Richardson, Paul G.

Key Points IRd was associated with a consistent PFS benefit vs placebo-Rd in RRMM patients with high-risk and standard-risk cytogenetics. The addition of ixazomib to Rd overcomes the poor PFS associated with high-risk cytogenetics in patients with RRMM.

Key Points PVD is an active combination in relapsed lenalidomide-refractory MM patients. PVD with weekly bortezomib offers a simpler, more convenient, and well-tolerated regimen option.

SummaryPeripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib‐induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1–4, 8–11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient‐level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules.

SummaryThe oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double‐blind, placebo‐controlled Phase III TOURMALINE‐MM1 study of ixazomib‐Rd (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression‐free survival versus placebo‐Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo‐Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long‐term IRd treatment. Safety data from TOURMALINE‐MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

AbstractIgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mg dL−1 with 19% of patients presenting with levels >6,000 mg dL−1. International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t(11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P = 0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes.

Purpose The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma–related renal impairment (RI). Methods Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. Recommendations All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m 2 to 140 mg/m 2 ) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A).

Key Points Elderly patients with myeloma are heterogeneous and assessment strategies are needed to define the frailty profile. The proposed frailty score aims to better assess patients and provide them with more suitable therapies.

Purpose To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.