Abstract: Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 and is approved for intravenous (IV) infusion across lines of therapy for MM. In phase 3 clinical studies, DARA IV plus Rd for RRMM (POLLUX) and DARA IV plus VMP for transplant-ineligible (TIE) NDMM (ALCYONE) led to deep and durable responses and reduced the risk of disease progression or death by ≥56% (Kaufman J, Blood 2019. 134[Suppl 1]:1866; Mateos M, Lancet 2020). In the phase 1b MMY1001 study of DARA IV plus carfilzomib/dexamethasone (Kd) in RRMM, DARA IV plus Kd was well tolerated and demonstrated deep responses, regardless of prior lenalidomide treatment (Chari A, Blood 2019.134[Suppl 1] :1876). In the phase 3 CANDOR study, DARA IV plus Kd reduced the risk of disease progression or death by 37% in pts with RRMM (Dimopoulos M, Lancet 2020). A formulation of DARA for subcutaneous administration (DARA SC) was developed (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.). Advantages of DARA SC include reduced administration time (3-5 minutes) and lower rates of infusion-related reactions (IRRs). The phase 2 PLEIADES study is evaluating the safety and efficacy of DARA SC combined with SoC for MM, including D-Kd for RRMM, D-Rd for RRMM, and D-VMP for TIE NDMM. In the primary analysis of the D-Rd and D-VMP cohorts in PLEIADES, D-Rd and D-VMP demonstrated clinical activity and safety comparable to corresponding DARA IV regimens, with low rates of IRRs, leading to approval in the United States (Chari A, Clin Lymphoma Myeloma Leuk 2019.19[10] :e16-e17). Here, we present the primary analysis of the D-Kd cohort and updated data for the D-Rd and D-VMP cohorts of PLEIADES. Methods: RRMM pts with 1 prior line of therapy (including 2 consecutive cycles of lenalidomide therapy) received 28-day cycles of Kd (K: 20 mg/m2 IV Cycle 1 Day 1, escalated to 70 mg/m2 on Cycle 1 Days 8 and 15, then 70 mg/m2 on Days 1, 8 and 15 of each cycle thereafter; d: 40 mg IV or PO QW) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). RRMM pts with ≥1 prior line received 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg IV or PO QW for each cycle) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). TIE NDMM pts received 9, 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly in Cycle 1 and QW in Cycles 2-9; M [9 mg/m2] and P [60 mg/m2] PO on Days 1-4 of Cycles 1-9) with DARA SC (QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ in 28-day cycles). All pts were treated until disease progression/unacceptable toxicity. Overall response rate (ORR) was the primary endpoint for each cohort. Additional outcomes were VGPR or better rate, CR or better rate, duration of response, minimal residual disease (MRD)-negativity rate, DARA serum concentrations, and safety. Results: At the time of the clinical cutoff for the D-Kd cohort, 66 pts were treated and the median duration of follow-up was 8.7 months. The ORR for D-Kd was 84.8% (90% CI, 75.7-91.5; Table) and response rates were consistent with DARA IV plus Kd in CANDOR (Dimopoulos M, Lancet 2020). For the updated analysis of the D-Rd cohort (n=65), median follow-up was 23.1 months, and the ORR was 93.8% (90% CI, 86.5-97.9; Table). Response rates for D-Rd were consistent with DARA IV plus Rd in POLLUX (Kaufman J, Blood 2019. 134[Suppl 1]:1866). For the updated analysis of the D-VMP cohort (n=67), median follow-up was 22.6 months. The ORR for D-VMP was 89.6% (90% CI, 81.3-95.0; Table), and response rates were consistent with DARA IV plus VMP in ALCYONE (Mateos M, Lancet 2020). The median duration of DARA SC administration was 5 minutes for all D-Kd injections. The safety profile of D-Kd was consistent with DARA IV as combination therapy with SoC regimens. The rates of IRRs and injection-site reactions were comparable to those observed with DARA SC monotherapy in the COLUMBA study (Mateos M, Lancet Haematol 2020). Additional data will be presented including MRD-negativity rates for all cohorts and updated safety data for the D-Rd and D-VMP cohorts. Conclusions: The primary analysis of the D-Kd cohort demonstrated comparable clinical activity and safety to DARA IV plus Kd. With extended follow-up in the D-Rd and D-VMP cohorts, clinical activity was comparable to corresponding DARA IV-containing regimens (DARA IV plus Rd [POLLUX]; DARA IV plus VMP [ALCYONE] ). A low incidence of IRRs and a short duration of administration were reported in the D-Kd cohort in PLEIADES. Table 1 Disclosures Moreau: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Chari:Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding; Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero:Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Kite: Consultancy, Honoraria. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. 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. Sureda Balari:BMS: Speakers Bureau; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Magen:AbbVie: Research Funding; Merck Sharpe and Dohme: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sano: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding. Iida:Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck Sharpe Dohme: Research Funding; AbbVie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Takeda, Celgene/Bristol-Myers Squibb, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Sanofi: Honoraria; Celgene: Other: Personal fees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Yang:Janssen: Current Employment. Kosh:Janssen: Current Employment. Delioukina:Maria Delioukina: Current Employment. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Goldschmidt:GlaxoSmithKline (GSK): Honoraria; Merck Sharp and Dohme (MSD): Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Incyte: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding. OffLabel Disclosure: This abstract includes discussion of a combination therapy with subcutaneous daratumumab plus carfilzomib and dexamethasone, which is currently under investigation in clinical trials, but has not yet been approved. Subcutaneous daratumumab is approved as monotherapy and in combination with other standard-of-care regimens for the treatment of multiple myeloma.

Abstract: A large number of studies have suggested that being a woman represents a potential risk factor for the development of adverse drug reactions ( ADR s). The aim of this study is to further explore the differences between men and women with regard to reported ADR s, particularly those associated with psychotropic drugs. We used spontaneous reports of suspected ADR s collected by M idi‐ P yrénées ( F rance), V eneto ( I taly) and C astilla y L eón ( S pain) R egional P harmacovigilance C entres ( J anuary 2007– D ecember 2009). All the reports including a psychotropic medication were selected in a first step; age distribution, seriousness and type of ADR s were compared between men and women. Reports of nonpsychotropic drugs were similarly identified and treated. The absolute number of reports and the proportion, considering population, were higher in women than in men. This was observed for all reports, but was particularly higher for psychotropic drugs (592 vs. 375; P   〈  0.001) than for nonpsychotropics drugs (5193 vs. 4035; P   〈  0.001). Antidepressants were the most reported (women, 303; men, 141; P   〈  0.001); the reporting rates (number of reports divided by exposed patients in the same period, estimated through sales data) for these drugs, however, were not significantly different between women (0.87 cases per 10 000 treated persons per year) and men (0.81 cases per 10 000 treated persons per year). Although there was a higher number of reports of ADR s in women, ADR reporting rates might be similar as highlighted by the case of antidepressants. Antidepressant ADR s in fact were similarly reported in men and in women. Gender differences are sometimes subtle and difficult to explore. International networks, as the one established for this study, do contribute to better analyse problems associated with medications.

Abstract: Nuclear protein of the testis ( NUT ) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology. Methods: The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external “experts.” No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, “strength” of recommendations were categorized by grading (grade A to E). Results: Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology ( NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B). Conclusions: This project leads to a consensus strategy based on international experience with this very rare disease.

Abstract: Patients with Hailey-Hailey and Darier diseases present with disabling inflammatory lesions located in large skin folds, which are often exacerbated or induced by sweating. Quality of life is highly impaired because of pain and recurrent skin infections. An improvement in skin lesions after botulinum toxin A injections has previously been reported in some patients but no prospective interventional studies are available. The aim of this open-label, 6-month, interventional pilot study (NCT02782702) was to evaluate the effectiveness and safety of botulinum toxin A for patients with moderate to very severe skin lesions located in folds. Results Thirty patients (26 Hailey-Hailey/4 Darier) were included. Botulinum toxin A proved effective within the first month in two-thirds of patients, taking all study parameters (itchiness, cutaneous pain, sweating and odour, infections, psychosocial impairment and quality of life) into account and persisted during the 6-month follow-up period. No patient was classed as a BtxA non-responder, but 11 (37%) Hailey-Hailey patients (the most severe ones), experienced a relapse during the study. No serious side effects were reported. Mild transient clear fluid discharge at the site of the injections was reported for 27% of patients. Conclusions Botulinic toxin seems to be an effective and safe treatment for Hailey-Hailey and Darier diseases. Nevertheless, it may prove insufficient for the severest of Hailey-Hailey cases and could be considered as supplementary to other conventional treatments. Further studies are required to confirm our results on larger Darier cohorts.

Abstract: Amyloid light‐chain (AL) amyloidosis is a rare disease in which plasma‐cell‐produced monoclonal immunoglobulin light chains misfold and become deposited as fibrils in the extracellular matrix. λ6 subgroup light chains are particularly fibrillogenic, and around 25 % of amyloid‐associated λ6 light chains exist as the allotypic G24R variant that renders the protein less stable. The molecular details of this process, as well as the structures of the fibrils, are unknown. We have used solid‐state NMR to investigate different fibril polymorphs. The secondary structures derived from NMR predominantly show β‐strands, including in former turn or helical regions, and provide a molecular basis for previously identified fibrillogenic hotspots. We have determined, by using differentially 15 N: 13 C‐labeled samples, that the β‐strands are stacked in‐register parallel in the fibrils. This supramolecular arrangement shows that the native globular folds rearrange substantially upon fibrillization, and rules out the previously hypothesized fibril formation from native monomers.