ALBERT

Description: Introduction: The advent of anti-tyrosine kinase has revolutionized the treatment of chronic myeloid leukemia. Indeed, from 2000, the IMATINIB has become internationally the gold standard of treatment for CML chronic phase, while the allogeneic bone marrow transplant was previously, the 1st intention choice, when an HLA-matched donor is available. The aim of this study is to evaluate the efficiency and the toxicity of a treatment with Imatinib(copy), drug used in Algeria to treat patients with a CML chronic phase. The main objective is to evaluate the overall survival and the progression-free survival to these patients. Materials and methods: This is a longitudinal study, National, multicenter, retrospective, which included Algerian patients with chronic phase CML and treated with Imatinib between January 2007 and December 2013. A technical form was established and distributed to different hematology services nationwide, to collect and analysis the following data: Patient's general characteristics, disease circumstances of discovery, clinical and para-clinical examinations at diagnosis (blood count, blood smear, bone marrow aspiration, karyotype, molecular biology, Sokal prognostic classification score and Eutos score). The treatment: Imatinib 400 mg / d, a therapeutic assessment is made according to the ELN recommendations adapted to our conditions and capabilities in Algeria: The complete hematologic response (CHR) at 03 months and molecular response and / or cytogenetic and / or Fish at 03, 06.12, 18.24 months and more according to capabilities. At 03mois and / or 6 months we search a bcr / abl rate

Description: Introduction: Chronic lymphocytic leukemia (CLL) is the most frequent leukemia of the adult in Europe and North Africa. It is rare on the Asian and African continents. It affects mainly elderly people over 60 years. The main objective is determining the rate of average annual incidence, and secondly establishing the distribution of this complaint according to the different health regions of the country and precise the epidemiological characteristics. Patients and Methods: It is a national, descriptive, retrospective epidemiological study carried out for a period of 05 years : from January 2009 to December 2013. Information collection is done thanks to the setting up of a technical data sheet sent out to the appropriate services. This technical data sheet is about the geographic data of the patient (place of birth, place of residence, place of taking charge of the disease and the date of the diagnosis), anthropologic data (age at the diagnosis, sex), as well as the clinico-biological data. The working of the responses was done on SPSS 19 .0. In our study, the diagnosis is carried before an hyperlymphocytosis 〉 5000/ mm3, a cytological examination of the blood smear and an immunophenotyping operation by cytometer operation in flow. Results: 17 hematology departments have participated in this study with 1210 cases listed, of which 68,1% (824 pts) are men. The average annual recruitment is of 242 cases. The average annual incidence rate, calculated according to the data of the national statistics office is estimated at 0,66 / 100.000 inhabitants.This incidence does not increase over the years and stays relatively stable (2009 = 0,67; 2010 = 0,57; 2011 = 0,63; 2012 = 0,67; 2013 = 0,74/100.000 inhts). The geographic distribution of the pts according to their places of residence, shows that the majority among them are from the north of the country particularly the center (0,80/100.000 inhts). Incidence increases over age, going among men from 0,06 for 100.000 inhts between 30 - 39 years to 11,94 / 100.000 inhts at 80 years and over and among women from 0,04 for 100.000 inhts to 6,08 for 100.000 inhts. The average incidence rate is of 0,85/100.000 inhts among men and of 0,42/100.000 inhts among women. The average age at the diagnosis is of 67,5 years (33 - 98 years). 30,1% (365 pts) incident cases are observed among the patients over 75 years and 14,1% (171 pts) among the patients below the age of 55 years. The profession that is most found is farming 12.2% (78/635 precised). The diagnosis is late in Algeria, the first symptome which brings the patient to consultation is the tumoral syndrome (44% (363 / 825 precised)) in an average diagnosis period of time of 07 months (01 - 96 months). The stage C (classification of Binet) is equally predominant, found in 41,1% (492 / 1172 precised). In terms of biology : the average rate of lymphocytes is of 92500/mm3 (5000-900 000/mm3). The morphological study on blood smear finds 88,2% (1066 / 1208 precised) of typical CLL and 50% of Gambrest cells. The cytometer operation in flow done in 746 cases (61,6%) shows a score of matutes 〉 4 in 92,3% and in 7,7% is equal to 3. the cytogenetic operation (Caryotype and Fish) done in only one hematology department (CAC of Blida) among 102 patients (8.4%). Comments: The rate of incidence in Algeria is weak compared to that of other countries. The rate of incidence standardized to the world population is of 0,52 cases/100.000 inhts and to the European population is of 0,68 cases p 100.000 inhts. The young age of the population may explain this incidence and that some patients at the stage A are not diagnosed. The CLL affects more frequently men. The average age at the diagnosis is of 67,5 year. However, 30,1% of the incident cases are observed among the patients over 75 years in Algeria versus 45 à 50% of incident cases in Europe and this may be explained by the young age of our population. The CLL are placed 5th among the malignant hemopathies: the rate of incidence for the year 2009 : LNH = 1.96; LH = 1.2; MM = 0.96; AML = 0.85; CLL = 0.67; CML = 0.44; ALL = 0.32. Conclusion: the CLL can be diagnosed and differentiated from the other lymphoproliferative syndromes thanks to the morphological examination of the lymphocytes at the blood smear completed by an immunophenotyping operation of the peripheral blood . This study represents only an epidemiological approach of the CLL in Algeria. The incidence is still weak in our country; it affects as in the other countries the elderly people with a masculin predominance. Disclosures No relevant conflicts of interest to declare.

Description: The Belgrade laboratory rat (b/b rat) has hereditary, hypochromic, microcytic anemia with a variety of red cell abnormalities. Although this anemic syndrome has been recently ascribed to the defective delivery of iron to the developing red cell, the basic hematopoietic defect is still unknown. In this article we present evidence that the b/b rat has an additional hematologic defect. We have found that the megakaryocyte number in the marrow of the b/b rat is decreased to one half that of the normal rat, but the maturation rate of recognizable megakaryocytes is accelerated and the size is increased. The platelet count is moderately reduced. These findings indicate that megakaryocytopoiesis in the anemic b/b rat is abnormal and suggest that the genetic defect may involve the progenitors of the megakaryocyte cell lineage. Alternatively, the megakaryocytic abnormalities may be secondary to the severe anemia.

Description: Introduction : Among genetic diseases in hematology, β Thalassemia ranks second after sickle cell disorders in Algeria. Given the seriousness and cost of the care that arises, a national action plan is needed. As a starting point, a national survey is essential to know the epidemiological situation of this disease. Objective : To determine the soci-demographic, diagnosis and evolution characteristics of major and intermediate thalassemia in Algeria. Materiels and Methods : This is a multicenter, retrospective, analytical study of 775 patients with thalassemia major (TM: 598 cases) and intermediate (TI: 177 cases). This national survey is representative of 21 services (Hematology: 19, Pediatrics: 03). The data was collected from medical records on a survey card distributed to all relevant services. Results : As of January 1, 2017, the prevalence of β Thalassemia estimated from this study is of the order of 3.47 cases per 100 000 inhabitants. The current average age of major thalassemia (MT) is 17.90 years, with extremes of [1-44 years], that of intermediate form (IT) is 23 years old with extremes of [1-61 years], the sex ratio is 1.15. The concept of consanguinity is specified in 499 patients and is present in 49.30% of cases, the geographical origin of patients is variable, 53% are from the center of the country and 43% from the east. The circumstances of the diagnosis are known in 87.25% of subjects, these are clinical symptoms in 93.91% of patients, with an average age at diagnosis of 16.31 months for MT and 5.5 years for IT. The diagnosis is neonatal in only 5.68% of cases. Blood cells transfusion needs are known in 80% of our cohort, 86% receive a systematic and regular diet; 554 patients are on chelation therapy, the main modality being deferoxamine or Deferasirox type monotherapy. 40 MT patients received Hematopoetic Stem Cell Transplantation. The monitoring of iron overload was based mainly on the determination of ferritinemia, only 8.8% of patients received cardiac and hepatic MRI. Various complications associated with iron overload have been reported, the most common being: Hepatic injury (48%), heart disease (36%), diabetes (30%), hypothyroidism (29.17). %), with average ages of onset of 26.67, 18, 19, and 14.50 years, respectively. In addition, viral serology was performed in 536 patients, 64 (11.9%) of whom were carriers of anti-HCV Ab. Conclusion : The quality and life expectancy of thalassemic patients has improved significantly in recent years; complications related to iron overload remain the leading cause of death, the means of evaluation remain insufficient in our country. In addition, the care of our patients must be standardized on the national territory. Disclosures No relevant conflicts of interest to declare.

Description: Background: Proteasome inhibitors (PIs) are important agents against myeloma, but innate and acquired resistance limit their effectiveness. We previously found Tight junction protein (TJP)-1 to be a modulator and potential biomarker of PI sensitivity, via studies of bortezomib resistant models and clinically annotated gene expression profiling (GEP) databases of patient samples. Also, we showed that its expression reduced EGFR/JAK1/STAT3 pathway activation and proteasome capacity. However, the molecular mechanisms by which TJP1 expression suppressed EGFR signaling and enhanced PI sensitivity were not understood. Methods: We performed co-immunoprecipitation (co-IP) studies to understand interactions of TJP1 with EGFR, and evaluated the impact of various cytokines on proteasome capacity. Also, genetic and pharmacologic approaches were used to modulate EGFR/JAK/STAT activity to determine the effects on PI sensitivity. Finally, gene set enrichment analyses (GSEA) were performed to determine if EGFR activation signatures could be identified in primary samples, and if they correlated with outcomes. Results: Previous studies of TJP1 focused on myeloma models, but since bortezomib is also approved for mantle cell lymphoma, we sought to determine if TJP1 influenced sensitivity here as well. Suppression of TJP1 using shRNAs reduced the sensitivity of JeKo-1 and MINO cells to bortezomib. In addition, murine embryonic stem cells (mESCs) with TJP1 knockout were more resistant to PIs than was the case for wild-type mESCs. Moreover, the TJP1 knockout mESCs expressed higher levels of both activated EGFR and immunoproteasome subunits PSMB8 and 9, and had greater levels of proteasome chymotrypsin-like (ChT-L) activity. Also, re-introduction of TJP1 into the knockout mESCs ehanced their PI sensitivity, and reduced the ChT-L activity. Co-IP studies showed that IP of TJP1 also led to detection of EGFR, and vice versa. Phospho-specific antibodies showed that TJP1 precipitated predominantly the non-phosphorylated, inactive EGFR. Indeed, when cells were treated with EGF and extracts were subjected to IP for TJP1, reduced levels of EGFR were precipitated. Evaluating other receptor tyrosine kinases, we found that TJP1 precipitated IGF-1R but not IL-6R. Therefore, we treated myeloma cells with EGF, IL-6, or IGF-1; all reduced PI sensitivity, but only EGF enhanced proteasome ChT-L activity and capacity. Moreover, shRNA-mediated EGFR knockdown, or pharmacologic inhibition with erlotininb in myeloma cells reduced JAK1/STAT3 activity, levels of PSMB8 and 9, and ChT-L activity, and enhanced the activity of bortezomib. Since the PSMB8 and PSMB9 promoters have consensus STAT3 binding sites, we knocked down STAT3 and found that this also reduced PSMB8 and 9 and ChT-L activity, and enhanced the efficacy of bortezomib. In a mouse model of lytic bone destruction by xenografted RPMI 8226 cells, the ability of bortezomib to increase bone trabecular volume was blunted by TJP1 suppression, consistent with a lower anti-myeloma effect. Lastly, we used publically available EGF-stimulated and EGFR inhibitor gene signatures to examine the clinically annotated GEP data from myeloma patients. This showed that: 1) TJP1 expression in myeloma samples from patients on the University of Arkansas Total Therapy studies was positively correlated with known signatures of inhibitors of EGFR signaling; 2) in GSEA, signatures of EGF and EGFR signaling were significantly positively enriched when genes were ranked by correlation with TJP1; and 3) an EGFR-related gene set had significant negative correlation with survival duration in the Total Therapy 3 dataset. Conclusions: Taken together, our data support the role of TJP1 as a negative regulator of EGFR signaling through its ability to specifically bind, and possibly stabilize the non-phosphorylated form of EGFR. Furthermore, they demonstrate that TJP1 influences proteasome capacity through EGFR/JAK/STAT signaling, and that approaches to suppress this pathway hold promise to overcome PI resistance and achieve PI sensitization. Finally, they validate a heretofore underappreciated role for EGF/EGFR signaling in myeloma pathobiology and patient outcomes. Disclosures Mulligan: Millennium Pharmaceuticals: Employment. Usmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding. Orlowski:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Daratumumab (DARA) is a human monoclonal IgG1κ CD38-targeting antibody that functions through several mechanisms of action (MOA), including CDC, ADCC, ADCP and induction of apoptosis. An additional, novel role of immune modulation and increased adaptive immune response was revealed from translational studies of DARA (16 mg/kg) in single-agent, phase 1/2 studies (SIRIUS [MMY2002] and GEN501; Krejcik J et al, Blood 2016;128:384-94). To further explore the ability of DARA to promote adaptive T-cell responses, we profiled T-cell repertoires (TCR) to evaluate T-cell clonality, expansion, and diversity from samples collected in POLLUX (MMY3003), a phase 3, randomized, open-label, multicenter study for patients with relapsed/refractory MM, in which DARA was tested in combination with lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone alone (DRd vs. Rd; Dimopoulos MA et al, N Engl J Med 2016; in press). Methods: T-cell receptor beta (TCRβ) sequencing for repertoire profiling was conducted on whole blood samples collected at baseline and eight weeks after DARA treatment (cycle 3 [C3]) from subjects on both arms using the ImmunoSEQ assay (Adaptive Biotechnologies. Seattle, WA, USA). 133 subjects in DRd and 124 subjects in Rd treatment groups were included in this analysis and represented a balanced subgroup of the POLLUX clinical trial subjects. T-cell metric changes were compared between arms with ANOVA, including the treatment arm and visit interaction term. Within treatment-arm changes were evaluated with a Wilcoxon signed-rank test comparing baseline to on-treatment values per patient. Results: Consistent with the randomized treatment groups, no baseline differences were observed in T-cell repertoire metrics between the treatment arms, including T-cell clonality, diversity (or richness), and T-cell fraction. Similar to prior findings from DARA monotherapy studies, significantly larger increase of TCRβ clonality was observed in the DRd arm (median of 0.166 at baseline to 0.263 at C3). Interestingly, there was no increase in TCRβ clonality in the Rd arm (median of 0.175 at baseline to 0.175 at C3). The change in TCRβ clonality between C1 and C3 was significantly different between DRd and Rd (p=3.26E-10), demonstrating that the addition of DARA to Rd induces a specific clonal expansion of T cells. Estimated richness (diversity), on the other hand, slightly decreased with DRd treatment but not with Rd treatment (median of 503,951 at baseline to 427,096 at C3 [p= 1.01E-04] vs 572,182 to 532,806 [p= 3.58-01]). Among patients in both treatment groups, a bigger increase in T-cell fraction was observed in DRd vs Rd (median of 0.231 at baseline to 0.278 at C3 [p= 2.62E-3] vs 0.228 to 0.249 [p= 1.91E-01]). Although there were no significant differences in baseline characteristics in T-cell clonality, richness, and T-cell fraction, quartile analysis demonstrated that high baseline TCR richness predicted for better PFS with DRd but not for Rd. Conclusion: DARA in combination with lenalidomide plus dexamethasone specifically induced robust increases in T-cell clonality, which was not observed within the control lenalidomide plus dexamethasone arm. Interestingly, baseline TCR richness was associated with improved PFS in DRd subjects. This observation is similar to results with immune checkpoint inhibitors (Postow MA et al, J Immunother Cancer 2015;3:23), and together with the significant increase in T-cell clonality, provides further evidence for the immunomodulatory activity of DARA, even in combination therapy. These data support DARA's immune-modulatory MOA and provide additional insights into DARA's effect on the TCR in combination with standard of care treatment. Figure Figure. Disclosures Chiu: Janssen: Employment. Casneuf:Janssen R&D, Beerse, Belgium: Employment; Johnson & Johnson: Equity Ownership. Axel:Janssen Pharmaceuticals Research and Development: Employment. Lysaght:Immuneering Corp: Employment; Janssen: Research Funding. Bald:Janssen: Employment. Khokhar:Janssen: Employment. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Amgen: Consultancy, Research Funding, Speakers Bureau; 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, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding. Goldschmidt:Onyx: Honoraria, 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, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Ahmadi:Janssen: Employment. Chan:Adaptive Biotechnologies: Employment; University of Washington: Other: Visiting scholar. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment.

Description: Introduction Plerixafor has recently been reported to be associated with an increased risk for developing MDS in patients with hematologic malignancies (Deol A et al. 2013; Bone Marrow Transplant 48:1112-6). Our group has extensive experience with plerixafor and we sought to confirm this finding. Patients and Methods A total of 294 patients treated at our institution between 2003-2013 (MM: 252, NHL: 22, Hodgkin: 4, Waldenstrom macroglobulinemia: 4, Amyloidosis: 4, LCDD: 2, other: 6) were identified as having received plerixafor as part of their mobilization regimen (62% male/ 38% female, median age 63.2 years (range 26-85)). Metaphase karyotypes for all 294 patients were reviewed for cytogenetic abnormalities typical for MDS (MDS-Ca). Clinical MDS/AML was defined as the condition for which specific MDS/AML therapy was required and administered. Of these, 11 patients developed MDS-Ca or clinical MDS prior to plerixafor administration and were excluded from further evaluation. For statistical analyses we divided our group by age (60) and looked at variables our group has found to correlate with development of MDS-Ca or clinical MDS, i.e. albumin, hemoglobin, and platelet count immediately prior to mobilization and inadequate HPC collection (defined as

Description: Abstract 2933 Background: MM patients have a significantly increased risk of developing certain SPMs subsequent to their initial diagnosis, including a 3.49-fold increased risk of leukemia and, specifically, an 8.32-fold increased risk of acute non-lymphocytic leukemia (but no overall increased risk of solid tumor SPMs; Surveillance, Epidemiology and End Results [SEER] data 1973–2000). The relative SPM risk increases with age and time after initial diagnosis; the risk of leukemia rises from a 1.22-fold increase within 1 year after diagnosis to 3.12-fold, 7.01-fold, and 5.45-fold increases at 1–4, 5–9, and ≥10 years, respectively. An elevated risk of SPMs may be particularly associated with the use of specific therapeutic agents, including conventional or high-dose cytotoxic chemotherapy. Here we report an analysis of data from four phase 3, randomized, controlled trials of Btz alone or in combination to determine whether Btz treatment is associated with an increased SPM risk. Methods: Data were reviewed from: 1) the APEX study of Btz versus high-dose dexamethasone (Dex), and 2) the MMY-3001 study of Btz plus pegylated liposomal doxorubicin (PLD) versus Btz in patients with relapsed or refractory MM after 1–3 prior therapies; 3) the VISTA study of Btz plus melphalan-prednisone (VMP) versus MP in previously untreated transplant-ineligible patients; and 4) the HOVON65/GMMG-HD4 study of Btz, doxorubicin, and Dex (PAD) induction plus Btz maintenance post-transplant versus vincristine, doxorubicin, and Dex (VAD) induction plus thalidomide (Thal) maintenance in previously untreated transplant-eligible patients. Planned duration of Btz therapy was 39 weeks in APEX, 24 weeks in MMY-3001, 54 weeks in VISTA, and 9 weeks induction plus 2 years of maintenance in HOVON65/GMMG-HD4. For APEX, MMY-3001, and VISTA, clinical trial databases were reviewed for events within the MedDRA system organ class of ‘neoplasms’, and new malignancies developing during or after treatment were recorded (excluding non-melanomatous skin cancers and in situ malignancies). In addition, for VISTA, data were obtained from an SPM survey after a median follow-up of 5 years. For HOVON65/GMMG-HD4, data were prospectively collected; median follow-up was 42 months. The incidence rate (IR) of SPMs was expressed as the number per 100 patient-years (pt-yrs). Results: The risk of SPMs with Btz-based therapy appeared uniformly low across all four phase 3 studies in different MM patient populations (Table). A total of 25 SPMs were seen in 1718 Btz-treated patients, including three cases of acute myeloid leukemia/myelodysplastic syndromes, one B-cell malignancy, and one case of cutaneous T-cell lymphoma (in a patient with substantial prior alkylating agent exposure for treatment of MM), plus 20 reports of solid tumors (reflecting the higher overall incidence of these tumors). The IR ranged from 0 in the single-agent Btz arm of MMY-3001 to 1.66 with VMP in VISTA, with an IR of 0.88 in APEX and 0.3 in the PAD arm of HOVON65/GMMG-HD4; median age of Btz-treated patients was highest in VISTA, at 71 years. Overall rates (%) also appeared higher in VISTA, probably due to the longer follow-up and older population, plus the potential effects of concomitant chemotherapy. In the three studies with non-Btz control arms, the IR did not appear to be increased with Btz-based therapy versus the control arm, and across all Btz-containing arms in the four studies, the IRs for hematologic malignancies and solid tumors were consistent with SEER estimates (2004–2008 data) of the overall incidence of malignancies in the US population, of 1.1, 1.9, and 2.4 per 100 pt-yrs in individuals aged 55–64, 65–74, and 75–84 years, respectively. Conclusions: Btz-based therapy for MM does not appear to be associated with an increased risk of either hematologic or solid tumor SPMs, with IRs consistent with SEER data for IRs in the overall US population. Disclosures: San Miguel: Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Orlowski:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Onyx: Consultancy; Cephalon: Consultancy; Centocor: Consultancy; Celgene: Consultancy, Research Funding. Goldschmidt:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Satler:Millennium Pharmaceuticals, Inc.: Employment. Esseltine:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership; Johnson & Johnson: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Ponsillo:Millennium Pharmaceuticals, Inc.: Employment. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. King:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Desai:Janssen Global Services: Employment; Johnson & Johnson: Equity Ownership. Lutska:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Gifkins:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.

Description: Introduction Lenalidomide-based therapies are a standard of care for patients with newly diagnosed, transplant-ineligible MM. Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody which has single-agent activity in heavily pretreated MM patients. As previously reported in 3 phase 3 studies, the addition of DARA to standards of care in both relapsed refractory (D-Rd, DARA plus bortezomib and dexamethasone [D-Vd]) or transplant-ineligible NDMM (DARA plus bortezomib, melphalan, and prednisone [D-VMP]) resulted in a ≥50% reduction in the risk of disease progression or death (Palumbo A, et al. N Engl J Med 2016;375:754-766; Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331; Mateos MV, et al. N Engl J Med 2018;378:518-528). Of these, the POLLUX study with D-Rd showed the greatest benefit with a 63% reduction in risk of disease progression or death in patients with MM who had at least one prior line of therapy. Based on the efficacy and tolerable safety profile of D-Rd, we conducted a phase 3 study (MAIA) to evaluate D-Rd vs Rd in transplant-ineligible NDMM. Here we report the prespecified interim analysis of the MAIA study. Methods Patients ineligible for high-dose chemotherapy with autologous stem cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to Rd ± DARA. Stratification was based on International Staging System stage (ISS [I, II, III]), region (North America vs other), and age (

Description: Background: Treatment of multiple myeloma has evolved considerably in the past few years with availability of several news drugs as well as increasing use of multidrug combinations. These changes have no doubt led to the improved survival seen among patients with MM. We have previously shown that outcomes of patients intolerant or refractory to one of the IMiDs and bortezomib had a poor outcome. Since that time, other drugs of the same class as well as new classes of drugs have been introduced for the treatment of MM. We designed this retrospective study to estimate the outcomes in patients with relapsed myeloma, who have become refractory to the current generation IMiDs and proteasome inhibitors. Patients and Methods: Patients with relapsed multiple myeloma who have received at least 3 prior lines of therapy, is refractory to both an IMiD (lenalidomide or pomalidomide) AND a proteasome inhibitor (bortezomib or carfilzomib), and has been exposed to an alkylating agent were identified from multiple centers. The time patients met the above criteria was defined as T0, and details of all treatment regimens before and after T0 were collected using electronic CRFs. The study was approved by the IRB at the respective centers. Results: 543 patients were enrolled in this study; median age was 62 years (31-87) and 61% were males. Patients were enrolled from centers in North America (n=181), Europe (n=318), and Asia Pacific (n=44). Patients were diagnosed between 2006 and 2014, the median duration between diagnosis of myeloma and study entry (T0) was 3.1 years (0.3 to 9). The median (95% CI) estimated follow up from diagnosis and from T0 were 61 (57, 66) months and 13 (11, 15) months respectively. The median number of lines of therapy prior to T0 was 4 (3-13), 48% had a prior transplant. The median OS from T0 for the entire cohort was 13 (11, 15) months. For these 462 patients, the median number of recorded regimens was 2 (1-9). The overall response and the depth of response to each line of treatment following T0 are as shown in the table. The median (95% CI) PFS and OS from T0 was 5 (4, 6), and 15.2 (13, 17), respectively. The overall survival for the 81 patients with no treatment post T0 was only 2.1 months. In a multivariate analysis, duration from diagnosis to T0, ISS stage III and number of lines of therapy were all associated with inferior PFS, as well as OS, and in addition, serum creatinine〉2 mg/dL at T0 also predicted inferior OS. Conclusions: The study provides the expected outcome following development of myeloma that is refractory to a PI and an IMiD. The outcomes of these patients appear to be better than we had seen historically in patients refractory/ intolerant to bortezomib and IMiDs, highlighting the increased treatment options available for these patients. However, there is decreasing response rate to sequential regimens highlighting the development of drug resistance. The data provides a bench mark for comparison of new therapies that are being evaluated in this disease. Table Table. Disclosures Dimopoulos: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Hillengass:Sanofi: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; LeoPharma: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Pierre Fabre: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Cavo:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Karyopharma: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. van de Donk:Amgen: Research Funding; Janssen: Research Funding; BMS: Research Funding; Celgene: Research Funding. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ludwig:Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Usmani:Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: 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, Research Funding, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees. Shustik:Janssen: 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; Millenium: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Celgene: Consultancy; Bristol Myers: Consultancy; Amgen,: Consultancy; Janssen: Consultancy. Durie:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy.