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Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.

Background: Systemic AL amyloidosis is a rare disease characterized by amyloid fibril deposits, most commonly in the heart and kidneys; there are currently no health authority-approved treatments. Therapies for the treatment of multiple myeloma (MM), including bortezomib, cyclophosphamide, and dexamethasone (VCd), have been shown to improve outcomes in AL amyloidosis, but more effective therapies are needed to achieve deep and rapid hematologic responses, reverse amyloid-mediated organ dysfunction, and improve overall survival. Daratumumab is an anti-CD38 monoclonal antibody approved as monotherapy or in combination with other agents for the treatment of MM. ANDROMEDA (NCT03201965) is a randomized, open-label, active-controlled phase 3 trial of VCd ± daratumumab subcutaneous (DARA SC) in patients with newly-diagnosed AL amyloidosis. After a median follow-up of 11.4 months, the complete hematologic response rate was 53% for DARA SC + VCd (DARA-VCd) and 18% for VCd (odds ratio, 5.1; 95% CI, 3.2-8.2; P Methods: Patients with newly-diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic MM were randomized 1:1 to DARA-VCd or VCd and treated for six 28-day cycles; thereafter, patients in the DARA-VCd group received DARA SC alone every 4 weeks for up to 24 cycles. PROs were assessed on Day 1 of Cycles 1-6 for both treatment groups and every 8 weeks thereafter in the DARA-VCd group. PRO assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), the EuroQol 5-dimensional descriptive system (EQ-5D-5L), and Short Form-36 (SF-36). Improvements in EORTC QLQ-C30 global health status (GHS) and fatigue scale scores and SF-36 mental component summary (MCS) score were secondary endpoints. Assessment of physical functioning, symptom improvement, functional improvement, and health utility as measured by the SF-36, EORTC QLQ-C30 with supplemental symptom items, and the EQ-5D-5L were exploratory outcomes. Patients completed PRO questionnaires prior to study assessments or study drug administration. Analyses of PROs were performed on the intent-to-treat analysis set; patients without a baseline or post-baseline assessment were censored at date of randomization. Compliance with PRO assessments was calculated as the number of assessments received divided by the number of assessments expected at each time point. Descriptive statistics are provided for all PRO endpoints at each time point by treatment group. A distribution-based method was used to define worsening/improvement in scores. Time to worsening/improvement, hazard ratios, and associated 95% confidence intervals were estimated using Kaplan Meier methods and Cox proportional hazards regression. Change from baseline at each time point up to Cycle 6 (Week 24) was calculated using a mixed effects model with repeated measures with patients as a random effect and baseline value, treatment group, time (weeks), treatment-by-time interaction, and stratification factors as fixed effects. Results: A total of 388 patients were randomized (DARA-VCd, n=195; VCd, n=193). Compliance rates for all PRO questionnaires were >90% at baseline and >83% through Cycle 6. Median time to improvement was shorter and median time to worsening was longer in the DARA-VCd group than in the VCd group for EORTC QLQ-C30 GHS and fatigue scales and EQ-5D-5L visual analog scale (VAS) (Table 1). Least squares mean scores for EORTC QLQ-C30 GHS and fatigue, EQ-5D-5L VAS, and SF-36 MCS remained stable in the DARA-VCd group but worsened compared with baseline in the VCd group; between-group differences are shown in Table 2. The greatest between-group differences in PRO score changes from baseline were observed at Week 16 (Cycle 4). After Cycle 6, patients in the DARA-VCd group reported improvements in mean GHS and fatigue scores that continued while on treatment (Figure). Conclusions: Patients with AL amyloidosis treated with DARA-VCd experienced clinical improvements without any decrement in health-related quality of life over 6 cycles. Following Cycle 6, improvements in GHS and fatigue were reported in patients in the DARA-VCd group. These findings further support the value of DARA-VCd in patients with AL amyloidosis. Disclosures Sanchorawala: UpToDate: Patents & Royalties; Abbvie: Other: advisory board; Proclara: Other: advisory board; Caleum: Other: advisory board; Regeneron: Other: advisory board; Oncopeptide: Research Funding; Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Minnema:Servier: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding. Lee:Janssen: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding. Gibbs:Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. Mollee:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: 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, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Schönland:Janssen: Honoraria, Other: travel support to meetings, Research Funding; Prothena: Honoraria, Other: travel support to meetings, Research Funding; Takeda: Honoraria, Other: travel support to meetings, Research Funding. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Kim:BMS, Takeda, Amgen, Celgene, Janssen: Consultancy, Honoraria, Research Funding. Cibeira:Janssen, Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Amgen: Honoraria, Other: Educational lectures. Beksac:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, 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, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valent:Celgene: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau. Wong:GSK: Research Funding; Roche: Research Funding; Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Fortis: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig:Janssen: Speakers Bureau. Bumma:Amgen: Speakers Bureau; Sanofi: Speakers Bureau. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau:Janssen: Current Employment, Current equity holder in publicly-traded company. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Comenzo:Caleum: Consultancy; Amgen: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Unum: Consultancy; Karyopharm: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.

Background: Current therapies for multiple myeloma (MM) delay disease progression and prolong survival but most patients (pts) eventually relapse or become refractory (RR). Daratumumab (D), an anti-CD38 antibody (Ab), plus bortezomib (V), a proteasome inhibitor (PI) and dexamethasone (d), is approved for the treatment of MM in pts who have received ≥1 prior line of therapy. Venetoclax (Ven), a potent and selective oral BCL-2 inhibitor, demonstrated anti-myeloma activity in pts with t(11;14) RRMM. This 3-part Phase 1/2 study is investigating the combination therapy VenDd +/- V in pts with RRMM. Treatment of pts with t(11;14) RRMM using VenDd (part 1) and pts with RRMM (irrespective of t(11;14) status; part 2) with VenDVd demonstrated a tolerable safety profile and an overall response rate (ORR) of 95.8% and 91.7%, respectively (Bahlis N et al. J Clin Oncol 2021). Part 3 further evaluates the safety and efficacy of VenDd vs DVd in pts with t(11;14) RRMM, with preliminary results presented here. Methods: Part 3 of this Phase 1/2, multicenter, dose-escalation and expansion study (NCT03314181) evaluates the safety and efficacy of VenDd vs DVd in pts with t(11;14) RRMM. The study was expanded to further interpret the pt safety profile in light of the increased incidence of infections in pts in the Ven arm of the BELLINI study (Kumar SK et al. Lancet Oncol 2020). Pts were randomized 4:2:5 to receive VenDd at 400 (Ven400Dd) or 800 mg (Ven800Dd), or DVd. Randomization was not stratified due to small sample size. Eligible pts must have received ≥1 prior line of therapy, including an immunomodulatory agent (IMiD), and be non-refractory to PIs or anti-CD38 Ab. This interim analysis was conducted to evaluate the safety profile of pts in part 3 only. No statistical comparisons were conducted for safety or efficacy. Treatments in Part 3 were as follows: VenDd cycles (C) were 28-day: daily, oral Ven (400 mg or 800 mg) + D (1800 mg SC [Cycle, C1, 2: Days 1, 8, 15, 22; C3-6: Days 1, 15; C7+: Day 1]) + d (40 mg total weekly); DVd C1 - 8 were 21-day, C9+ were 28-day: D (1800 mg SC [C1 - 3: Days 1, 8, 15; C4 - 8: Day 1; C9+: Day 1]) + V (1.3mg/m 2 [C1 - 8: Days 1, 4, 8 and 11]) + d (20 mg [C1 - 3: Days 1, 2, 4, 5, 8, 9, 11, 12 ,15; C4 - 8: Days 1, 2, 4, 5, 8, 9, 11,12; C9+: Day 1]). Results: As of 10 May 2021, 11, 7 and 16 pts were enrolled in the Ven400Dd, Ven800Dd and DVd arms, respectively. The median age (range) was Ven400Dd: 58.0 (42 - 75); Ven800Dd: 57 (53 - 82); and DVd: 68.5 (51 - 77). Median prior lines of therapy (range) were 1.0 (1 - 6) in Ven400Dd; 1.0 (1 - 3) in Ven800Dd; and 2.0 (1 - 3) in DVd. Pts with ISS I%/II%/III% disease were Ven400Dd: 54.5/9.1/0; Ven800Dd: 57.1/14.3/0; DVd: 25.0/25.0/31.3. All pts in the Ven400Dd and Ven800Dd arms had an ECOG performance status of ≤1. In the DVd arm, 87.5% and 12.5% of pts had a ECOG performance status of ≤1 and 2, respectively. Prior PI%/IMiD%/anti-CD38 Ab% exposure were Ven400Dd: 100/90.9/0; Ven800Dd: 100/100/0; DVd: 93.8/100/0. The most common adverse events (AEs) occurring in ≥5% of pts in ≥2 treatment groups included insomnia, fatigue, diarrhea, and nausea (Table). Grade 3/4 AEs (≥5% of pts in ≥2 treatment groups) were mainly hematologic toxicities (Table). There were no grade 3/4 infections occurring in ≥2 treatment groups. Serious AEs were observed in a total of 6 pts. In the Ven400Dd arm, 1 pt had a femur fracture and 1 pt had non-cardiac chest pain. In the Ven800Dd arm, 1 pt had febrile neutropenia and 1 pt had tonsil cancer. In the DVd arm, 1 pt had pyrexia and upper respiratory tract infection, and a second pt had hyperglycemia, autonomic neuropathy, distributive shock, disseminated cryptococcosis, and cytomegalovirus infection. No deaths were reported in part 3 of the study. The median treatment duration based on D exposure at the time of data cut was 6.5, 5.6, and 3.9 months for the Ven400Dd, Ven800Dd, and DVd arms, respectively. The preliminary ORR was 72.7%, 100%, and 62.5% for the Ven400Dd, Ven800Dd, and DVd arms. The preliminary rate of very good partial response or better (≥VGPR) was 72.7%, 100%, and 31.3% for the Ven400Dd, Ven800Dd, and DVd arms. Follow-up is still immature, and responses may deepen with time. Conclusion: The preliminary results from part 3 of this novel randomized, phase 2 study of t(11;14)-selected RRMM pts treated with VenDd vs DVd demonstrate a tolerable safety profile. Updated analyses, including response rates with longer follow-up and minimal residual disease status, will be included at presentation. Figure 1 Figure 1. Disclosures Kaufman: Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; Sutro, Takeda: Research Funding; Fortis Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Quach: Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baz: GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy; Merck: Research Funding; BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding. Harrison: Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Plesner: Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding; Genmab, Genentech, Roche: Research Funding. Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Sehgal: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kang: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Lash-Fleming: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Bahlis: Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a potent and selective oral BCL-2 inhibitor being investigated in the treatment of relapsed/refractory multiple myeloma.

Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that is currently being evaluated as a targeted therapy for the treatment of t(11;14) relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown promising efficacy with a tolerable safety profile in the phase 1/2 study (NCT03314181). VenDd is hypothesized to have increased anti-myeloma activity based upon complementary mechanisms of pro-apoptotic effects on tumor cells as well as potentially enhanced T-cell activation and clonal expansion, which has been shown to be associated with achieving deep sustained response to D-based therapy in MM. Results presented herein describe the immunomodulatory effects observed upon VenDd treatment in t(11;14) RRMM patients, including effects on the T-cell repertoire. Methods: Peripheral blood samples from t(11;14) RRMM patients (n=18) treated with VenDd (NCT03314181) were collected at day 1 of cycles 1-5 to characterize effects on B-, T-, and NK-cell populations by multicolor flow cytometry. TCRβ sequencing (ImmunoSEQ, Adaptive Biotechnologies) was also conducted on peripheral blood samples collected from t(11;14) RRMM patients (n=31) treated with VenDd at day 1 of cycles 1, 3, 5, and 9 to assess changes in T-cell clonality, defined as the extent of mono- or oligoclonal expansion by Simpson clonality index, and T-cell richness, defined as the number of clones with unique TCRβ rearrangements after computationally down-sampling to a common number of T-cells. Results: Consistent with previous findings with Ven, rapid and sustained depletion of B-cells (CD19+/CD5-) was observed in patients treated with VenDd (median absolute count: 115 cells/ml at baseline vs 13 cells/ml at C2D1 (89% decrease), p Conclusions: Treatment of t(11;14) RRMM patients with VenDd resulted in selective depletion of B-cells, NK-cells, and immunosuppressive regulatory T-cells, but not CD8+ T-cell subsets. Increased T-cell clonality indicates focusing of the T-cell repertoire and generation of an adaptive anti-myeloma immune response upon treatment with VenDd. The study is continuing with a randomized, open-label expansion that will further evaluate the safety and efficacy of VenDd in patients with t(11;14) RRMM, including correlative studies between the observed immune modifications and patient outcome. Figure 1 Figure 1. Disclosures Bahlis: Genentech: Consultancy; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman: Fortis Therapeutics: Research Funding; Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; BMS: Consultancy, Research Funding; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Amgen: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Baz: BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Merck: Research Funding; GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy. Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Genmab, Genentech, Roche: Research Funding; Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding. Moreau: Celgene BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Mantis: AbbVie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Harrison: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that is being investigated as therapy for the treatment of relapsed/refractory multiple myeloma.

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

Amyloidosis is a collection of diseases caused by the misfolding of proteins that aggregate into insoluble amyloid fibrils and deposit in tissues. While these fibrils may aggregate to form insignificant localised deposits, they can also accumulate in multiple organs to the extent that amyloidosis can be an immediately life-threatening disease, requiring urgent treatment. Recent advances in diagnostic techniques and therapies are dramatically changing the disease landscape and patient prognosis. Delays in diagnosis and treatment remain the greatest challenge, necessitating physician awareness of the common clinical presentations that suggest amyloidosis. The most common types are transthyretin (ATTR) amyloidosis followed by immunoglobulin light-chain (AL) amyloidosis. While systemic AL amyloidosis was previously considered a death sentence with no effective therapies, significant improvement in patient survival has occurred over the past 2 decades, driven by greater understanding of the disease process, risk-adapted adoption of myeloma therapies such as proteosome inhibitors (bortezomib) and monoclonal antibodies (daratumumab) and improved supportive care. ATTR amyloidosis is an underdiagnosed cause of heart failure. Technetium scintigraphy has made noninvasive diagnosis much easier, and ATTR is now recognised as the most common type of amyloidosis because of the increased identification of age-related ATTR. There are emerging ATTR treatments that slow disease progression, decrease patient hospitalisations and improve patient quality of life and survival. This review aims to update physicians on recent developments in amyloidosis diagnosis and management and to provide a diagnostic and treatment framework to improve the management of patients with all forms of amyloidosis.

Background: Systemic AL amyloidosis is characterized by the deposition of insoluble amyloid fibrils produced by light chains synthesized by clonal CD38+ plasma cells. Combining daratumumab (DARA) with bortezomib, cyclophosphamide, and dexamethasone (VCd) has demonstrated significantly improved outcomes in patients with AL amyloidosis. The classification of hematologic complete response (CR) in this disease is evolving, and the absolute reduction of the involved free light chain (iFLC) and the difference between iFLC and uninvolved free light chain (dFLC) are being recognized as very meaningful endpoints. Here, we present results from the ANDROMEDA study (NCT03201965) to demonstrate the impact of achieving deep reductions of iFLC and dFLC on major organ deterioration progression-free survival (MOD-PFS), a novel, key secondary endpoint in this study. Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease (serum monoclonal protein ≥0.5 g/dL by protein electrophoresis or serum free light chain ≥5.0 mg/dL with an abnormal kappa:lambda ratio or dFLC ≥50 mg/L), ≥1 involved organ, cardiac stage I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 subcutaneous [SC] weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every other week in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of FLC levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if iFLC Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and 65% of patients had ≥2 organs involved. The proportions of patients with heart and kidney involvement were 71% and 59%, respectively, and the proportions of patients with cardiac stage I, II, and IIIA were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). The rates of deep hematological responses by all criteria strongly favored the DARA-VCd treatment arm (Table). MOD-PFS was longer in patients achieving deep hematological responses by all criteria (Figure). In addition, the corresponding MOD-PFS was similar regardless of the hematological response criteria used. Conclusions: Regardless of the criteria used, the addition of DARA to VCd increased the rates of deep hematologic responses in patients with newly diagnosed AL amyloidosis, which, in turn, was associated with prolonged MOD-PFS. These results support the benefit of DARA in this patient population. References 1. Comenzo RL, et al. Leukemia. 2012;26(11):2317-25 2. Sidana S, et al. Leukemia. 2019;34(5):1472-75 3. Muchtar E, et al. Leukemia. 2019;33(3):790-94 4. Manwani R, et al. Blood. 2019;134(25):2271-2280 Disclosures Comenzo: Amgen: Consultancy; Sanofi: Consultancy; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Unum: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Caleum: Consultancy. Kastritis:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Minnema:Celgene: Other: travel support, Research Funding; Kite, a Gilead Company: Speakers Bureau; Amgen: Consultancy; Servier: Consultancy. Wechalekar:Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria. Jaccard:Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding; Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding. Sanchorawala:Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Gibbs:Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. Mollee:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Kim:Amgen, BMS, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Cibeira:Janssen, Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Amgen: Honoraria, Other: Educational lectures. Beksac:Deva: 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, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valent:Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Wong:Fortis: Research Funding; GSK: Research Funding; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig:Janssen: Speakers Bureau. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company.

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS., This Expert Consensus Document from the International Kidney and Monoclonal Gammopathy Research Group includes an updated definition of monoclonal gammopathy of renal significance (MGRS) and recommendations for the use of kidney biopsy and other modalities for evaluating suspected MGRS

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high-efficacy COVID-19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID-19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID-19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority. Refereed/Peer-reviewed

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.

Purpose Immunoglobulin M (IgM)–related light chain (AL) amyloidosis, which accounts for 6% to 10% of all AL amyloidosis cases, is a rare and poorly studied clinical entity. Its natural history and management is not clearly defined. Prognostic and response criteria for AL amyloidosis in general have not been validated in this population. Patients and Methods We retrospectively gathered data for 250 patients diagnosed with IgM AL amyloidosis from three European amyloidosis centers. Clinical features, hematologic response, and overall survival (OS) were analyzed. The current staging and response criteria in non-IgM AL amyloidosis was applied to this series to assess its utility in this patient cohort. Results Patients with IgM AL amyloidosis have a significant IgM paraprotein (median, 10 g/L), less frequent lambda light chain isotype, and evaluable difference between involved and uninvolved free light chains (dFLCs; > 50 mg/L) in only two thirds of patients. Bone marrow showed clear non-Hodgkin lymphoma as the underlying disorder in 54% of patients. Cardiac involvement (45%) is less common but there is more frequent lymph node (20%) and neuropathic (28%) involvement compared with non-IgM AL. Fifty-seven percent of patients achieved a hematologic response (14% very good partial response/complete response [VGPR/CR]), with median OS not reached for patients achieving VGPR/CR, 64 months for PR, and 28 months for nonresponders (P < .001). On multivariate analysis, cardiac involvement, advanced Mayo disease stage, neuropathic involvement, and liver involvement were independent factors that had an impact on survival. Combining abnormal N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T with liver involvement and the presence of neuropathy gives a better risk model: median OS of patients with none, one, or two or more abnormal factors was 90, 33, and 16 months, respectively. Conclusion IgM AL amyloidosis is a distinct clinical entity. Low-risk disease can be defined by combining cardiac involvement with novel prognostic markers. Deeper hematologic responses translate into improved outcomes, yet deep responses remain dismally poor, which highlights the urgent need for novel therapies.

8511 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells in vitro. It has shown synergistic activity with bortezomib (V) and dexamethasone (d). Combination of the CD38 monoclonal antibody daratumumab (D) with Ven is hypothesized to further increase anti-myeloma activity based on dual mechanisms of pro-apoptotic effects on tumor cells and enhanced immune stimulation. Methods: This ongoing Phase 1/2, nonrandomized, multicenter study (NCT03314181) is evaluating safety, efficacy and pharmacokinetics (PK) of VenDd +/- V in patients (pts) with relapsed/refractory MM. In Part 1, pts with t(11;14) who received ≥1 prior line of therapy (PI and an immunomodulatory drug) were treated with VenDd [Ven QD + D 16 mg/kg IV + d 40 mg weekly]. In Part 2, pts irrespective of t(11;14) status, non-refractory to PIs and who received 1–3 prior lines of therapy were treated with VenDVd [Ven QD + D 16 mg/kg IV + V (1.3 mg/m2) + d (20 mg)]. A randomized, open-label expansion (Part 3) will further evaluate and compare safety and efficacy of VenDd (400 or 800 mg Ven dose levels) with control DVd in pts with t(11;14). Results: As of Dec 05, 2019, 48 pts were enrolled. Part 1 included 24 pts with t(11;14), median age 63 (range 51–76). Part 2 included 24 pts, median age 65 (range 41–80) of which 6 (25%) had t(11;14). Frequent adverse events (AEs; VenDd/VenDVd) were fatigue (71%/25%), diarrhea (58%/46%), nausea (46%/50%), insomnia (33%/50%), upper respiratory tract infection (33%/21%), cough (42%/9%), and dyspnea (25%/25%). Frequent Grade ≥ 3 AEs in pts on VenDd were neutropenia (17%), hypertension (12%), fatigue and hyperglycemia (8% each), and in pts on VenDVd were insomnia (21%), diarrhea and thrombocytopenia (8% each). Nine pts had infection-related Grade ≥ 3 AEs (5 VenDd, 4 VenDVd). Eighteen pts had a serious AE (11 VenDd, 7 VenDVd) with pyrexia (n = 3) being most common. One pt on VenDVd died of progressive disease. PK analyses showed that addition of D and V did not impact Ven exposure. Median follow-up time (VenDd/VenDVd) was 10 and 9 months. Overall response rate in VenDd/VenDVd was 96%/92% and 96%/79% had ≥ very good partial response rate. Median progression free survival and duration of response were not reached. Conclusions: Pts treated with VenDd +/- V continue to demonstrate a tolerable safety profile with encouraging efficacy, notably among pts with t(11;14) treated with VenDd. Safety, efficacy, PK, and cytogenetics analyses will be updated for presentation. Clinical trial information: NCT03314181 .

Autologous stem cell transplantation (ASCT) is an effective treatment for amyloid light-chain (AL) amyloidosis leading to both deep and durable clonal responses with excellent median overall survival of over five years with those attaining a complete hematologic response and surviving relapse free

The outcomes and responses to treatment remain poorly studied among patients with systemic AL amyloidosis who require further treatment following prior novel agent-based therapy. We report here treatment with lenalidomide-dexamethasone in 84 AL amyloidosis patients with relapsed/refractory clonal disease following prior treatment with thalidomide (76%) and/or bortezomib (68%). On an intention-to-treat (ITT) basis, the overall haematological response rate was 61%, including 20% complete responses. The median overall survival (OS) has not been reached; 2-year OS and progression-free survival (PFS) was 84% and 73%, respectively. Achieving a free light chain (FLC) response was an independent good prognostic factor for OS in multivariate analysis. There was no impact of prior thalidomide or bortezomib therapy on response rate, OS or PFS. 16% achieved an organ response at 6 months, with a marked improvement in organ responses in patients on long term therapy (median duration 11 months) and 55% achieving renal responses by 18 months. Lenalidomide/dexamethasone therapy achieves good haematological responses in patients with AL amyloidosis with relapsed/refractory clonal disease. The rate of renal responses among patients who received prolonged treatment was unexpectedly high, raising the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits.

Background: Novel and more effective therapies for multiple myeloma (MM) have led to increasing overall survival, but most patients (pts) will eventually relapse or become refractory (RR). The proteasome inhibitor (PI) bortezomib (V), the anti-CD38 antibody daratumumab (D), and dexamethasone (d) are key agents for combination therapy in first-line and RR settings. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in BCL-2-dependent MM cells in vitro. Encouraging clinical efficacy has been observed with Ven monotherapy in t(11;14) pts, and with VenV in pts irrespective of disease genetic background. In view of MM intraclonal heterogeneity, the addition of D to Ven +/- PI is postulated to further enhance antitumor activity of Ven-based regimens in RRMM. Methods: M15-654 (NCT03314181) is an ongoing Phase 1/2, nonrandomized, multicenter study of combination therapy consisting of VenDd +/- V in pts with RRMM. The primary objective is to evaluate the safety, tolerability, and preliminary efficacy of VenDd +/- V. In Part 1, VenDd was evaluated in t(11;14) MM pts who received ≥1 prior line of therapy that included a PI and an immunomodulatory drug (IMiD). In Part 2, VenDVd was evaluated in MM pts irrespective of t(11;14) status who were non-refractory to PIs and received 1 - 3 prior lines of therapy. Each regimen was evaluated in a dose escalation and expansion phase. In each part, Ven dose escalation was initiated at 400 mg daily (QD) and escalated to 800 mg QD if acceptable safety and tolerability were observed. Escalation cohorts had ≥3 pts, and escalation decisions were based on a Bayesian optimal interval design and the number of pts with a dose limiting toxicity (DLT). In Part 1, cycles (C) were 28-day: Ven QD + D 16 mg/kg intravenous (IV) (C1, 2: Days 1, 8, 15, 22; C3 - 6: Days 1, 15; C7+: Day 1) + d 40 mg total weekly. In Part 2, C1 - 8 were 21-day, C9+ were 28-day: Ven QD + D 16 mg/kg IV (C1 - 3: Days 1, 8, 15; C4+: Day 1) + V 1.3 mg/m2 subcutaneous (C1 - 8, Days 1, 4, 8, 11) + d 20 mg (C1 - 3: Days 1, 2, 4, 5, 8, 9, 11, 12, 15; C4 - 8, Days 1, 2, 4, 5, 8, 9, 11, 12) and 40 mg weekly for C9+. Results: As of 13 May 2019, 48 pts were enrolled. Of 24 t(11;14) pts treated in Part 1 with VenDd, median age was 63 (range, 51 - 76), median prior lines of therapy was 2.5 (range, 1 - 8), 14 (58%) had ISS II/III disease, and 24 (100%) received both prior PI and IMiD (46% refractory to PI, 71% refractory to IMiD, 42% double refractory). Of 24 pts treated in Part 2 with VenDVd, median age was 64 (range, 41 - 80), median prior lines of therapy was 1 (range, 1 - 3), 14 (58%) had ISS II/III disease, and 6 (25%) were t(11;14). Twenty-two (92%) pts received prior PI, 17 (71%) received prior IMiD (33% refractory), and 15 (63%) received prior PI + IMiD. The most common adverse events (AEs; VenDd/VenDVd) were fatigue (54%/21%), diarrhea (50%/42%), nausea (33%/38%), insomnia (29%/42%), cough (21%/8%), headache (21%/4%), upper respiratory tract infection (21%/17%), constipation (8%/33%), infusion related reaction (8%/33%), peripheral neuropathy (4%/25%), and dyspepsia (4%/21%). Grade 3/4 AEs were seen in 63%/54% of pts. The most common Grade 3/4 AEs in pts receiving VenDd were neutropenia (13%), fatigue, hyperglycemia, and hypertension (8% each); in pts receiving VenDVd, the most common were insomnia (17%), diarrhea, and thrombocytopenia (8% each). There were 6 pts with infection-related Grade 3/4 AEs (3 VenDd, 3 VenDVd). No AEs of tumor lysis syndrome were observed. Eleven pts had a serious AE (5 VenDd, 6 VenDVd), the most common being pyrexia in 3 pts. One pt treated with VenDd had a DLT of febrile neutropenia, and 1 pt treated with VenDVd died due to progressive disease. No infection-related deaths were seen. Pharmacokinetic analyses demonstrated that addition of D and V did not impact Ven exposure. Median time on study is 3.6 months (m; 8.1 m escalation, 2.8 m expansion) in the VenDd arm and 3.1 m (5.8 m escalation, 2.4 m expansion) in the VenDVd arm. The objective response rate (ORR) was 92% and 88% in pts receiving VenDd and VenDVd, respectively (Table). Conclusions: This first analysis of pts treated with VenDd +/- V demonstrate a tolerable safety profile with encouraging efficacy, notably among t(11;14) pts treated with VenDd who had an ORR of 92%. No new safety signals were observed. Although the study is currently on partial clinical hold, enrolled pts continue to be followed. Analysis will be updated at presentation. Disclosures Bahlis: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Baz:Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Karyopharm: 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. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Quach:Amgen: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Ho:Celgene: Membership on an entity's Board of Directors or advisory committees. Vangsted:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Gibbs:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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. Salem:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Pesko:AbbVie: Employment, Other: Stock/stock options. Westrup:AbbVie: Employment, Other: Stock/stock options. Vue:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Bueno:AbbVie: Employment, Other: Stock/stock options. Kaufman:Takeda: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Winship Cancer Institute of Emory University: Employment; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

Purpose To report a rare case of transthyretin (TTR) familial amyloid cardiomyopathy with retinal microangiopathy and vitreous amyloid as the initial manifestation. Methods A 54-year-old woman presented with bilateral retinal microangiopathy, presumed idiopathic retinal vasculitis. She subsequently developed retinal ischemia associated vitreous hemorrhage and was treated with panretinal laser photocoagulation. Clinical eye signs remained stable for 6 years with the absence of overt inflammation. However, the patient developed chest pain and atrial flutter and underwent echocardiography, cardiac magnetic resonance imaging, and Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy to investigate possible cardiac amyloidosis. Sequencing of the TTR gene was conducted and a rectal biopsy performed for tissue diagnosis. A full neurologic screen was also conducted. Results Cardiac investigations were highly suggestive of an amyloid cardiomyopathy. The rectal biopsy stained positive for Congo red with demonstration of apple green birefringence, confirming amyloid, and immunostaining confirmed the TTR subtype. Gene sequencing revealed heterozygous TTR mutation encoding E89K variant. No significant neuropathy could be detected. Conclusion Amyloid should be considered as a masquerade diagnosis in cases of retinal microangiopathy, especially in the absence of inflammation. Liaising with physicians for systemic evaluation and TTR gene sequencing is essential for early diagnosis and management of this rare condition.

Weight loss is common in systemic immunoglobulin light chain amyloidosis but there are limited data on the impact of nutritional status on outcome. Using the Patient-Generated Subjective Global Assessment (PG-SGA) score, we prospectively examined nutritional status in 110 consecutive newly-diagnosed, treatment-naïve patients with immunoglobulin light chain amyloidosis attending the UK National Amyloidosis Centre. At study entry, 72 of 110 (66%) patients had a PG-SGA score of 4 or over, indicating malnutrition requiring specialist nutritional intervention. Number of amyloidotic organs, elevated alkaline phosphatase, presence of autonomic neuropathy and advanced Mayo disease stage were independently associated with poor nutritional status (P

About 4% of African Americans possess the isoleucine 122 (V122I) variant of transthyretin, associated with cardiac amyloidosis beyond ages of 55 to 60 years. Transthyretin amyloidosis associated with variant V122I (ATTR V122I) is likely to be an important cause of heart failure in Afro-Caribbean populations, but the high prevalence of left ventricular hypertrophy (LVH) and lack of awareness of this genetic disorder pose diagnostic hurdles. We report the electrocardiographic (ECG) features of ATTR V122I in the largest clinical series to date.Patients with ATTR V122I were identified in collaboration with the UK National Amyloidosis Centre. The ECG at presentation was assessed for cardiac rhythm, axis, and voltage complex size.We include 64 patients with ATTR V122I, with a median age of 74 years (range, 57-88 years). Normal or increased ECG voltage was present in 44.3% of patients, and overall 25% met the criteria for LVH. A significant negative correlation between voltage complex size and duration of illness was seen (P.05). First-degree heart block was evident in 56% of patients in sinus rhythm. During follow-up (n = 17; median, 28 months), 50% of patients with initial first-degree heart block required pacing.Electrocardiographic voltages meet the criteria for LVH in one quarter of patients with ATTR V122I cardiac amyloidosis. The widely held belief that cardiac amyloidosis is associated with low-voltage complexes is likely to contribute to underdiagnosis of ATTR V122I. First-degree heart block is common at diagnosis and identifies patients at high risk for subsequent pacing requirement.

Bortezomib has shown great promise in the treatment of amyloid light-chain (AL) amyloidosis. We present our experience of 43 patients with AL amyloidosis who received cyclophosphamide, bortezomib, and dexamethasone (CVD) upfront or at relapse. Of these, 74% had cardiac involvement and 46% were Mayo Cardiac Stage III. The overall hematologic response rate was 81.4%, including complete response (CR) in 41.9% and very good partial response with > 90% decrease in difference between involved/uninvolved light chain (VGPR-dFLC) in 51.4%. Patients treated upfront had higher rates of CR (65.0%) and VGPR-dFLC (66.7%). The estimated 2-year progression-free survival was 66.5% for patients treated upfront and 41.4% for relapsed patients. Those attaining a CR or VGPR-dFLC had a significantly better progression-free survival (P = .002 and P = .026, respectively). The estimated 2-year overall survival was 97.7% (94.4% in Mayo Stage III patients). CVD is a highly effective regimen producing durable responses in AL amyloidosis; the deep clonal responses may overcome poor prognosis in advanced-stage disease.

Aims Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant. Methods and results Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45–78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years. Conclusion Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging.

The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as “primary”), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Laser microdissection and tandem mass spectrometry–based proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease.

Purpose Chemotherapy in AL (primary or light chain) amyloidosis is associated with improved survival, but its effect on renal outcome has not been examined systematically. The purpose of this study was to evaluate the effect of chemotherapy on clinical outcome among patients with renal AL amyloidosis. Patients and Methods We evaluated factors influencing survival among 923 patients with renal AL amyloidosis observed during a 21-year period, including 221 patients who became dialysis dependent. Factors associated with renal outcome were analyzed, including serum free light chain (FLC) response to chemotherapy using a simple subtraction formula applicable to all stages of chronic kidney disease. Patient survival and graft survival were analyzed in 21 renal transplantation recipients. Results Median survival from diagnosis for the whole cohort was 35.2 months. Magnitude of FLC response with chemotherapy was strongly and independently associated with overall survival (P < .001) and renal outcome. Evaluable patients achieving more than 90% FLC response had a significantly higher rate of renal responses and lower rate of renal progression compared with patients achieving a 50% to 90% response, whose renal outcomes were, in turn, better than patients achieving less than 50% FLC response (P < .001). Median survival from dialysis dependence was 39.0 months, and median survival from renal transplantation was 89.0 months. Conclusion Renal outcome and overall outcome in AL amyloidosis are strongly associated with FLC response to chemotherapy and are best among patients achieving more than 90% suppression of the amyloidogenic monoclonal component. Survival on dialysis was substantially superior to that previously reported, and renal transplantation should be considered in selected patients with AL amyloidosis with end-stage renal disease.

BACKGROUND & METHODS Cfz/Dex is a standard of care in relapsed MM, and renal impairment is a poor prognostic factor. The ALLG MM16 trial was initiated to assess the feasibility of treating patients (pts) who have significant RI (eGFR 15 - 40 ml/min) with Cfz/Dex, and to determine whether an early reduction in serum free light chains (SFLC), with a short half-life, could predict renal outcome. A pre-planned interim analysis was conducted after Cycle 1 of the 32nd registered pt, to assess disease and renal response, predictive value of early SFLC measurements and tolerability. Of concern was whether acute kidney injury (AKI) in the early stages of Cfz treatment may be more common in pts with RI. eGFR was calculated using the MDRD formula. SFLC was measured by the FreeLite assay. RESULTS Patient characteristics Mean age was 56.7 ±1 yr; Stage II/III: 4/28. Median eGFR at enrolment was 27 (IQR 21-32) ml/min. The first 11 pts received Cfz 20/27 mg/m2. After a safety analysis, the next 21 pts were treated at 20/56 mg/m2. Twelve pts were treatment naïve (TN) (all receiving 20/56) and 20 pts had relapsed MM (median 3 prior lines; range 1 - 8). One to 29 cycles were administered, median 4.5 in 20/27 and 4 in 20/56 group. Median follow up was 5.1 (0.1 - 26.5) months. Disease Response Of pts who received ≥4 cycles, 83% achieved ≥PR. In TN pts, best response rates were sCR 33%, CR 17%, VGPR 33%, PR 17%; in relapsed pts, CR 17%, VGPR 25%, PR 33%, PD 25%. Renal response After the first 2 cycles, 24% of pts had a complete renal response (IMWG criteria). To determine if Cfz acutely worsened eGFR, change in eGFR from baseline to day 7 (D7) and D28 was calculated. D7 eGFR showed substantial improvement in TN compared to relapsed pts (+5.6 vs -1.2 ml/min). At D28, the improvement in TN vs relapsed pts (+21.4 vs +3.5 ml/min), and in the 20/56 vs 20/27 group (+14.2 vs +3.5 ml/min) was more pronounced. Comparable results were seen in serum creatinine. Early free light chain kinetics Mean change in involved SFLC after 1 & 2 cycles were -54.5% and -67.0% respectively, with mean increase in eGFR of 9.3 and 11.4 ml/min. Involved LC reduction was significantly greater in 20/56 vs 20/27 doses (at C2D1, 81 vs 13%; p Tolerability A total of 25 pts have ceased treatment: disease progression (10), CR after 10 cycles per protocol (2), autologous transplant (3), AE (8), investigator or pt decision (1 each). Total AEs (CTCAE V.4.0) were more frequent in more severe RI (78% in 30-60 ml/min; 89% 15-30 ml/min). AEs ≥Grade (Gd) 3 occurred in 50%. The most common ≥Gd 3 AEs were thrombocytopenia (12.5%), cardiac dysfunction (12.5%) and anemia (9%). AEs of particular interest were hypertension (Gd 2 - 3, 19%) and tumour lysis syndrome (6%). There was only 1 case (3%) of AKI (Gd 2). More respiratory AEs occurred in the 20/56 compared to 20/27 cohort (5 vs 1) and all 3 cases of cardiac dysfunction occurred in 20/56 group, but there were no differences in other AEs. To date 8/32 pts have died, all in relapsed MM group - primary causes were myeloma (5), infection (1), respiratory failure (1) and chronic kidney injury (1). CONCLUSIONS In MM pts with RI, Cfz/dex showed disease response rates comparable to pts with normal renal function in ENDEAVOR. There was no increased AKI due to Cfz; instead, creatinine and eGFR improved with time, with a greater improvement in the 20/56 dose group and in TN pts. Our results also demonstrate the value of early SFLC kinetics measured at C1D3 and C1D10 in predicting renal response. A suboptimal early ∆LC may be an appropriate indicator to use a higher dose density to achieve a better renal outcome. Disclosures Ho: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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, Other: Travel to meeting; Celgene: Other: Travel to meeting ; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Mollee: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: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bryant:Celgene: Consultancy, Honoraria. Trotman:PCYC: Research Funding; Beigene: Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board. Gibbs:Amgen: Honoraria. Joshua:Amgen: Honoraria.

Osteonecrosis of the Jaw (ONJ) is a recently recognised and potentially highly morbid complication of bisphosphonate therapy in the setting of metastatic malignancy, including myeloma. Members of the Medical and Scientific Advisory Group of the Myeloma Foundation of Australia formulated guidelines for the management of bisphosphonates around the issue of ONJ, based on the best available evidence in June 2008. Prior to commencement of therapy, patients should have an oral health assessment and be educated about the risks of ONJ. Dental assessment should occur 6 monthly during therapy. If tooth extraction is required, sufficient time should be allowed for complete healing to occur prior to commencement of bisphosphonate. As the risk of ONJ increases with duration of bisphosphonate therapy, we recommend annual assessment of dose with modification to 3 monthly i.v. therapy or to oral therapy with clodronate for those with all but the highest risk of skeletal-related event. Established ONJ should be managed conservatively; a bisphosphonate "drug holiday" is usually indicated and invasive surgery should generally be avoided. These recommendations will assist with clinical decision making for myeloma patients who are at risk of bisphosphonate-associated ONJ.

Cardiac involvement is not regarded as a feature of Henoch-Schönlein purpura (HSP). We report a patient with HSP who developed significant cardiac symptoms, which resolved with immunosuppression. We review previous cases of HSP with cardiac features, none of which showed a response to treatment, and discuss evidence that cardiac involvement is more common than recognized. The implications for investigation and treatment of this condition are discussed.

The Hyper-CVAD chemotherapy regimen is being increasingly applied to a number of haematological malignancies. We assessed the impact of Hyper-CVAD on peripheral blood stem cell (PBSC) yields and examined the optimal timing of PBSC collection when using this regimen. Seventy-four consecutive patients were identified in whom an attempt was made to collect PBSC, usually on recovery from cycle A or B. Where PBSC collection was attempted after cycle 3B, only 18% (3/17) of patients successfully mobilized. Fifty-seven patients were mobilized on recovery from cycle 1B (n = 13), 2A (n = 22), 2B (n = 14) or 3A (n = 8). Compared with cycle 2A, 1B was not superior in achieving the minimum ofor =2 x 10(6)/kg CD34+ cells (100% vs. 77%, p = 0.13), but was superior in terms of total CD34+ yield (21.4 vs. 3.2 x 10(6)/kg, p0.001), achieving the target CD34+ cell count ofor =5 x 10(6)/kg (92% vs 36%, p = 0.002), and obtaining both a minimum (92% vs. 18%, p0.001) and target (77% vs. 0%, p0.001) graft with a single apheresis. There were no significant differences in PBSC yields following cycles 2A, 2B and 3A. Hyper-CVAD has substantial stem cell toxicity which can be readily circumvented by using the early chemotherapy cycles for mobilization.

Aim: Cardiac amyloidosis is a protein deposition disease that can be difficult to diagnose and has a poor prognosis if diagnosis or treatment are delayed. The two major subtypes are AL and transthyretin (ATTR). Both have vastly different treatments so confirming the correct amyloid subtype is crucial. A tissue biopsy is usually required for the diagnosis of amyloidosis and to distinguish between the subtypes. No blood test, echocardiography or cardiac MRI can reliably distinguish between AL and ATTR. With a cardiac biopsy, distinguishing AL from ATTR can be challenging with immunohistochemistry, and time consuming with mass spectrometry. Recently, Gillmore et al demonstrated bone scintigraphy with 99mTc-DPD tracer can reliably diagnose ATTR, avoiding endomyocardial biopsies to confirm the subtype in most cases. [1] 99mTc-HDP is a tracer similar to 99mTc-DPD and is more readily available in Australian and the USA. We sought to examine the use of 99mTcHDP bone scintigraphy in Australia and determine the accuracy of this tracer to diagnose cardiac amyloidosis and distinguish between the AL and ATTR subtypes. Methods: All patients with confirmed ATTR or AL who had 99mTcHDP bone scintigraphy were analysed. Results were correlated with histology, NT ProBNP, Troponin-T, free light chains, cardiac MRI and echocardiography. Grading was conducted with Perugini scoring.[1] Results: 25 patients with amyloidosis diagnosed by cardiac MRI and/or biopsy, had 99mTcHDP bone scintigraphy. 18 were confirmed ATTR, 7 AL. Two ATTR patients had hereditary disease (Thy60Ala and Gly109Lys), the remainder were wildtype. 17 (94%) patients with ATTR and 2 (29%) AL had positive scans. The negative ATTR patient had localized bladder disease only with a normal echocardiogram and cardiac biomarkers. All ATTR patients with positive scans had Perugini scores of 2 or 3, including the 2 patients with hereditary mutations, while the two positive AL only had scores of 1. All 11 patients with amyloid features on cardiac MRI had positive scans. Mean NTproBNP values for ATTR and AL were 530pmol/L and 1396pmol/L respectively. The two AL amyloidosis patients with positive bone scans had higher NTproBNP values. No ATTR patient had a detectable plasma cell dyscrasia. Conclusion: Bone scintigraphy with 99mTcHDP tracer is an easily accessible, rapid and non-invasive method of diagnosing cardiac amyloidosis. In our small series, all patients with Perugini scores 2 or 3 had ATTR, while those with negative or Perugini score 1 scan either had AL or no cardiac amyloidosis. There was a suggestion that AL patients with higher NTproBNP scores were more likely to have positive scans. This suggests that the 99mTcHDP tracer can be used like 99mTc-DPD to aid in the diagnosis of cardiac amyloidosis, and, as suggested by Gillmore et al, can confirm the ATTR subtype in those with no detectable plasma cell dyscrasia and Perugini score 2 or 3 scans, thus hastening accurate diagnosis and avoiding cardiac biopsies. Reference: Gillmore JD, Maurer MS, Falk RH, Merlini M, Damy T, Dispenzieri A, et al. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12 Disclosures No relevant conflicts of interest to declare.

Background Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis ( ATTR wt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTR wt compared with cardiac‐isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTR wt from baseline factors. Methods and Results All patients with biopsy‐proven ATTR wt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTR wt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTR wt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTR wt had evidence of a plasma cell dyscrasia. Older age and lower N ‐terminal pro‐ B ‐type natriuretic peptide ( NT pro‐ BNP ) were factors significantly associated with ATTR wt. Patients aged 70 years and younger with an NT pro‐ BNP ATTR wt, as were patients older than 70 years with an NT pro‐ BNP Conclusions Factors at baseline associated with a worse outcome in ATTR wt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro‐ BNP level can aid in distinguishing ATTR wt from AL amyloidosis.

Background Systemic AL Amyloidosis causes multiorgan dysfunction through interstitial expansion. We measured the extracellular volume fraction (ECV) in the : heart, liver, spleen and skeletal muscle in healthy volunteers and patients with Systemic Amyloidosis to test the hypotheses that (1) tissue ECV is greater in systemic AL Amyloidosis than in health and (2) ECV tracks organ amyloid burden. Methods Healthy volunteers (n=70; 35 male; 35 female; median age 46 years) and patients with systemic AL Amyloidosis (n=56; 36 male; 20 female; median age 62 years), with clinical indications for CMR scanning, additionally underwent multi-organ ECV measurement. Technical details were: gadoteric acid, 0.1mmol/Kg plus infusion, multibreathhold T1 measurement and equilibrium imaging of heart, liver spleen and biceps muscle at 1.5T (Siemens Avanto). Amyloidosis patients also underwent serum amyloid P component (SAP) scintigraphy to score liver and spleen involvement by amyloid. Results ECV of the heart, liver, spleen and muscle was significantly elevated in patients with amyloidosis (0.40, 0.33, 0.42 and 0.12 respectively) compared to healthy controls (0.25, 0.30, 0.34 and 0.09 respectively) (P

Background— Cardiac involvement predicts outcome in systemic AL amyloidosis and influences therapeutic options. Current methods of cardiac assessment do not quantify myocardial amyloid burden. We used equilibrium contrast cardiovascular magnetic resonance (EQ-CMR) to quantify the cardiac interstitial compartment, measured as myocardial extracellular volume (ECV) fraction, hypothesizing it would reflect amyloid burden. Methods and Results— Sixty patients with systemic AL amyloidosis (65% men, median age 65 years) underwent conventional clinical cardiovascular magnetic resonance, including late enhancement, equilibrium contrast cardiovascular magnetic resonance, and clinical cardiac evaluation, including ECG, echocardiography, assays of N-terminal pro-brain natriuretic peptide and Troponin T, and functional assessment comprising the 6-minute walk test in ambulant individuals. Cardiac involvement in the amyloidosis patients was categorized as definite, probable, or none, suspected by conventional criteria. Findings were compared with 82 healthy controls. Mean ECV was significantly greater in patients than healthy controls (0.25 versus 0.40, P P R =0.56, P R =0.69, P R =0.53, P =0.006). ECV was associated with smaller QRS voltages ( R =0.57, P R =0.36, P =0.03). Conclusions— Myocardial ECV measurement has potential to become the first noninvasive test to quantify cardiac amyloid burden.

The simultaneous presentation of chronic lymphocytic leukaemia (CLL) and cutaneous T-cell lymphoma (CTCL) is a very rare occurrence where optimal treatment is unknown. We present the case of a 65-yr-old man who was successfully treated with alemtuzumab monotherapy for both disorders, but at a cost of severe infectious morbidity and prolonged pancytopenia.

Systemic AA amyloidosis is a recognised complication of inflammatory bowel disease. AA amyloidosis is a potential cause of end-stage renal failure and mortality but little is known of the natural history of this condition in inflammatory bowel disease. We evaluated the clinical phenotype, disease progression and outcome amongst 26 patients with inflammatory bowel disease and AA amyloidosis followed prospectively at a single center between 1989 and 2010. Twenty-two patients had Crohn’s disease and four had ulcerative colitis. Fistulae and abscesses occurred in ten cases, all of whom had Crohn’s disease. Amyloidotic proteinuric renal dysfunction occurred in all of the cases. It resolved in five patients with well-controlled inflammation, but was progressive in all of the other patients. Fifteen patients reached end-stage renal disease after a median time of 6.3 years from development of renal dysfunction (by Kaplan–Meier estimate), six of whom subsequently proceeded to renal transplantation. There were five functioning grafts at census 0.8, 3.2, 4.2, 20.1 and 24.6 years after transplantation. One graft failed 14.5 years after renal transplantation because of amyloid recurrence in a patient with sustained chronic inflammatory activity. AA amyloidosis remains a serious complication of both Crohn’s disease and ulcerative colitis, and is characterized by proteinuric renal dysfunction that may resolve following suppression of inflammatory activity. Patient and graft survival are excellent in patients who undergo renal transplantation.

Introduction: The introduction of novel agentshas revolutionised the treatment of multiple myeloma, with improvements in survival of newly diagnosed and relapsed/refractory patients. However, despite these advances, the role for allogeneic haematopoietic stem cell transplantation (HSCT) in the treatment of these patients remains in question. Reduced-intensity conditioning (RIC) HSCT with Seattle regimen (30 mg/m2 fludarabine and 2 Gray total-body irradiation, TBI) for multiple myeloma has been reported to be an effective treatment with low upfront toxicity, and the potential for graft-versus-myeloma effect (Niederwieser D et al, Blood, 2003). Its use as part of tandem HSCT (autologous HSCT followed by RIC-HSCT) is associated with a treatment-related mortality (TRM) rate as low as 15% (Björkstrand B et al, J Clin Onc, 2011). However, data on survival following auto-HSCT/RIC-HSCT is inconsistent and no unifying consensus has been reached regarding the optimal timing of RIC-HSCT in the treatment algorithm. In this retrospective multi-centre study, we investigated the safety, tolerability and efficacy of RIC-HSCT in multiple myeloma patients in remission following previous auto-HSCT. Methods: A retrospective series was conducted for early-phase, high-risk myeloma patients who underwent RIC-HSCT following prior auto-HSCT in two tertiary transplant centres in Manchester in North West England, between November 2006 and July 2014. Results: Over the eight-year period, 42 myeloma patients (male n=29, female n=13) underwent Seattle-conditioned RIC-HSCT following prior auto-HSCT. 66.6% (n=28) were performed in tandem. Median age at RIC-HSCT was 52 years (range 41-65), and median β2-microglobulin at diagnosis was 3.1 mg/L (range 1.6-18.0). 16 patients had cytogenetics assessed at the time of diagnosis, of which loss of TP53 and translocation of chromosome 14 were most common. 37 patients (88.1%) had previously been exposed to immunomodulatory agents (IMiDs). 53.3% patients (n=24) were in first remission at RIC-HSCT, whilst 37.8% (n=17) were in second remission. 31.1% (n=14) of RIC-HSCTs were performed after second auto-HSCT following previous relapse and re-induction chemotherapy. 34 patients (55.9%) had achieved at least a very good partial response (VGPR) prior to RIC-HSCT. RIC-HSCT was performed a median of 20 months (range 10-89) from diagnosis. Two patients (4.8%) required re-transplantation for failed engraftment, but subsequently engrafted following in vivo T cell-depleting regimens. Mortality at early and interim time-points was low relative to registry and trial series, with TRM of 2.4% (n =1) and 9.5% (n=4) at day 100 and 365, respectively. 37 patients (82.2%) experienced chronic graft-versus-host disease (GVHD). Chronic skin GVHD was observed in 21 patients (grade 1-2: n=20; grade 3-4: n=1); chronic gastrointestinal GVHD in four patients (grade 1-2: n=1; grade 3-4: n=3); chronic hepatic GVHD in six patients (grade 1-2: n=4; grade 3-4: n=2); chronic oral GVHD in 17 patients (grade 1-2: n=17); and chronic ophthalmic GVHD in five patients (grade 1-2: n=5). There was an association between GVHD and enhanced disease control, as complete response rates increased from 26.5% to 51.5% by day 100 post-RIC-HSCT. However, 22 patients (48.9%) eventually relapsed with a median time to relapse of 6.5 months. 13 patients remain in CR one year post-RIC-HSCT. Relapse was treated with escalating donor lymphocyte infusions (DLI, n=13) or IMiDs (n=16). Response to lenalidomide at relapse was potentiated, despite the majority of patients having prior exposure to IMiDs. The median length of follow-up from diagnosis was 27 months (range 1-90). Median overall survival (OS) has not been reached; OS at two years was 69.2% (Figure 1). Conclusions: In this retrospective series we demonstrate the feasibility of Seattle-conditioned RIC-HSCT in multiple myeloma. We observed a very low early TRM of 9.5% and presence of allo-immune disease control (graft-versus-myeloma effect), thereby augmenting IMiD efficacy. Chronic GVHD was prevalent and relapse occurred in a significant proportion of patients, but salvage with DLI and IMiDs highlighted the efficacy of the graft-versus-myeloma effect elicited by RIC-HSCT. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Disclosures Cavet: Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Speaker. Tholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Gibbs:Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

Amyloidosis is a heterogeneous group of diseases characterized by normally soluble proteins deposited extracellularly in an abnormally folded, insoluble fibrillar form. This can lead to organ impairment and premature death. This article discusses the pathogenesis, classification system and means of diagnosis of the amyloid diseases.

Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery.

e186 PO-180 LECT2 Amyloidosis: not just a Hispanic disease J. Ramzy, P. Mollee, F. Kwok, J. Gilbertson, P. Hosking, M. Fraenkel, P. Renaut, G. Stewart, D. Booth, S. Gibbs Victorian and Tasmanian Amyloidosis Service, Monash University Eastern Health Clinical School, Melbourne, Australia; Princess Alexandra Amyloidosis Centre, Brisbane, Australia; Westmead Amyloidosis Clinic, Westmead Hospital, Sydney, Australia; National Amyloidosis Centre, UCL Medical School, London, UK; Department of Anatomical Pathology, Victorian and Tasmanian Amyloidosis Service, Monash University Eastern Health, Melbourne, Australia

Alemtuzumab is effective therapy for B- and T-cell lymphoproliferative disorders (LPD) but is associated with prolonged lymphopenia. Myeloid haematological toxicities are less well described, especially in T-cell disorders, and are usually transient. We report myeloid toxicities in a phase II trial of alemtuzumab for T-cell LPD. Five of 11 patients treated developed severe neutropenia and thrombocytopenia. Three cases had prolonged cytopenias (32-88+ weeks), including two with severe marrow hypoplasia. We observed three incidences of trilineage morphological myelodysplasia, two with new clonal cytogenetic abnormalities. Alemtuzumab can be associated with prolonged severe multilineage cytopenias, marrow hypoplasia and myelodysplasia in T-cell LPD.

Senile systemic amyloidosis (SSA) is a rare cause of heart failure due to the deposition of wildtype transthyretin. The clinical features and outcome are ill defined; our aim was to evaluate the natural history of the disease in the UK in a group of thoroughly characterised patients. The series included all cases of biopsy proven transthyretin (TTR) amyloidosis with wildtype TTR gene sequencing who were prospectively followed up between January 2001 and May 2010. Clinical, biochemical, ECG and echocardiographic evaluation were performed at presentation to our centre. Patient survival was estimated using Kaplan–Meier analysis. 55 patients with histologically proven SSA; 36 (65.5%) from cardiac, 14 (25.4%) from GI tract, 3 (5.5%) from bladder, 1 (1.8%) from fat and 1 (1.8%) from carpal tunnel tissue were identified. 49 (89%) were male. The median age at diagnosis and death were 74 (range 66–89) and 79 (range 69–84) years respectively. Survival from symptom onset and diagnosis was 7.04 (range 0.54–8.41) and 4.58 (range 0.07–5.41) years respectively. In recent years more patients have been diagnosed with 2 (3.6%), 14 (25.5%) and 39 (70.9%) patients between 2001–2003, 2004–2006 and 2007–2009 respectively. The most common presentation was with breathlessness in 28 patients (51%). Twenty-four patients (43.6%) had prior carpal tunnel operations. Twelve (21.8%) patients had a history of ischaemic heart disease. Fifteen had had a coronary angiogram; 8 were reportedly normal and 7 required intervention. Arrhythmias were common, 20 patients (36.3%) had a history of atrial fibrillation and 6 (10.9) had pacemakers in situ. ECG findings were; 24 (43.6%) in AF, 6 (10.9%) first degree block, 10 (18.2%) left bundle and 6 (10.9%) right bundle branch block, 27 (49%) T wave changes, 11 (20%) 0.03 (45%). Ten patients (18%) had a detectable paraprotein and 2 (3.6%) had bence jones proteins. SSA is present in >25% of the very elderly at post mortem but was rarely diagnosed during life. It is becoming more frequently recognised perhaps due to widespread use of cardiac MRI. Most patients are male but women can be affected. A history of carpal tunnel syndrome is common. The diagnosis is often made after the onset of breathlessness. Systolic and diastolic dysfunction can be seen on echocardiogram. A positive troponin is a common finding with a subsequent normal coronary angiogram. Incidental paraproteins are prevalent in up to 8% of this population and it is important to obtain a tissue diagnosis to rule out AL amyloidosis. With supportive management medium term outcomes are good.

TO THE EDITOR: We have read with interest the recent study by Madsen and colleagues in the Scandinavian Journal of Gastroenterology [1]. The authors clearly highlight the plethora of potential gast...