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Background: In part 1 of the two-part CASSIOPEIA study, treatment before and after autologous haematopoietic stem-cell transplantation (HSCT) with daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) significantly improved rates of stringent complete response and progression-free survival versus bortezomib, thalidomide, and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma., Methods: CASSIOPEIA is an ongoing randomised, open-label, active-controlled, parallel-group, phase 3 trial done at 111 academic and community practice centres in Europe. Transplantation-eligible adults with newly diagnosed multiple myeloma were randomly assigned (1:1) to D-VTd or VTd. Treatment consisted of four 28-day cycles of induction therapy before autologous HSCT and two 28-day cycles of consolidation therapy after. In this prespecified secondary analysis, patient-reported outcomes were assessed using the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire at baseline, after induction (cycle 4, day 28), and after consolidation (day 100 after autologous HSCT). The analysis was done in all patients in the intention-to-treat population with a baseline and at least one post-baseline patient-reported outcome assessment. The trial is registered at ClinicalTrials.gov (NCT02541383)., Findings: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled and randomly assigned D-VTd (n=543) or VTd (n=542). Questionnaire completion rates were high at baseline (511 [94%] of 543 in the D-VTd group vs 510 [94%] of 542 in the VTd group). Compliance rates (calculated from the number of completed surveys as a proportion of the predicted number of participants still on study treatment) were high at post-induction (431 [84%] of 513 vs 405 [80%] of 509) and post-consolidation (414 [90%] of 460 vs 386 [88%] of 438) assessments and were similar between treatment groups. Mean changes in global health status scores from baseline to post-induction were not different between the D-VTd group (3·8 [95% CI 1·6 to 6·0]) and VTd group (2·9 [0·7 to 5·1]; p=0·43), or from baseline to post-consolidation between the two groups (D-VTd group, 9·7 (95% CI 7·4 to 11·9) vs VTd group, 8·7 (6·5 to 11·0; p=0·45). Improvements from baseline in EORTC QLQ-C30 global health status and EQ-5D-5L visual analogue scale scores were observed in post-consolidation scores in both groups. Post-consolidation scores showed significantly greater mean decreases in pain (-23·3 [95% CI -26·6 to -20·0] in the D-VTd group vs -19·7 [-23·0 to -16·3] in the VTd group; p=0·042), significantly smaller reductions in cognitive functioning (-5·0 [-7·6 to -2·4] vs -7·9 [-10·6 to -5·3]; p=0·036), and significantly greater improvements in emotional functioning (13·0 [10·4 to 15·5] vs 9·5 [6·9 to 12·1]; p=0·013) and in constipation (-3·2 [-7·3 to 0·9] vs 1·8 [-2·4 to 6·0]; p=0·025) with D-VTd versus VTd. Between-group differences in change from baseline for all other scales were not significant., Interpretation: D-VTd and VTd were associated with on-treatment health-related quality of life improvements from baseline in transplantation-eligible patients with newly diagnosed multiple myeloma. The significantly greater reductions in pain, less deterioration of cognitive functioning, and greater emotional functioning improvements complement the clinical benefits observed with D-VTd versus VTd, and support the addition of daratumumab to standard regimens in patients with newly diagnosed multiple myeloma., Funding: Intergroupe Francophone du Myélome, The Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research and Development., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) has proved effective and safe in patients with end-stage relapsed/refractory multiple myeloma (RRMM), otherwise characterized by a very poor outcome. MM remains an incurable disease with unavoidable relapses, and the outcome after pomalidomide is still dismal. However, some patients demonstrate prolonged survival even beyond pomalidomide therapy.We sought to analyze the treatment of RRMM patients following Pom-Dex therapy and the response and survival after this next treatment line.We studied 134 patients treated with Pom-Dex until progression across two IFM studies. Seventy percent of these patients received further therapy after Pom-Dex. Among the treated patients, one third responded and one third maintained stable disease. The median OS for treated patients was 12 months (6.5;17), with 22 and 12.5% of patients surviving beyond 2 and 3 years, respectively. The factors associated with a better outcome were exposure to a triplet-based regimen containing a novel agent, response to therapy, absence of adverse cytogenetic, and a longer time from diagnosis to post pomalidomide therapy.This study suggests that patients relapsing after Pom-Dex therapy can still benefit from a further line of treatment. A subset of these treated patients even displayed a prolonged OS, while the prognosis remained very poor without treatment. An active approach could therefore be recommended even in this adverse situation, however guided by the patients' prognosis factors.

Background: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide., Design: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment., Results: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months., Conclusion: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).

POEMS syndrome is a rare disorder characterized by polyneuropathy, monoclonal gammopathy, multiorgan involvement, and elevated vascular endothelial growth factor levels. Localized bone lesions require irradiation, whereas young patients with disseminated disease receive intensive treatment with stem cell support. Treatment of older and non responding patients is not yet standardized. We report the use of a combination of lenalidomide and dexamethasone in 20 patients with POEMS syndrome. Four patients were newly diagnosed, and 16 had relapsed or progressed after treatment. All but one of the patients responded: clinical improvements were noted in neuropathies (16/20) organomegaly (13/13), peripheral edema (14/15), and pulmonary hypertension (5/5). At least a very good partial response was noted in 68% of patients, with partial responses in 26%. Serum VEGF levels fell markedly in all 17 patients with available values. Twelve patients had 18-FDG-PET/CT at diagnosis (11 with positive findings), and nine patients during follow-up. The number of lesions fell markedly in five cases and remained stable in two cases, while two patients became negative. During a median follow-up of 22 months, four patients relapsed. Toxicity, predominantly hematological, was mild and manageable. Lenalidomide thus appears to be effective in POEMS syndrome, inducing high rate of clinical and biological responses., (Copyright © 2012 Wiley Periodicals, Inc.)

New treatment options are required for primary systemic amyloid light chain (AL) amyloidosis. This phase 1/2 dose-escalation study aimed to determine the maximum tolerated dose (MTD) of lenalidomide in combination with melphalan and dexamethasone (M-dex), and assess the efficacy and tolerability of this therapy for patients with de novo AL amyloidosis. Twenty-six patients were enrolled across 4 cohorts: M-dex + lenalidomide 5, 10, 15, and 20 mg once daily on days 1 to 21 in a 28-day cycle. No dose limiting toxicity (DLT) was observed in cohorts 1, 2, and 3. 4. Seven patients in cohort 4, M-dex + lenalidomide 20 mg/day, experienced DLT. MTD was defined as 15 mg of lenalidomide. A complete hematologic response was achieved in 42% at the dose of 15 mg of lenalidomide per day. After a median follow-up of 19 months, estimated 2-year overall survival (OS) and event-free survival (EFS) were 80.8% and 53.8%, respectively. Hematologic and organ responses were both associated with superior EFS rates (P = .0001). A higher EFS was also observed in patients whose free light chains decreased by more than 50% during therapy (P = .019). Lenalidomide 15 mg/d + M-dex is a new effective combination therapy in patients with newly diagnosed AL amyloidosis. This study is registered at www.clinicaltrials.gov as NCT00621400.

The article discusses a study that evaluates the efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) as consolidation therapy in myeloma patients who underwent an autologous stem cell transplantation (ASCT). It demonstrates that the VTd regimen significantly contributed to improve outcomes with an acceptable toxicity profile in multiple myeloma. It shows an impressive complete response rate in relation to the consolidation that transform into a prolonged time to progression.