PURPOSE To provide evidence-based recommendations on the treatment of multiple myeloma to practicing physicians and others. METHODS ASCO and Cancer Care Ontario convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and some phase II studies published from 2005 through 2018. Outcomes of interest included survival, progression-free survival, response rate, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 124 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed for patients with multiple myeloma who are transplantation eligible and those who are ineligible and for patients with relapsed or refractory disease.

• Presented are results from the phase 2 dose-expansion study of the combination of carfilzomib, lenalidomide, and dexamethasone (CRd).• CRd was well tolerated with robust, rapid, and durable responses.We previously reported a phase 1b dose-escalation study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in relapsed or progressive multiple myeloma where the maximum planned dose (MPD) was carfilzomib 20 mg/m 2 days 1 and 2 of cycle 1 and 27 mg/m 2 days 8, 9, 15, 16, and thereafter; lenalidomide 25 mg days 1 to 21; and dexamethasone 40 mg once weekly on 28-day cycles. Herein, we present results from the phase 2 dose expansion at the MPD, focusing on the 52 patients enrolled in the MPD cohort. Median follow-up was 24.4 months. In the MPD cohort, overall response rate (ORR) was 76.9% with median time to response of 0.95 month (range, 0.5-4.6) and duration of response (DOR) of 22.1 months. Median progression-free survival was 15.4 months. ORR was 69.2% in bortezomib-refractory patients and 69.6% in lenalidomide-refractory patients with median DOR of 22.1 and 10.8 months, respectively. A median of 9.5 (range, 1-45) carfilzomib cycles were started with 7.7% of patients requiring carfilzomib dose reductions and 19.2% discontinuing CRd due to adverse events (AEs). Grade 3/4 AEs included lymphopenia (48.1%), neutropenia (32.7%), thrombocytopenia (19.2%), and anemia (19.2%). CRd at the MPD was well tolerated with robust, rapid, and durable responses. This trial was registered at clinicaltrials.gov as #NCT00603447. (Blood. 2013;122(18):3122-3128) IntroductionOver the past 15 years, patients with multiple myeloma (MM) have experienced significant gains in survival, yet nearly all patients will eventually relapse and succumb to their disease.1 Triplet combinations with targeted agents (eg, bortezomib with thalidomide or lenalidomide and dexamethasone) have been shown to improve response rates, disease control, and survival outcomes compared with doublet combinations in patients with MM, including those with advanced or high-risk disease.2-5 These combinations, however, have also been associated with increased toxicity.For instance, in recent phase 1/2 studies, the combination of bortezomib, lenalidomide, and high-dose dexamethasone (RVD) was shown to be highly efficacious in both the newly diagnosed and the relapsed/refractory settings, but there were high rates for some types of adverse events (AEs) that are associated with the individual agents, including neutropenia (lenalidomide) and peripheral neuropathy (bortezomib). 6,7 Similarly, in a recent phase 3 study by the European Group for Blood and Marrow Transplantation (EBMT), the addition of bortezomib to the combination of thalidomide and dexamethasone (VTD) significantly improved the primary end point of time to progression compared with the combination of thalidomide and dexamethasone (TD) alone (19.5 vs 13.8 months; P 5 .001) in patients with relapsed or progressive MM, but was also associated with a higher incidence of grade 3/4 AEs (71% vs 57%; P 5...

Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.