Abstract: Introduction. Ibrutinib is a first-in-class, oral, once-a-day Bruton's tyrosine kinase inhibitor that achieves high overall response rates and durable remissions in patients with chronic lymphocytic leukemia (CLL) including those with high-risk features (unmutated IGHV, TP53 abnormalities, 11q deletion). Survival with continuous single-agent ibrutinib in previously-untreated CLL patients is comparable to an age-matched general population (Figure 1). IBRORS is an observational, retrospective, multicentre study to describe the characteristics and clinical outcomes of patients with CLL treated with single-agent ibrutinib in routine clinical practice in Spain. This present analysis reviews the subset of patients in IBRORS who received ibrutinib as the first-line of treatment. This series includes a significant number of patients with high risk cytogenetic/molecular alterations (del17p/TP53 M), which corresponds with the approved indication for first-line CLL patients in Spain at the time. Methods. Adult patients diagnosed with CLL treated with single-agent ibrutinib in first-line, or at first or second relapse since its commercialization in Spain (between January 2016 to January 2019) were included in the IBRORS study. Clinical characteristics of patients, efficacy and tolerability of ibrutinib as first-line treatment were analyzed here. A Kaplan-Meier analysis was performed for overall survival (OS) and progression-free survival (PFS). Results. 84 patients, from a total of 269 included in IBRORS, received single-agent ibrutinib as first-line treatment. The median age was 71.3 years (range 63-77) at the time of ibrutinib initiation. 56.3% of patients presented with an intermediate/high-risk Rai-Binet stage, and the majority of patients (98.6%) had an ECOG PS of 0-1. 91.7% of patients had at least 1 high risk molecular cytogenetic factor (unmutated IGHV, TP53 abnormalities, 11q deletion or complex karyotype) described in table 1. Baseline comorbidities of patients are described in table 2. Concomitant medication included anticoagulants (9.5% patients; vitamin K antagonist [n=4], Apixaban [n=1] and LMWH [n=3] patients), antiplatelet agents (11.9% patients), and antihypertensives (50% patients). The overall response rate (ORR) was 79.5%; 14/84 (16.6%) achieved a complete response (CR), 14/84 (16.6%) achieved CR unconfirmed, 27/84 (32.14%) achieved a partial response (PR) and 12/84 (14.2%) a PR + lymphocytosis. The median PFS and OS were not reached, and the estimated PFS at 24 months was 84.5% (73.4-95.6%). OS and PFS curves are represented in figure 2. The PFS of each patient subgroup with high-risk cytogenetic characteristics was similar to that of all patients in the first-line cohort: del17p/TP53 mutation (HR = 0.963 [95% CI 0.188-4.928]; p = 0.964), del11q (HR = 0.042 [95% CI 0.000-682.736] ; p=0.521), unmutated IGHV (HR = 0.391 [95% CI 0.110-1.394]; p = 0.148). The median duration of exposure to ibrutinib was 17.3 (11.9-25.6) months. Dose reduction of ibrutinib occurred in 17/84 (20.2%) patients, 8/84 (9.52%) due to toxicity (4 hematologic toxicity and 4 non-hematologic toxicity). 27/84 (32.1%) patients had temporary interruption of treatment. 15/84 (17.8%) patients permanently discontinued ibrutinib including 6 (7.14%) patients due to progression, 4 (4.76%) due to toxicity and 5 for other reasons. Safety: 49/84 (58.3%) patients developed at least one adverse event (AE), while 12/84 (14.2%) patients developed at least one serious adverse event (SAE). Twelve (14.3%) patients reported at least one haematological toxicity while 53 patients (63.1%) recorded at least one non-haematological toxicity. Only 1 patient experienced grade 3 atrial fibrillation, which did not lead to discontinuation. The most common AEs are described in table 3. Conclusion. This population of previously-untreated CLL patients, enriched for high-risk genomic features, reflects the initial approval of ibrutinib for the treatment of first-line patients with del17p in Spain. Single-agent Ibrutinib as the first-line treatment in this real world population was effective regardless of risk factors and well tolerated, with a low rate of discontinuation due to toxicity. Findings are consistent with those reported in clinical trials. Disclosures Loscertales: AbbVie: 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; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Arguiñano:AbbVie: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria; Novartis: Honoraria. Hernandez-Rivas:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Pérez Persona:Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Loriente:Janssen Cilag: Current Employment. Villanueva:Janssen Cilag: Current Employment.

Abstract: One randomized trial showed that tandem transplant resulted in a significantly longer EFS and OS in patients failing to achieve CR or near-CR with a single transplant. However, other studies failed to show benefit from a second transplant. The aim of our study was to investigate the efficacy in terms of response improvement and survival from a second transplant intensification in patients with chemosensitive disease who failed to achieve CR or near-CR with a first high-dose procedure. Patients diagnosed with MM from Oct 1999 to Dec 2004 younger than 70 years received 6 courses of VBMCP/VBAD and responding patients were intensified with busulphan/melphalan or MEL-200 followed by stem cell support. Patients not achieving CR or near-CR were planned to undergo a second transplant (second auto with CVB - cyclophosphamide, etoposide and BCNU - or MEL-200 intensification or an allo-RIC with Fludarabine/MEL-140 conditioning, if sibling donor available). Eighty-eight patients received a second autologous transplant while 26 underwent an allo-RIC. Thirty-seven percent of the patients given a second autologous transplant improved their response status (CR 11%, near-CR: 6%, PR: 9% and MR 11%) while 63% showed “no change”, progressive disease or early death. A response was observed in 45% of patients undergoing the allo-RIC (CR: 33%, PR: 4%, MR: 8%). The CR rate was significantly higher with allo-RIC (33% vs. 11%, p= 0.02). There was a trend towards a higher TRM with the allo-RIC (5% vs. 16%, p=0.09). Although the median EFS (26 vs 19 m) and OS (57 m vs not reached in allo-RIC) from the second high-dose procedure were not significantly different, there is a plateau in the “allo-RIC” group beyond 3 years of the second procedure not observed in the autologous arm. Conclusions: an allo-RIC transplant after an autologous procedure results in a significantly higher CR rate than a second autologous transplant, and despite the lack of significant differences in survival between the two transplant modalities, there is a plateau in the allogeneic group not observed in the autologous arm.

Abstract: The Spanish Acquired Hemophilia A (AHA) Registry is intended to update the status of AHA in Spain. One hundred and fifty-four patients were included and retrospectively followed for a median of 12 months. Patients were predominantly male (56.3%), with median age at diagnosis of 74 years. AHA was more frequently idiopathic (44.1%) and autoimmune disorder-associated (31.7%). Thirty-four percent of patients were on antithrombotic therapy at diagnosis. Hemostatic treatment was used in 70% of patients. Recombinant activated factor VII was more frequently infused (60.3% vs 20.6% activated prothrombin complex concentrate). Only 1 patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy. Steroids alone were less efficient than the other strategies (68.2% vs 87.2%, P = .049), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%, vs steroids/calcineurin inhibitors, 81.2%, vs rituximab-based regimens, 87.5%). Female sex and high inhibitor levels influenced CR negatively. Thirty-six deaths (23.8%) were reported. Main causes of death were infection (15 patients, 9.9%) and hemorrhage (5 patients, 3.3%). All hemorrhage-related and half the infection-related deaths occurred within 2 months of diagnosis. Prior antithrombotic therapy was inversely associated with survival, irrespective of age. Median age of nonsurvivors was significantly higher (79 vs 73 years in survivors). Patients dying of infection were older than the other nonsurvivors (85 vs 78 years). In summary, fatal infection in the first months is common in our series. Antithrombotic therapy is associated with mortality. Particular care should be taken to avoid misdiagnosis.

Abstract: Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients in which the primary endpoint is the assessment of bone marrow minimal residual disease negativity by next generation flow (NGF). However, alternative methods of tumor burden evaluation in serum, like Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS), a polyclonal antibody-based technology to identify intact immunoglobulins, have been also evaluated. Patients and Methods: Ninety HRsMM patients included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and ASCT and 2 further cycles of consolidation with the same regimen. All patients received maintenance with lenalidomide up to 2 years. SPEP and IFE were performed using standard procedures and MRD was analyzed by flow cytometry following EuroFlow recommendations. QIP-MS assessment has been previously described (1) and allowed us the characterization of the isotype of each Ig trough immunoprecipitation with paramagnetic beads as well as the measurement of the molecular mass of each Ig for each specific patient, with enough precision and accuracy to establish clonality. Standard response assignment was carried out as per the IMWG guidelines. Results: First, we confirmed the higher sensitivity of QIP-MS to identify the presence of a serum M-spike as compared to conventional protein immunofixation electrophoresis methods. Amongst patients in CR, QIP-MS identified the M-spike in 18/30 (60%) post-induction, 18/47(38%) post-ASCT and 25/58(43%) post-consolidation. Interestingly, similar results were obtained with MRD-NGF post-induction [17/30(57%)] and post-ASCT [15/47(32%)] although the positive rate post-consolidation [15/58(26%)] was higher with QIP-MS. Then, we analyzed the overall concordance between the results obtained with QIP-MS and MRD-NGF at the three timepoints of disease evaluation, finding an overall concordance of 81% post-induction (n=76), 70% post-transplant (n=76) and 68% post-consolidation (n=77). Thus, when compared to the results of MRD-NGF, QIP-MS demonstrated sensitivities of 100%, 79% and 77% post-induction, post-ASCT and post-consolidation, and negative predictive values (NPV) of 100%, 79% and 82% at each respective time-point. (P & lt; 0,0001; P = 0,0004; P = =,0012) Evaluation of discrepant cases showed 14 out of 22 MRD-NGF-negative patients post-induction for whom QIP-MS identified a M-spike; in some cases (i.e. IgG MM isotype) this may be related to a longer immunoglobulin half-life. There were no cases with detectable disease by NGF but QIP-MS negative. By contrast, post-ASCT, QIP-MS was negative in seven MRD-positive patients, two of whom became MRD-NGF-negative after consolidation; at last follow-up, none of them have progressed. On the other hand, sixteen patients with negative MRD-NGF after ASCT had a detectable M-spike by mass spectrometry. Of note, the M-spike became undetectable after consolidation in six out of these 16 patients. Post-consolidation, there were 7 patients in which MRD-NGF was positive but QIP-MS negative: MRD evaluation during maintenance is pending but none of them have so far progressed. By contrast, there were 18 patients with the M-spike detectable by QIP-MS but MRD-NGF negative: follow-up of these patients will address their outcome but, the only patient that has progressed so far had MRD-NGF negative post-induction, becoming positive post-transplant and consolidation, but the M-spike was detectable by QIP-MS throughout. Conclusions: M-spike monitoring by QIP-MS shows a moderate concordance with the MRD assessment by NGF in this group of HRsMM homogeneously treated. Longer follow-up will allow us to unravel the outcome of discordant cases and to define the specificity of QIP-MS and its complementary value to NGF. North S, Barnidge D, Brusseau S, Patel R, Haselton M, Du Chateau B, et al. QIP-MS: A specific, sensitive, accurate, and quantitative alternative to electrophoresis that can identify endogenous m-proteins and distinguish them from therapeutic monoclonal antibodies in patients being treated for multiple myeloma. Clinica Chimica Acta 2019;493:S433. Disclosures Puig: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; The Binding Site: Honoraria; Takeda, Amgen: Consultancy, Honoraria. Mateos:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; EDO: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rodriguez Otero:Takeda: Consultancy; Kite Pharma: Consultancy; BMS: Honoraria; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios: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. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:AbbVie: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. De Arriba:Amgen: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Ocio:Mundipharma: Research Funding; Pharmamar: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy; Takeda: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy, Honoraria; BMS: Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Lahuerta:Takeda, Amgen, Celgene and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction:Renal impairment (RI) is a common complication of multiple myeloma (MM). Almost 20% of patients (pts) present with RI at diagnosis, while approximately 40%-50% of pts will develop RI during the course of their disease. However, there is little information on the renal response of pts with relapsed refractory MM (RRMM) receiving treatment with new drugs in clinical practice. Aims: This is an observational, prospective, multicenter study conducted in pts with RRMM and RI (defined as an estimated glomerular filtration rate [eGFR] 〈 50 mL/min) to evaluate renal response to the administered therapy in pts with moderate (creatinine clearance [CrCl] 30-50 mL/min) or severe (CrCl 〈 30 mL/min) RI. Secondary objectives include MM response rate, overall survival, safety, and health resource utilization. We present results from an interim analysis 4 mos after completion of the inclusion period (cutoff: June 13, 2016). Methods:Renal and MM responses were evaluated according to International Myeloma Working Group criteria. Both eGFR by the Cockroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas were compared to analyze renal response. Results:Overall, 312 pts (mean ± SD age 75 ± 9 yrs, 50% male, 57% in first relapse) were included in the study; 217 (70%) had moderate and 95 (30%) had severe RI, respectively. Anti-myeloma therapies administered were lenalidomide (LEN; 35% of pts), bortezomib (BORT; 21%), different chemotherapy regimens (CT; 22%), and other non-CT treatments (22%). Median follow-up was 7 mos (range, 0-39 mos). To date, 123 pts (39%) have discontinued treatment, 12% due to adverse events (AEs), and 37% have died. The main causes of death were disease progression (8.3%) and infections (6.4%). The mean baseline eGFR according to CG and MDRD formulas was 38.7/41.7 (± 8.5/11.8) mL/min in the moderate RI subgroup and 20.3/20.1 (± 8.0/10.1) mL/min in the severe RI group, with a strong correlation (coefficient 0.91) between the CG and MDRD eGFR. Overall, 13.5% (95% CI, 9.7%-17.2%) of patients had a renal response (5.8% renal complete response [renalCR], 0.3% renal partial response [renalPR] , and 7.4% renal minor response [renalMR]) according to the CG formula while responses measured by the MDRD formula, were 17.3% (9.9% renalCR, 0.3% renalPR, and 7.1% renalMR). Median time to best renal response was 1.8 mos (range, 0.5-8.9 mos). After adjusting for demographic and clinical characteristics, there were no significant differences in GFR improvement between pts receiving LEN- and BORT-based treatments (P = 0.706). Arterial hypertension and female sex were statistically significantly associated with poor renal response. The overall MM efficacy response rate (≥ PR) was 33.4%, achieved after a median of 3.4 mos (range, 0.07-37.8 mos). For pts receiving BORT and LEN, respectively, the overall response rates were 43.5% and 44.8%, whereas only 23% of pts receiving CT achieved at least PR. Progression-free survival was 13.3 mos with LEN-based, 6.8 mos with BORT-based, and 7.5 mos with CT-based therapies (P = 0.006). Conclusions: Preliminary results of this study in pts with RRMM and RI show that LEN- and BORT-based therapies are the regimens most commonly used in clinical practice in these pts. Overall, these therapies can improve RI in approximately 13% of cases, with no differences seen in renal function improvement between LEN- and BORT-based treatments. Disclosures De La Rubia: Amgen, Bristol Myers, Celgene, Janssen: Consultancy. Morales:Celgene: Consultancy. García-Muñoz:Celgene, Roche: Consultancy. Duran:Celgene: Employment.

Abstract: Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios: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. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: The BCL-2 inhibitor venetoclax (Ven) has been approved on monotherapy or combined with rituximab in relapsed/refractory CLL patients (pts) and combined with obinutuzumab in previously untreated CLL pts. However, evidence from clinical trials can be difficult to generalize to real-world patient populations. The VENARES study assesses the real-world use of Ven following approval to inform of subpopulations underrepresented in clinical trials. Methods: This is Spanish non-interventional retrospective, multicenter post-marketing observational study. The main objective was to evaluate the effectiveness of Ven in adult CLL pts by the overall response rate (ORR) at 9 months (mo) after the first Ven dose administration. Secondary objective was to evaluate the effectiveness for the Ven monotherapy and the Ven combined with rituximab subpopulations. Consecutive adult pts with diagnosis of CLL who have initiated Ven at least 9 mo before the inclusion in the study were included. Data of pts are retrospectively reviewed until the date of last follow-up or death. Results: 125 pts diagnosed with CLL and who met the eligibility criteria were analyzed. The median age was 72 years (67 - 77) with 76.8% being older than 65 years. Most patients were male (68.8%), had a concurrent disease (65.6%). ECOG PS was recorded in 76 pts: 40 pts (32%) had PS 0, 30 pts (24%) PS 1 and 6 pts (4.8%) PS 2. Pts had received a median of 4 prior lines of therapy (range 1-13 lines). At baseline, among the 92 pts with known Binet stage, 31 (33.7%) had stage C and 38 (41.3%) had stage B; bulky nodes ≥ 5 cm were present in 20 of 87 pts; 49 pts (39.2%) had an absolute lymphocyte count ≥ 25 x 10 9/L and 33 of 54 pts (61%) baseline beta-2 microglobulin value above of 3500 ng/mL. In total, 29 of 90 patients (32%) assessed had Cr 17p deletion, 28 of 86 patients (32%) tested had TP53 mutations, and 46 of 56 patients (82%) who were tested had unmutated immunoglobulin heavy-chain variable (IGHV) status. Ven was administered as monotherapy in 71 pts (57.6%), combined with rituximab in 36 pts (28.8%), combined with obinutuzumab in 5 pts (4%) and combined with other drugs in 13 pts (10.4%). 83 of 125 patients included were evaluable for the primary objective of the study: the ORR at 9 mo was 84.3% (70 patients): CR/CRi in 44 (53%) pts, PR/nPR in 26 pts (31.3%), SD in 9 pts (10.8%) and PD in 4 pts (4.8%). By treatment, in the evaluable patients, ORR at 9 months were 79.2% (38 of 48 patients) in the Ven monotherapy group, with 45% of CR/CRi, and 92.3% (24 of 26 patients) in the Ven combined with rituximab, with 61% CR/Cri. The median duration of PFS was not reached at the time of the analysis (1-June-2021). Kaplan-Meier estimates of the probability of PFS at 24 mo was 75.4% (95% CI, 58.2 - 86.3). Disease progression occurred in 21 pts. Assessment of minimal residual disease (MRD) was available for 32 patients (25.6%) on the basis of peripheral-blood samples, bone marrow or both. Best undetectable MRD was reached in fourteen patients (43.8%). uMRD was more common in pts treated with Ven combined with R (83.3%, 5 of 6 pts) than in pts treated with Ven monotherapy (33.3%, 7 of 21 pts). Adverse events (AEs) were reported during Ven therapy in all 125 patients, 93 of these pts reported AEs related to Ven. Related to Ven, 67 patients (53.6%) experienced at least one AE: 52 pts (41.6%) had neutropenia being grade 3 and 4 in 22 (42.3%) and 9 (17.3%) pts, respectively. 9 pts (7.2%) had febrile neutropenia. Thrombocytopenia and anemia were less common occurring in 5.6% and 2.4%, respectively. Tumor lysis syndrome (TLS) occurred in 4 of 125 pts during ramp-up (3 laboratory and 1 clinical), 2 of them were related to Ven both lab TLS. None of the pts discontinued therapy due to TLS. Richter transformation was observed in 6 pts (4.8%). Other common AEs was diarrhea (10.4%), but most cases were mild. Conclusions: Our first real-world data show that Ven monotherapy or combined with rituximab is effective in highly pre-treated CLL patients, ORR at 9 mo was 84.3% in all population and PFS estimate at 24 mo was 75.4% with similar outcomes to those in the pivotal clinical trials. The safety profile of Ven was consistent with prior experience of Ven in monotherapy or combined with rituximab and no new safety signals were detected. Disclosures Baltasar: Janssen, Abbvie: Consultancy. Terol: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; BMS: Consultancy; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment. Moreno: Janssen, Abbvie: Research Funding; Abbvie, Janssen, AstraZeneca: Speakers Bureau; Abbvie, Janssen, AstraZeneca, Beigene: Membership on an entity's Board of Directors or advisory committees. Osorio: Janssen, Abbvie, Roche: Consultancy. De la Cruz: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirkin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Serna: AbbVie, AstraZeneca, Roche: Speakers Bureau; ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy. Arguiñano: Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Speakers Bureau; Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Consultancy. Loscertales: Janssen, Abbvie, Roche, Gilead: Speakers Bureau; Janssen, Abbvie, Astra-Zeneca, Beigene, Roche, Gilead: Consultancy. García: Janssen, Roche, Gilead, Celgene: Consultancy; Janssen, AbbVie: Research Funding; Janssen, Roche, Gilead, AbbVie, Celgene: Other: medical meetings funding. Pérez Persona: BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Pérez-Encinas: Janssen: Consultancy. Caballero: Celgene, Janssen, Novartis, Abbvie: Speakers Bureau; Celgene, Janssen, Amgen: Consultancy. Ruiz-Zorrilla: Abbvie: Current Employment. Moreno: abbvie: Current Employment. Ferrà: Janssen, Roche, Gilead, Takeda, Abbvie: Consultancy; Janssen, Roche, Gilead, AbbVie: Other: medical meetings funding.

Abstract: Continuous treatment with lenalidomide (R) and dexamethasone (d) is a standard of care for multiple myeloma (MM) patients (pts) not candidates for autologous stem cell transplantation (ASCT). As previously reported, the addition of Clarithromycin (C) to Rd has proven to be safe and effective, and case-control analyses suggested a significant additive value with the combination. C optimizes the therapeutic effect of glucocorticoids by increasing the area under the curve, has immunomodulatory effects and may have direct antineoplastic properties. However, there are not randomized phase III trials confirming these results. GEM-Claridex in an open, randomized, phase III trial for untreated newly diagnosed MM pts ineligible for ASCT. Enrolled pts were randomly assigned 1:1 to receive 28-day cycles of R (25mg po qd days 1-21), d (40mg po [20mg in pts & gt;75 years], days 1, 8, 15 and 22) plus or minus C (500mg po bid) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and minimal residual disease (MRD) negativity rate and safety. MRD was evaluated in 99 pts using Euroflow NGF (limit of detection, 2x10-6). As expected, most pts in CR were tested for MRD whereas the majority of pts with missing MRD data achieved VGPR or less and were thus considered as MRD-positive for intent to treat analyses. Two hundred and eighty-eight pts were included (144 to C-Rd and 144 to Rd). Median age was 76 (range: 65-93), 36.8% of pts had ISS 3 and 15.6% presented with high-risk cytogenetic abnormalities. Key baseline characteristics were well balanced between the two arms. The addition of C to Rd resulted in deeper responses with a ≥ complete response (CR) rate of 20.1% in the C-Rd arm compared to 11.2% in the Rd arm (p = 0.037). Also, the ≥ very good partial response (VGPR) rate was 52.8% in the C-Rd arm as compared to the 37.1% in the Rd arm (p = 0.007). MRD analysis was performed at suspected CR and yearly afterwards. On intent-to-treat, 5/144 (3,5%) and 9/143 (6,2%) of pts achieved undetectable MRD with C-Rd and Rd, respectively (p = 0,7). With a median follow-up of 16 months (range, 1-47), no significant differences were observed in PFS: in the C-Rd arm the median was 23 months and has not been reached in the Rd arm (p = 0.09); furthermore, although disease progression and/or death rate was comparable in both arms (C-Rd: 57/144 [39.6%] vs Rd: 45/144 [31.2%] ), a trend towards shorter PFS was observed in the C-Rd group (Figure 1). This effect was less evident in younger ( & lt;75) pts (median PFS, C-Rd: 24 months vs Rd NR, p = 0,588) but, in older pts (≥ 75), the addition of C to Rd resulted into a significant deleterious effect on PFS (median PFS, C-Rd: 19 vs Rd 28 months, p = 0.03) (Figure 2a and 2b). Irrespectively of treatment arm, pts with MRD negative had significantly longer PFS (NR vs 26 months, p = 0,03). Concerning OS, no differences have been identified (p = 0.41), although median has not been reached yet in any arm. Out of the 33 and 28 deaths documented in the C-Rd and Rd arms respectively, the percentage of pts dying w/o documented PD was significantly higher in the C-Rd group (27/33 [82%] vs 13/27 [48%] , p = 0.004). Furthermore, in the C-Rd arm, the most frequent causes of death were severe infections (14/27 [52%] and cardiovascular events 6/27 [22%] ) the majority of them occurring in older (≥75) pts (20/27, 74%). The most common G3-4 adverse events (AE) in the C-Rd and Rd arms were hematologic (neutropenia: 10,4% vs 16,7% [p = ns] and anemia: 2,1% vs 6,9% [p = 0,04] , respectively). G3-4 infections occurred in 16% of cases in both arms and were the most frequent non-hematological AE. 7% of pts in both arms developed G3-4 GI toxicity and there were no differences between the two arms in G3-4 skin-related AEs (2,8% vs 3,5%). Only one case of invasive SPM (colon cancer) in the C-Rd arm was reported. In conclusion, the addition of C to Rd in transplant ineligible newly diagnosed MM pts significantly increases the rate and depth of responses but it is not associated with an improved PFS and OS due to a higher proportion of deaths in the C-Rd arm, mostly infectious, in pts & gt; 75 years and being early deaths. Overexposure to steroids due to the delayed clearance induced by C in this elderly population could explain our results. Figure Disclosures Puig: The Binding Site: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Oriol:Celgene Corporation: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. De La Rubia:AbbVie: Consultancy; AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Amor:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Martín Sánchez:GILEAD SCIENCES: Research Funding. Rossi:BMS: Research Funding; Janssen, Celgene, Amgen: Consultancy. Coleman:Merck: Research Funding; Pharmacyclics: Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Mateos:EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria.