in the sequential arm applied to both t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (36 months vs 29 months) and 4-years OS (63% vs 68%) in the whole series and no differences were observed between the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Martínez-López:Novartis: Honoraria, Speakers Bureau. Oriol:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

Description: Introduction:SMM is an asymptomatic and heterogeneous plasma cell disorder. The Spanish Myeloma Group demonstrated that patients at high risk of progression benefit from early treatment with Rd. In addition, our preliminary results of the curative approach (GEM-CESAR) showed encouraging results (Mateos ASH 2017). Aim: The primary end-point was to evaluate the Minimal Residual Disease negative (MRD-ve) rate by next generation flow (NGF) after induction and ASCT and the sustained MRD-ve rate at 3 and 5 yrs after ASCT as secondary end-points. Our aim was to increase the MRD -ve rate from 34% (reported in NDMM patients after VTD and ASCT) to 50%. As all patients have completed induction and ASCT, we report the results of the primary end point, efficacy and safety after induction and ASCT. Methods: In this phase II single arm trial, 90 SMM patients at high-risk of progression (〉50% at 2 yrs), younger than 70 yrs and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCsBM compartment by immunophenotypingof 95% plus immunoparesis (Spanish criteria). Asymptomatic MM patients with any of the three biomarkers recently included into the definition of active MM were allowed to be included. Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2followed by ASCT was given as intensification therapy and three months later, patients received two KRd consolidation cycles followed by maintenance with R at dose of 10 mg on days 1-21 plus dex at dose of 20 mg weekly for up to 2 yrs Results: Between June 2015 and June 2017, the 90 SMM patients at high risk of progression were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. The primary end point of the trial was met, since 55% of the patients who completed induction and ASCT achieved MRD -ve by NGF (sensitivity 3 x 10-6). Upon analyzing the results after induction, 88 patients completed the 6 induction cycles and were evaluable for response (two patients early discontinued): the ORR was 98% including 41% of ≥CR (32% sCR and 9% CR) and 41% of VGPR rate. Two patients were mobilization failures and one patient rejected ASCT. Two additional patients experienced biological progression before ASCT and went off the study. Eighty-three patients, therefore, proceeded to HDT-ASCT and were evaluable at day +100: the ORR was 100% including ≥CR in 63% of the patients (51% sCR and 12% CR) and VGPR rate in 23%. The MRD-ve rate increased from 31% after induction to 55% with the ASCT. No differences in outcome have been observed according neither to the definition of high risk (Mayo or Spanish model) nor ultra high risk SMM. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were the most frequent non-hematological AE observed in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three patients reported hypertension (G2 in two and G3 in one). Thirteen patients required lenalidomide dose reduction whilst carfilzomib was not reduced in any patient. In four patients, dexamethasone was reduced. In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All patients engrafted. Consolidation and maintenance phases are ongoing. After a median follow-up of 17 months (5-36), 94% of patients remain alive and free of progression and 97% of them alive. Three patients experienced biological progression and discontinued the study: one of them was refractory to the rescue therapies and died and the other two are receiving rescue therapies. One additional patient died early during induction due to a massive ischemic stroke unrelated to the treatment. Conclusions: Although longer follow-up is required, this "curative strategy for high risk SMM" continues being encouraging with an acceptable toxicity profile. The study has met its primary endpoint. The depth of response improved over the treatment: 63% of patients who completed induction and ASCT achieved ≥CR with a MRD-ve rate of 55%. Disclosures Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Ocio:AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Alegre:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. García Mateo:Binding Site: Research Funding; Amgen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Honoraria. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Novartis: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

Description: Abstract 475FN2 Background: An IMiDs® immunomodulatory agent, Len has a dual mechanism of action: its tumoricidal effect directly leads to tumor cell death, and its immunomodulatory effect may keep the tumor in remission. A phase 3, randomized, placebo (Pbo)-controlled trial, MM-015 compares MPR-R with fixed-duration MPR and MP induction in transplant-ineligible NDMM pts. Interim results showed unprecedented reduction in disease progression risk with MPR-R (Palumbo et al, IMW 2011); this analysis focuses on pts aged 65–75 yrs in whom the greatest benefit was observed. Methods: A total of 459 pts aged ≥ 65 yrs with NDMM were enrolled. Induction consisted of nine 28-day cycles of melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), and Len 10 mg (D1-21) (MPR-R and MPR) or melphalan and prednisone with Pbo (MP). After induction, MPR-R pts received Len 10 mg (D1-21) maintenance until progression; MPR and MP pts received Pbo. Pts with progressive disease (PD) could enroll in an open-label extension phase to receive Len 25 mg (D1-21) ± dexamethasone 40 mg (D1-4, 9–12, and 17–20). This analysis includes data up to Feb 28, 2011 (median follow-up, 30 mos). Results: There were 116/152 (76%), 116/153 (76%), and 116/154 (75%) of MPR-R, MPR, and MP pts, respectively, aged 65–75 yrs. Nearly 50% had ISS stage III disease, 〉 40% had β2-microglobulin 〉 5.5 mg/L, and 40% had CrCL 〈 60 mL/min. With a median follow-up of 30 mos, MPR-R reduced progression risk by 70% and significantly prolonged median PFS (31 mos) vs MP (12 mos; hazard ratio [HR]: 0.30 [95% CI, 0.20–0.45]; P

Description: In MM patients relapsing after MRD-negativity, the disease could reemerge from immature cells or from undetectable MRD. However, it remains unknown if immature cells have the same genetic background as MM plasma cells (PCs), as well as the amount of MRD that persists below the limit of detection (LOD) of next-generation techniques. To obtain further insight, we compared the biological landscape of MM PCs at diagnosis to that of CD34 progenitors, B cells and normal PCs isolated from patients with negative MRD by next-generation flow (NGF) after treatment. We performed whole-exome sequencing (WES, mean depth: 90x) with the 10XGenomics Exome Solution for low DNA-input as well as deep NGS of B-cell receptor immunoglobulin (BcR IG) gene rearrangements (mean, 69,975 sequences), in a total of 68 cell-samples isolated from the bone marrow (BM) of 7 MM patients with MRD-negativity by EuroFlow NGF after induction with VRD and auto-transplant (GEM2012MENOS65 trial). Patients with negative MRD were intentionally selected to avoid contamination with MM PCs during sorting of CD34 progenitors, B-cell precursors, mature B cells and normal PCs after induction and transplant. We investigated in these populations the presence of somatic mutations and clonotypic BcR Ig rearrangements detectable in MM PCs sorted at diagnosis, using peripheral blood T cells as germline control. We also performed WES in matched diagnostic MM PCs and MRD cells persisting after VRD induction in 14 cases as control. In another 6 patients with untreated MM, we performed single-cell RNA and BcR IG sequencing (scRNA/BcRIGseq) of total BM B cells and PCs (n=16,380) to investigate before treatment, if the clonotypic BcR IG sequence of MM PCs was detectable in other B cell stages defined by their molecular phenotype. We used multidimensional flow cytometry (MFC) to investigate the frequency of B cell clonality in BM samples from a larger series of 195 newly-diagnosed MM patients, prospectively enrolled in the GEM-CLARIDEX trial. Somatic mutations present in diagnostic MM PCs were detectable in the lymphopoiesis of 5/7 patients achieving MRD-negativity after treatment. In one case, out of 55 mutations present in diagnostic MM PCs, a single mutation in PCSK1N (VAF: 0.30) was detectable in normal PCs. In the other four patients, a total of 85 mutations were present in MM PCs and up to 10 (median VAF, 0.16) were found all the way from CD34 progenitors into B-cell precursors, mature B cells and normal PCs, but not in T cells. Of note, most mutations were reproducibly detected in each cell type after induction and after transplant. All somatic mutations shared by MM PCs and normal cells were non-recurrent, and genes recurrently mutated in MM (eg. ACTG1, ATM, DIS3, FAM46C, KRAS, LTB, MAX, TRAF3) were found in MM PCs but never in normal cells. Copy number alterations (CNA) were found only in MM PCs. By contrast, up to 513/827 (62%) mutations and 48/67 (72%) CNA were detectable in matched diagnostic MM PCs and persistent MRD cells, indicating that the few somatic variants present in normal cells were unlikely related to contaminating MRD below NGF's LOD. Accordingly, MM clonotypic BcR IG rearrangements were detectable in normal PCs (4/7patients) and in immature B cells (5/7 patients) but at much lower frequencies (mean of 0.02% in both). Of note, 9 additional clonotypes (mean 8.4%) were found in MM PCs of 5/7 patients (range, 1-3). scRNR/BcRIGseq unveiled that clonotypic cells were confined mostly but not entirely within PC clusters, and that in 1 patient another clonotype was detectable in mature B cells. Accordingly, using MFC we found in a larger series that 25/195 (13%) of newly-diagnosed MM patients display B-cell clonality (median of 0.7% BM clonal B cells, range 0.02%-6.3%). In conclusion, we show for the first time that MM patients bear somatic mutations in CD34 progenitors that specifically differentiate into the B cell lineage, likely before the disease onset. Because diagnostic, MRD (and relapse) MM PCs display great genetic similarity, these results suggest that undetectable MRD

Description: Background: The advent of immunotherapy renewed the interest in immune monitoring to identify determinants of treatment response. Flow cytometry is widely adopted in immunotherapy-based clinical trials, but manual analysis of multiparameter files poses a challenge to capture full cellular diversity and to provide unbiased reporting in large datasets. Methods: Here, we developed a semi-automated pipeline named "FlowCT" which, starting from compensated data obtained with standardized protocols, allows simultaneous analyses of multiple files and automated cell clustering. FlowCT starts with quality control and data normalization followed by an analytical stage with clustering algorithms, dimensional reduction techniques and cluster identification based on antigen expression. Statistical tools are included for immediate analysis of results. Results: As proof-of-concept, we used FlowCT in three different datasets. First, we applied FlowCT to bone marrow (BM) samples from three multiple myeloma (MM) patients stained with 17-color flow cytometry, to determine the increment in the complexity of analyzing 8 and 17 markers, chosen to characterize T cells. Of note, a single combination of CD3, CD4, CD8, CD45RA, CD56, CCR7, PD1 and TIGIT, allowed the identification of 31 lymphocyte subsets using FlowCT, which increased to 39 different clusters with 17 markers and unveiled a novel population of CD3- CD56- CD8+ CD16+ lymphoid cells in the MM immune microenvironment. Secondly, we applied FlowCT to matched peripheral blood (PB) and BM samples from 10 patients with smoldering MM, to objectively assess if PB represents a good surrogate of T-cell distribution in the BM. Using an 8-color combination to characterize CD4 T cells, up to 26 different subsets were identified, including several CD4 T helper (Th) type subsets. Of note, their distribution within PB CD4 T cells was similar to that found in BM, except for CD4 T CXCR3+CCR4+ effector memory and Th17 central memory subsets that decreased in the BM tumor immune microenvironment. Thirdly, we analyzed 30 BM samples from 10 MM patients studied every year during maintenance therapy, monitored with CD4, CD8, CD25, CD45RA, CD127, CCR7, PD1, and TCRγδ to characterize T cells. FlowCT identified 29 different T-cell populations, including 9 CD4 subsets, 14 CD8 subsets, 4 Tγδ cell subsets and 2 distinct Treg subsets. Longitudinal, semi-automated and unbiased analysis unveiled a significant fluctuation of CD4 naïve and transitional memory cells during maintenance, as well as a significant decrease of CD8 CD127- effector memory and transitional effectors cells after 2 years of maintenance. Conclusions: Here, we presented FlowCT, a pipeline optimized for the analysis of large flow cytometry datasets that could be easily implemented by research laboratories to unveil full cellular diversity, singular patterns of antigen expression, and to provide unbiased reporting in large studies, like clinical trials. Disclosures Puig: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; The Binding Site: Honoraria; Takeda: Consultancy, Honoraria. Borrello:WindMIL Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Aduro: Patents & Royalties: intellectual property on allogeneic MM GVAX; BMS: Consultancy; Celgene: Honoraria, Research Funding, Speakers Bureau. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. Mateos:Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee. Lahuerta:Takeda, Amgen, Celgene and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Paiva:Celgene, Janssen, Sanofi and Takeda: Consultancy; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 1811 Poster Board I-837 The prognostic significance of achieving complete remission (CR) in Multiple Myeloma (MM) has finally been accepted. However, available studies have been based on series with a median follow-up around 5 years. This time period is insufficient according to the current life expectation of MM. Aim To establish the real effect of prognosis of the different response categories in a cohort of MM patients treated with autologous stem cell transplantation (ASCT) after long term follow up. Patients and methods Follow-up from diagnosis of 344 MM patients transplanted between 1989 and 1998 has been updated. These patients were previously included in a study aimed at establishing the post-ASCT response significance in MM and to validate the EBMT classification (Br J Haemat 2000;109:438-46). It was possible to update the follow up of 322 patients as at April 2009. At this date 99 patients were alive with a median follow-up form diagnosis of 12.5 years. Response categories and evaluated cases were: i) Complete Response (IF-) (CR), n= 84 ii) near Complete Response (EF-/IF+) (nCR), n= 66 iii) Very good partial response (VGPR) (

Description: Abstract 3989 Background: Treatment patterns of multiple myeloma (MM) vary across the globe, mostly dictated by the availability and patient access to different drug therapies. The outcomes of patients with MM, especially relapsed myeloma can be significantly affected by the availability of newer treatments, as well as potential biological differences related to ethnicity. We have previously shown that the outcome of patients relapsing after therapy with bortezomib (Bz) and one or more of the IMiDs remain poor with the currently available treatments and represent a difficult group of patients to treat. We undertook the current analysis on a set of patients from United States, several European countries and South Korea. Methods: We designed a multicenter, retrospective study that enrolled 294 patients with relapsed MM, from 14 sites (122 from Europe, 107 from US, and 65 from Korea). Patients were refractory to Bz, defined as no response to prior Bz-containing regimen or disease progression within 60 days of a Bz-containing regimen. Patients were also relapsed, refractory, intolerant, and/or ineligible, to treatment with an IMiD (thalidomide or lenalidomide). The date patients satisfied the above entry criteria was defined as time zero (T0). Clinical and laboratory data from diagnosis and individual relapses were collected along with details of all MM drug therapies before and after T0. Responses were assessed by IMWG or EBMT criteria. The goal of the study was to compare the characteristics of patients who satisfy the above inclusion criteria, the therapies employed prior to and after T0 and clinical outcome among these patients from different parts of the world. Results: The mean (median, range) time to reaching T0 from diagnosis was 4.5 (4.0, 12.8), 4.2 (3.2, 18.6), and 3.2 (2.8, 9.6) years from diagnosis for patients from US, Europe and Korea, respectively, P=0.021. The mean (median, range) number of therapies for the three groups were 8 (8, 13), 4 (4, 10), 5 (4, 7), respectively; P=PR) to the initial therapy at diagnosis were 56%, 77% and 49% respectively for the US, European and Korean cohorts. Overall 220 patients had at least one therapy after T0, and 114 (52%) had a novel agent (Bz, len or thal) containing regimen as their first treatment after T0. Patients in US were more likely to receive additional therapies after the first post-T0 therapy; 62%, 32%, and 12% of patients from US, Europe and Korea, respectively, began a second post-T0 regimen within 2 years following time zero. The median number of therapies post T0 was 2, 1, and 1 for patients in US, Europe and Korea respectively. The response rates to the first regimen after T0 were 15%, 33% and 19% for the US, European and Korean cohorts, and were similar between those receiving a regimen with one of the novel drugs compared to rest. Patients younger than 60 years and those with prior transplants were more likely to respond to post T0 regimens. The median time to progression or death from T0was similar for the three patient cohorts, 5 months (Figure 1A). The median overall survival (95% CI) from T0 was 13 months (10, 16), 7 (5,9) and 8 (4,9) respectively for the US, European and Korean cohorts (Figure 1B). Conventional prognostic factors, especially the ISS stage was predictive of OS post T0. Additionally, presence of extramedullary disease was associated with a shorter overall survival. Conclusion: The results of the current study demonstrate significant differences between different parts of the world in terms of the treatment patterns both in the setting of initial therapy as well as treatment of relapsed disease. Patients in the US were more likely to receive multiple regimens both before and after T0. This is likely a reflection of increasing numbers of new drugs that have gone into clinical trials and thus enhancing options. The study further highlights the poor outcome of patients who have relapsed after the new drugs, irrespective of the geographical location. Disclosures: Kumar: Merck: Consultancy, Honoraria; Genzyme: Consultancy; Celgene: Consultancy. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Sonneveld:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Siegel:Merck: Honoraria; Millenium: Honoraria, Research Funding, Speakers Bureau. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees.

Description: Recently, a significant improvement in time to progression (TTP) was reported for pegylated liposomal doxorubicin (PLD) + bortezomib combination therapy vs. bortezomib monotherapy in a phase III randomized trial in relapsed or refractory multiple myeloma (RRMM) (Orlowski, JCO 2007). This pre-specified analysis assessed the efficacy of PLD+bortezomib in RRMM based on the number of prior lines of therapy and previous anthracycline exposure status. Patients with ≥1 prior therapy were randomized to receive PLD at 30 mg/m2 on day 4 and bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least 2 cycles beyond CR, or optimal response unless disease progression, or unacceptable toxicities occurred. The baseline beta-2 microglobulin levels were comparable between the subgroup with ≥2 prior treatments and that with 1 treatment (median 3.98 vs. 4.01 mg/L), as well as between anthracycline-exposed and -naïve patients (median 3.91 vs. 4.55 mg/L). The improved TTP reported previously with PLD+bortezomib over bortezomib in the total study population was similarly observed in all four subgroups of patients (patients with ≥2 lines of prior therapy or 1 prior therapy, anthracycline-exposed (median 144 mg/m2 in both treatment arms) or -naïve groups (Table)), indicating a consistent therapeutic benefit favoring the PLD+bortezomib combination. Furthermore, TTP was comparable for the PLD+bortezomib combination between groups with ≥2 lines of prior therapy vs. 1 prior therapy (heterogeneity test, p=0.523), as well as patients who were anthracycline-exposed or -naïve (heterogeneity test, p=0.716). Incidence of treatment-related SAEs, grade 3/4 neuropathy, and symptomatic cardiac events was comparable between treatment arms in each subgroup (Table). PLD-related hand-foot syndrome was also

Description: Introduction: Disease control at five years would be a desirable endpoint for elderly multiple myeloma (MM) patients; however, the percentage of cases reaching this objective as well as the biomarkers to predict it, are not well defined. Objective and design: In order to gain further insight about long-term disease control (〉5 years progression-free) in elderly MM we have analyzed a homogeneous population of 435 newly-diagnosed transplant-ineligible (TNE) patients enrolled in two consecutive Spanish clinical trials (GEM2005MAS65, GEM2010MAS65), that included both proteasome inhibitors and immunomodulatory drugs. Results: Amongst the 435 patients included in this post-hoc study, only 18.8% remained alive and progression-free after five years of initiating treatment. Noteworthy, in these patients the overall survival (OS) rate at 10-years was 69.4%, as compared to 11.4% for those patients progressing during the first five years (p〈 0.001). Baseline variables significantly associated with long-term progression free survival in the univariate analysis were younger age, ISS 1, R-ISS 1, hemoglobin ≥ 12g/dl, normal LDH, and standard-risk cytogenetic abnormalities and the presence of a monoclonal gammopathy of unknown significance (MGUS)-like immunophenotypic profile in the bone marrow. Complete responses (CR) and minimal residual disease (MRD) negativity were also associated with long-term progression free survival. In the multivariate analysis, an hemoglobin level ≥12g/dl (OR 2.61; 95% CI 1.47 - 4.61, p=0.001) and a MGUS-like immunophenotypic profile in the bone marrow (OR 3.33; 95% CI 1.30 - 8.54, p=0.002) were the two baseline variables significantly and independently associated with a higher probability of long-term disease-free survival. When the depth of response (including MRD) was included in the logistic regression model, Hb level ≥12g/dl (OR 2.18; p=0.010) and the MGUS-like signature (OR 4.99, p

Description: We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P 〈 .001) both after conventional (median, 4.5 years vs 3.3 years; P 〈 .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.