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INTRODUCTION Myeloma cast nephropathy (CN) is the most common form of monoclonal immunoglobulin-mediated kidney disease, resulting from the precipitation of excessive amounts of monoclonal serum free light chains (sFLC) and causing around 70% of the cases of dialysis-dependent renal failure in multiple myeloma (MM)(Heher et al. 2013; Nasr et al. 2012; Sanders et al. 1991). In patients with acute renal failure, the finding of a high sFLC concentration with an abnormal sFLC ratio raises the clinical suspicion of CN (Hutchison et al. 2011). Although the histopathologic diagnosis of CN is established by renal biopsy, in routine clinical practice, the diagnostic yield of this procedure is often outweighed by the urgent need of anti-myeloma treatment and the risk of procedure-related complications. Recruitment of patients with CN into clinical trials is challenging and therefore real-world data on clinically suspected CN are necessary to understand the clinical characteristics, treatment and prognosis of these patients (Bridoux et al. 2017; Hutchison et al. 2019). METHODS We searched the population-based Danish Multiple Myeloma Registry for patients diagnosed with MM according to the International Myeloma Working Group criteria between 1st of January 2013 and 31st of December 2017 with a serum creatinine concentration of 200 µg/L or higher and a sFLC concentration of 1000 mg/L or higher at diagnosis. We conducted a retrospective patient chart review in eight Danish centers and assessed baseline characteristics, biopsy results, and overall survival. Anti-myeloma treatment, sFLC levels and renal function were registered during the first 12 months after MM diagnosis. RESULTS We identified 181 patients (176 with accessible clinical records). The median age was 72 years, the median serum creatinine was 384 µg/L, the median involved sFLC concentration was 5960 mg/L and dialysis dependent renal failure was present in 35%. Pre-myeloma estimated glomerular filtration rate (eGFR) was available in 80%, the median eGFR was 66 ml/min/1.73 m2. A kidney biopsy was carried out in 21% of patients and showed CN in 70% of cases. The median time from first sFLC measurement to initiation of therapy was 4 days. The number of lines of therapy ranged between zero and six. 173 patients received one, 35 patients received two and 14 patients received three lines of therapy during the first 12 months from diagnosis. High-dose melphalan with autologous stem cell transplantation (HDT-ASCT) was carried out in 45 (26%) patients. Bortezomib was administered as part of the first-line regimen in 163 (94%) patients. The most common first-line regimens were bortezomib-dexamethasone (n=67) and cyclophosphamide-bortezomib-dexamethasone (n=46). The first line of therapy resulted in very good partial response or better in 50% (Figure 1A), but was discontinued due to death, toxicity or progressive disease in 38% of patients. Dialysis dependency, eGFR and involved sFLC concentration were assessed at the end of the first cycle, at three months, six months and 12 months after initiation of therapy. At all these time points, achievement of renal recovery was associated with the magnitude of reduction of involved sFLC (Figure 1B). The median overall survival was 3.3 years (Figure 1C). At 12 months after diagnosis, 68% of patients were alive and 15% were dialysis dependent. Reduction of the initial involved sFLC concentration to ≤ 10% at three months was strongly associated with longer OS in a multivariate cox regression analysis adjusted for age and HDT-ASCT; hazard ratio 0.42, p=0.003. CONCLUSION In conclusion, we assessed a population-based cohort of newly diagnosed MM patients presenting with a serum creatinine of 200 µg/L or higher together with a sFLC of 1000 mg/L or higher. Although CN could have been clinically suspected in these cases, a kidney biopsy was only performed in one fifth of the population. Bortezomib-based therapy was initiated quickly and resulted in deep responses in most patients. Approximately one third of patients died within a year from MM diagnosis. Achievement of early and deep reduction in involved sFLC resulted in longer OS. Figure 1 Disclosures Szabo: Janssen: Consultancy. Vangsted:Takeda: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Celgene: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Plesner:Celgene: Consultancy; AbbVie: Consultancy; Genmab: Consultancy; Oncopeptides: Consultancy; Takeda: Consultancy; Janssen: Consultancy, Research Funding.

Background The indication for use of lenalidomide in second line of therapy has been based upon two phase III studies comparing lenalidomide and dexamethasone vs. placebo and dexamethasone (Weber 2007, Dimopoulos 2007) showing a TTP of 11.1 and 11.3 months respectively. In 2009 Stadtmauer et al showed that patients with only one prior therapy had significantly longer median TTP compared with those treated in later lines (17.1 months vs. 10.6 months). Here we report outcomes from the REVII trial in 2nd line treatment of MM, a two part study with first an observational part with standard treatment of lenalidomide combined with corticosteroids and then, a randomized part, where patients that had responded in the first part, were randomized to lenalidomide combined with dexamethasone or lenalidomide as a single drug. Methods 132 patients with multiple myeloma in first relapse were included in the first, observational part of the study, and treated with up to 9 cycles of lenalidomide combined with betamethasone or dexamethasone according to local routines. Patients that had achieved at least partial response and had consolidation treatment with at least two additional cycles were offered to take part in the second part of the study. In the second part 63 patients were randomized to be treated with either lenalidomide combined with dexamethasone (LenDex) or lenalidomide as a single drug (Len) for a maximum of 24 cycles. In the first part of the study the primary endpoint was time to response and secondary endpoints were quality of life, safety and cytogenetic markers as gain 1q21, t(4;14), t(11;14) and del17p. In the second part, primary endpoint was time to progression and secondary endpoint was safety. In the second part we also performed detailed NK/T-cells phenotype analyses. Survival data were calculated from first entry in the observational study. Data cutoff was 1st of July 2015, with a median follow-up of 21.4 months. Results A very high proportion of patients achieved PR or better (≥PR 84%). Of the patients 3% were primary refractory and 12% achieved a minor response or stable disease. Very good partial response or better (≥VGPR) was achieved in 44% of the patients. First response, at least PR, was achieved after a median of 7 weeks and best response after a median of 10 weeks. After randomizations no differences in responses between the Len and the LenDex group were found. Late responses were common and 7 of the patients received their best response after more than one year of treatment. Median overall survival (OS) was not reached. 61% of the participants were still alive at the data cut off. OS in the first part was 32 months and 78% of the patients in the second part were still alive at data cut off. Median time to progression (TTP) for the whole study was 16 months and for the first and second part 10 and 30 months respectively. After randomization TTP in the Len-group was 25 months and in the LenDex median TTP was not reached, 54% of the participants were still alive after 36 months of treatment. The difference between the two groups was not significant (p=0,48). Patients with gain1q21 had median OS of 31 months while 77% of patients with no gain 1q21 where still alive at the same time (p=0.054). TTP for patients with or without gain of 1q21 was 11 months vs. 28 months respectively (p=0.014). Patients with either gain 1q21, t(4;14) and/or del17p had a TTP of 11 months while patients with none of these chromosomal aberrations had a TTP of 30 months (p=0.0058). NK/T-cells phenotype data will be presented at the congress. Discussion Len/Dex was associated with a very high response rate at 2nd line treatment of MM. On achieving at least PR, continuing with dexamethasone in addition to len does not add any benefit for the patients regarding responses, TTP or OS. As expected, chromosomal abnormalities had a negative impact on TTP and OS. Disclosures Waage: Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Gimsing:Amgen: Honoraria. Mellqvist:Celgene, Amgen, Mundipharma and Novartis: Honoraria. Nahi:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.