Atypical midperipheral lattice corneal dystrophy presenting with adult onset and negative family history should arouse suspicion for an association with paraproteinemias or amyloidosis. Exclusion of TGFBI mutations should alert the clinician to the possibility of potentially life-threatening conditions, with referral for careful systemic evaluation.

The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.

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Background: The pivotal phase III MM009 and MM010 trials have established standard dose lenalidomide (len; 25mg daily, days 1-21 of 28 day cycle) and high-dose dexamethasone (dex; 40mg daily, days 1-4,9-12,17-20) [RD] as effective treatment for patients with relapsed/refractory multiple myeloma (RRMM). However, moderate toxicities were seen with RD that necessitated dose reduction in 76% and treatment cessation in 20% of patients. We prospectively investigated lower dose len-dex (rd) in a group of patients who were deemed at higher risk of myelosuppression and compared this to a matched cohort of patients who received RD in the MM009 and MM010 trials. Methods: RevLite was a multicentre phase II single-arm study across 12 centres in Australia and New Zealand of patients with RRMM, who were aged ≥60 years and/or with CrCL 20-59ml/min and/or platelets ≤75x109/L. Patients received rd (len 15mg daily, day 1-21 of a 28 day cycle and dex 20mg daily, days 1-4,9-12,17-20) until disease progression. The primary end point was overall response rate (ORR) and secondary endpoints were progression free survival (PFS) and adverse events (AE). A matched cohort of patients who received RD was extracted from the MM009/010 trials. Toxicities and survival outcome were compared between the cohort of patients receiving rd and RD. Results: A total of 149 patients (median age 69 years; male 60%) received rd in the RevLite trial. 65% of patients had prior thalidomide and 49% had at least 3 prior lines of treatment. ORR was 69.1% with CR 14.1%. With a median follow up of 28.4 months (0.2-63.5), median PFS was 8.9 months (95% confidence interval (CI): 6.9-11.5) and median OS was 30.5 months (20.0-36.2). Data of a total of 255 patients were extracted from the RD cohort in the MM009 and MM010 trials. Patients from the rd vs. RD cohort were similar in age, sex, ISS stage and CrCL. There was a higher prior exposure to thalidomide in the rd cohort (65% vs. 36% (RD)). ORR was similar between rd (69%; CR 14.1%) and RD (60%; CR 13.7%). No difference was seen in PFS (p=0.34) and OS (p=0.21). On multivariate analysis, after adjusting for other baseline prognostic factors, there was a trend for better OS with RD (HR 0.76 (95%CI 0.57-1.01), p=0.058). Grade 3-4 toxicities were lower with rd, mainly lower neutropenia (29 vs. 41%), infections (23.3 vs. 31.4%), and VTE (3 vs. 13%). Patients who were still on treatment after 3 years were on an average daily dose of 15mg in both groups. Conclusion: Lower dose len-dex is less toxic but remains efficacious in patients with RRMM who are at higher risk of myelosuppression. While this trial was not powered to detect non-inferiority of rd vs RD with respect to PFS and OS, rd was shown to induce a meaningful depth of response and PFS that was comparable to that seen with standard dose len-dex in patients who are aged ≥60 years and/or with renal impairment and/or with thrombocytopenia. These results reinforce the growing recognition of treatment attenuation in elderly or frail patients, and confirm that such practice with len-dex will not likely compromise patient response or survival outcome. Disclosures Quach: Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Harrison:Celgene: Honoraria, Research Funding. Li:Celgene Corp: Employment, Equity Ownership. Dimopoulos:Amgen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Prince:Celgene Corp, Amgen, Janssen: Honoraria, Research Funding.