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Thus far, the association between residual vein occlusion and immediate compression therapy and postthrombotic syndrome is undetermined. Therefore, we investigated whether compression therapy immediately after diagnosis of deep vein thrombosis affects the occurrence of residual vein obstruction (RVO), and whether the presence of RVO is associated with postthrombotic syndrome and recurrent venous thromboembolism. In a prespecified substudy within the IDEAL (individualized duration of elastic compression therapy against long-term duration of therapy for prevention of postthrombotic syndrome) deep vein thrombosis (DVT) study, 592 adult patients from 10 academic and nonacademic centers across The Netherlands, with objectively confirmed proximal DVT of the leg, received no compression or acute compression within 24 hours of diagnosis of DVT with either multilayer bandaging or compression hosiery (pressure, 35 mm Hg). Presence of RVO and recurrent venous thromboembolism was confirmed with compression ultrasonography and incidence of postthrombotic syndromeas a Villalta score of at least 5 at 6 and 24 months. The average time from diagnosis until assessment of RVO was 5.3 (standard deviation, 1.9) months. A significantly lower percentage of patients who did receive compression therapy immediately after DVT had RVO (46.3% vs 66.7%; odds ratio, 0.46; 95% confidence interval, 0.27-0.80; P = .005). Postthrombotic syndrome was less prevalent in patients without RVO (46.0% vs 54.0%; odds ratio, 0.65; 95% confidence interval, 0.46-0.92; P = .013). Recurrent venous thrombosis showed no significant association with RVO. Immediate compression should therefore be offered to all patients with acute DVT of the leg, irrespective of severity of complaints. This study was registered at ClinicalTrials.gov (NCT01429714) and the Dutch Trial registry in November 2010 (NTR2597).

Introduction Non-transplant eligible newly diagnosed multiple myeloma (NTE-NDMM) patients have a heterogeneous clinical outcome, which can be partly explained by differences in frailty level. Accordingly, intermediate-fit patients, according to the IMWG frailty index, have an inferior survival and higher rates of treatment discontinuation as compared to fit NTE-NDMM patients. The aim of this study was to prospectively investigate the efficacy and tolerability of the novel regimen ixazomib-daratumumab-low dose dexamethasone in intermediate-fit NTE-NDMM patients. This trail is registered at www.trialregister.nl as NTR6297. Methods In the phase II HOVON 143 study, intermediate-fit NTE-NDMM patients were treated with nine 28-day induction cycles, consisting of ixazomib 4mg (day 1, 8, 15), daratumumab 16mg/kg (cycle 1-2 on day 1, 8, 15, 22; cycle 3-6 on day 1, 15; cycle 7-9 on day 1) and dexamethasone (on days of daratumumab; cycle 1-2 20mg, subsequent cycles 10mg), followed by maintenance therapy of 8-week cycles with ixazomib (days 1, 8, 15, 29, 36, 43), and daratumumab (day 1), of maximum 2 years or until earlier progression. Inclusion criteria were NTE-NDMM patients who were intermediate-fit according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1 The primary endpoint was overall response rate (ORR) after nine induction cycles, defined by having at least a partial response (≥PR). Secondary endpoints were PFS, OS, event free survival (EFS, defined as either treatment discontinuation, progressive disease (PD), death, hematological adverse events (AE) grade 4 or non-hematological AE grade 3/4), and health-related quality of life (using the EORTC-QLQ C30 and -MY20). Results Sixty-five NTE-NDMM patients were included in the study of whom the demographics are described in Table 1. Median age was 76 years (range 65-80), 14% had a WHO≥2, 18% had ISS3 and 14% had high-risk cytogenetic abnormalities. The ORR was 71% (95% CI 63-73), including 23 (35%) patients with a very good partial response and 1 (2%) with a complete response. After a median follow-up time of 18.1 months (range 9.5-27.8), the median PFS was 17.4 months (95% CI 10.4-22.6), the median OS was not reached and 12-month OS was 92% (95% CI 82-97)(Figure 1). Eight patients died, 3/65 (5%) due to relapse and 5/65 (8%) due to other reasons, including one early death (≤60 days from registration). The median EFS was 5.3 months (95% CI 2.8-8.3). EFS defining events were non-hematological AEs grade 3/4 in 31 (48%), PD in 15 (23%), hematological AEs grade 4 in 2 (3%), treatment discontinuation in 2 (3%) and death in 1 (2%) patients (Figure 1). Thirty/65 (46%) patients did not proceed to maintenance therapy, due to PD (19/65 (29%)), toxicity (4/65 (6%)), incompliance (3/65 (5%)), sudden death (1/65 (2%)) or other reasons (3/65 (5%)). In addition, 7/65 (11%) patients had to discontinue ixazomib-only, all 7 due to PNP. Cumulative grade 3 or higher hematological AEs occurred in 8/65 (12%), mainly neutropenia (6%), whereas grade ≥3 non-hematological AEs were reported in 33/65 (51%) patients. Most common non-hematological grade ≥3 AEs were gastro-intestinal (14%), central nervous system AEs (11%) or infections (9%). Of 27/65 (42%) patients experiencing PNP, 4 (8%) had PNP grade 3. During induction, patients experienced a statistically and clinically (reaching minimal important difference thresholds) significant improvement in GHS/QoL, role functioning, and future perspective. In contrast, PNP worsened over time. Conclusion In intermediate-fit patients, ixazomib, daratumumab and dexamethasone is an effective and feasible regime, which improves QoL. However, treatment discontinuation due to toxicity (either the whole regimen (6%), but especially ixazomib only (11%)) or incompliance, which negatively affects PFS, remains a concern. This underscores the need to investigate novel monoclonal antibody-based treatment combinations with a higher efficacy to tolerability balance for intermediate-fit patients with NDMM. Figure 1 Figure 1. Disclosures Vekemans: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. van de Donk: Janssen Pharmaceuticals: 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; Cellectis: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: 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; Bristol Myers Squibb: 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; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Timmers: Gilead Sciences: Other: Travel, Accommodations, Expenses; Daiichi Sankyo Ned: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. van der Spek: Amgen: Other. De Waal: Celgene: Speakers Bureau; Roche: Other: Travel, Accommodations, Expenses. Nijhof: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: 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.

Introduction Since no curative options for Waldenstrom's Macroglobulinemia (WM) are available, novel safe and effective treatments are needed. Several new agents, including BTK inhibitors and proteasome inhibitors (PIs) have shown considerable efficacy. PIs have shown synergy with rituximab in newly diagnosed and relapsed patients, with bortezomib being most extensively used. However, WM patients often have disease-related polyneuropathy (PNP) and there is a considerable risk of bortezomib induced PNP or worsening of existing PNP. Additionally, it requires parenteral administration. In the current study, we aimed to investigate the efficacy and toxicity of the oral and less neurotoxic proteasome inhibitor ixazomib citrate in patients with relapsed WM. Given the fact that WM patients have a tendency to develop rituximab intolerance, we explored the use of subcutaneous rituximab. Methods We conducted a multicenter phase I/II trial of the Ixazomib, Rituximab, Dexamethasone (IRD) combination in patients with relapsed WM. The phase I part of the trial was performed according to a standard '3+3' design with a primary endpoint of dose limiting toxicity, aiming to establish the recommended phase II dose level (RP2D). For the phase II part the primary endpoint was overall response rate (ORR, at least minimal response (MR)) after 8 induction cycles. Treatment consisted of a total of 8 induction cycles q28 days with ixazomib citrate, 4 mg orally on day 1,8,15 and dexamethasone, 20 mg orally on day 1,8,15,22. In cycle 3 rituximab 375 mg/m2 iv on day 1 was added and in cycle 4-8 rituximab was given sc (1400 mg flat dose day 1). Subsequently, patients with at least a PR received 2 years of rituximab maintenance treatment (1400 mg sc q 3 months). Results With 60 patients, enrolment is complete. One patient was ineligible (rituximab refractory). Dose level 1 (ixazomib citrate 4 mg) was feasible and was taken forward as the phase II dose. Of the first 50 eligible patients included in the pre-final analysis and treated at the RP2D, the median age was 69 years (range 46-83) and 72% were male. The median number of prior treatments was 2 (range 1 to 7); 70% had an intermediate or high WM IPSS score. The median hemoglobin level was 10.2 g/dl (range 7.0-15.0) and the median IgM level was 3.4 g/dl (range 1.33-9.1 g/dl). 39/50 patients completed 8 cycles of induction therapy with a median relative dose intensity of 1.0 for all three drugs. Eleven patients went off protocol early (5 progression, 3 toxicity, 2 intercurrent death, 1 insufficient clinical benefit). 74% of patients achieved the primary endpoint (16%≥VGPR, 52%≥PR, 74%≥MR), and best ORR on protocol was 88% (2% CR, 22% VGPR, 44% PR, 20% MR). With a median follow-up of 19.5 months (range 7-49), the median duration of response and median progression free survival were not reached. A rapid and statistically significant decrease in IgM levels was seen already after cycle 2 (before the introduction of rituximab; IgM 3.93 to 2.37 g/dl, p Grade 3/4 toxicity was seen in 28% and 10% of patients respectively. 21 SAEs were reported in 15 patients, mostly infections. 6 patients died while on the trial (2 progressive disease, 1 progressive multifocal leukencephalopathy (symptoms present already at entry), 2 deaths considered unrelated in elderly patients (>80 years) with multiple pre-existing comorbidities, 1 graft versus host disease after progression and subsequent allogeneic stem cell transplantation. Conclusions Treatment with the combination of ixazomib citrate, sc rituximab and dexamethasone is feasible, easy to administer and shows promising efficacy with manageable toxicity in patients with relapsed or progressive WM. The final analysis for the primary endpoint for all 60 patients will be shown at the conference. Role of the funding source: the study was financially supported by grants from Takeda Oncology, Roche and the Dutch Cancer Society. Acknowledgments: the authors wish to acknowledge the trial coordinators and central datamanagers of HOVON data center and all patients and contributing centers for participation in the trial Figure IgM (A) and Hemoglobin (B) levels during treatment Disclosures Kersten: Gilead: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Kite Pharma: Honoraria, Research Funding; Miltenyi: Honoraria; Mundipharma: Honoraria, Research Funding. Minnema:Jansen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria. Vos:Celgene: Honoraria. Kastritis:Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Chamuleau:Genmab: Research Funding. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. OffLabel Disclosure: Ixazomib in Waldenstrom's Macroglobulinemia

Introduction Bortezomib (B) has been reported to be very effective in AL amyloidosis with overall response rates (ORR) varying between 50-80%. However, no prospective data have been published from multicenter studies on B treatment in de novo patients. Previously, we have demonstrated the positive long term effect of induction therapy followed by high dose melphalan (HDM) and autologous stem cell transplantation (SCT). We therefore investigated the efficacy and safety of B-Dexamethasone (BD) induction treatment followed by HDM + SCT to improve the complete response rate (CR) in de novo AL amyloidosis patients. This report is on the first 25 patients. Methods The HOVON 104 trial was performed in the Netherlands, Belgium and Germany from Jan 2012 to April 2016 and started with a randomized phase III design of BD versus dexamethasone (D) induction treatment followed by HDM + SCT. Due to slow accrual the D arm closed after including 7 patients. Patients with biopsy proven AL amyloidosis, aged between 18-70 years, with detectable M-protein and/or level of involved FLC > 50 mg/L, WHO performance status 0-2, NYHA stage 1-2 and ejection fraction > 45% were included. Major exclusion criteria were symptomatic orthostatic hypotension, NT proBNP level > 5000 pg/ml, Troponin T> 0.06 ug/l, Bilirubin > 2x ULN, eGFR < 30 ml/min, CTCAE grade peripheral sensory neuropathy > grade 2 or > grade 1 with pain. Inclusion and exclusion criteria were installed both at entry and before stem cell mobilization (SCM). B was given subcutaneously 1.3 mg/m2 twice a week for 2 weeks in a 21-day cycle, D 20 mg orally on each B and the following day. HDM dosage was 200 mg/m2. Hematological responses were defined according to consensus criteria with the addition of very good partial response (VGPR), defined as the difference between involved and uninvolved FLC (dFLC) < 40 mg/L. Cardiac, renal and liver response and progression criteria were defined according to consensus criteria with addition of NT proBNP. The primary endpoint was the proportion of patients with CR at 6 months after SCT. To demonstrate improvement from 30 to 50% with 80% power, 44 eligible patients were needed and 50 patients were registered. Results Median age was 60 years (range 26-70) and 68% were male. WHO performance status (PS) was 0-1 in 88% of patients and NYHA stage 1 in 52% and 2 in 44% of patients. Mayo cardiac risk score (2004) was I (28%), II (32%), III (36%). Organ involvement was 88% renal, 76% heart, 20% liver, 12% neurological, 4% gastrointestinal and 72% of patients had 2 or more organs involved. Bone marrow plasmacells were > 10% in 11 patients. Six of the 25 (24%) patients could not proceed to SCM. One patient due to low PS, one because of B related toxicity, two due to amyloidosis related complications and two patients died, both amyloidosis related. Of these 19 patients, 2 went subsequently off protocol because of ineligibility for HDM and one due to hematological progression. Sixteen out of 25 patients (64%) received HDM + SCT which was performed without any treatment related mortality (TRM). In total 29 SAEs were reported in 18 patients. The ORR after induction was 72% and ≥ VGPR in 56% of patients. The ORR in the 16 patients at 6 months after SCT was 75% and ≥ VGPR 63%. Median time to first response was 1 month. Intention to treat analysis demonstrated that the primary endpoint was met in 6 (24%) patients. Organ responses after induction were 9/22 renal and 3/19 heart, and at 6 months after SCT 9/14 renal and 5/13 heart. The first two BD cycles were given as planned in most patients, 80 and 70%, respectively, but doses were reduced and delayed thereafter for B in half of patients, mostly because of neurotoxicity. Mean cumulative dosage of B was 80% of planned. Also D was reduced in almost half of patients due to toxicity. The most common AEs during induction are shown in Table 1. Conclusions Analysis of 25 patients demonstrates that with BD treatment the dropout rate before HDM is 36% which is comparable to previous induction treatments. We therefore conclude that BD, given twice weekly, despite good efficacy, cannot prevent early amyloidosis related toxicity. The SCT procedure was without TRM. The hematological response rate is comparable to previously reported and renal response are 41% after BD and 64% at 6 months after SCT. Trial registration www.trialregister.nl ( NTR 3220), EudraCT 2010-021445-42 , supported by the Dutch Cancer Society (UU 2010-4884 ) and by an unrestricted grant from Janssen-Cilag Disclosures Minnema: Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Hazenberg:GSK: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Hegenbart:Jansen Cilag: Honoraria, Other: financial support of conference participation. Ypma:Advisory Board Sanofi (Plerixafor): Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Broijl:Celgene: Honoraria; Jansen Cilag: Honoraria; Amgen: Honoraria. Sonneveld:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.