We sought a regimen that incorporates optimal novel agents in transplant-ineligible patients that balances efficacy with toxicity. Our study evaluated modified lenalidomide-bortezomib-dexamethasone (RVD lite) in this population. RVD lite was administered over a 35-day cycle. Lenalidomide 15 mg was given orally days 1–21; bortezomib 1.3 mg/m2 weekly subcutaneously (SC) on days 1, 8, 15, and 22; and dexamethasone 20 mg orally day of and after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. Primary objective was to evaluate overall response rate (ORR). Secondary objectives included safety, progression free survival (PFS), and overall survival (OS). Fifty-three eligible patients screened between 4/17/13 and 5/20/15; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response (VGPR) or better. Median PFS was 35.1 months (95% CI, 30.9 - ∞) and median OS was not reached at a median follow-up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well-tolerated and highly effective regimen in the transplant-ineligible population with robust PFS and OS.

Although caregivers of patients with multiple myeloma (MM) play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking. We conducted a cross-sectional, multisite study of patients undergoing treatment with MM and their caregivers. Eligible caregivers were enrolled to 1 of 3 cohorts based on lines of therapy. Caregivers completed validated questionnaires to assess their QOL, psychological distress, and perceptions of prognosis. We enrolled 127 caregivers of patients with MM (newly diagnosed [n = 43], 2-3 lines of therapy [n = 40], and ≥4 lines of therapy [n = 44]). Caregiver QOL and psychological distress did not differ by line of therapy. The rate of clinically significant anxiety, depression, and posttraumatic stress disorder symptoms were 44.1% (56/127), 15.8% (20/127), and 24.4% (31/127), respectively. When examined in dyads, caregivers reported higher rates of clinically significant anxiety (44.4% [55/124] vs 22.5% [28/124]) compared with patients with MM. Most caregivers (84.2%, 101/120) reported that the oncologist had informed them that the patient’s cancer was incurable; however, only 50.9% (58/114) and 53.6% (59/110) of caregivers acknowledged the patient’s cancer was terminal and incurable, respectively. Caregivers of patients undergoing treatment for MM experience substantial psychological distress across the disease continuum, particularly anxiety. The majority of caregivers of patients with MM report that knowing the patient’s prognosis is extremely important and report that the oncologist told them that the patient was incurable. Nevertheless, a significant portion of caregivers believe that the patient’s MM is curable.

PURPOSE: This updated analysis examined survival outcomes after 60 months of follow-up in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with the 3-drug regimen of modified lenalidomide-bortezomib-dexamethasone (RVD lite) in this population. METHODS: RVD lite was administered over a 35-day cycle. Lenalidomide 15 mg was given orally days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously (SC) on days 1, 8, 15, and 22; dexamethasone 20 mg orally day of and after bortezomib for 9 cycles followed by 6 cycles of consolidation. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal, and hematologic function. Primary objective was to evaluate overall response rate (ORR). Secondary objectives included evaluation of safety, progression free survival (PFS), overall survival (OS), and the pharmacokinetic (PK) profile of intravenous (IV) and SC bortezomib. RESULTS: Fifty-three eligible patients enrolled between 4/17/13 and 7/25/15; 50 received at least one dose of therapy. As previously reported, the median age at study entry was 72 years (range 65-91). ISS stage was I in 19 (38%), II in 17 (34%), and III in 14 (28%) pts. Fatigue was the most commonly reported toxicity occurring in 37 (74%) and was mostly grade 1 or 2 in 29 (58%). Other grade 3 or greater toxicities included hypophosphatemia in 17 (34%), neutropenia in 7 (14%), and rash in 5 (10%) pts. Low grade peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. There were statistically significant improvements in scores of physical functioning (p=0.013), future perspective (p=0.023) and disease symptoms (p=0.001). Patients reported fewer symptoms across all symptom domains with the exception of diarrhea. The ORR was 86% and 66% of patients achieved a very good partial response (VGPR) or better. The median time to response was 1.1 months. At a follow-up of 61 months, median PFS was 41.9 months (95% CI, 31.2 - ∞) and median OS not reached. The 5-year overall survival was 61.3%. Sixty-six percent of patients received lenalidomide maintenance. CONCLUSIONS: RVD lite is a well-tolerated and highly effective regimen in the transplant-ineligible population with robust PFS and OS. Our data demonstrate that the benefits of more effective combination strategies observed in younger, fitter, transplant-eligible patients can be effectively used in older, transplant-ineligible patients with modifications in dose and schedule, without compromising efficacy. Disclosures O'Donnell: Celgene: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Yee:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Huff:Karyopharm, Sanofi, MiDiagnostics: Consultancy; Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Munshi:Celgene: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Oncopep: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder . Richardson:Bristol-Myers Squibb: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raje:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy.

BACKGROUND: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life (QOL), psychological distress, and perceptions of prognosis by line of therapy are lacking. METHODS: The authors conducted a cross-sectional, multisite study of patients undergoing treatment for MM (excluding maintenance) between June 2020 and January 2021. The authors conducted purposeful sampling and recruited patients to 3 cohorts based on lines of therapy: 1) newly diagnosed receiving first-line therapy; 2) 2 to 3 lines; and 3) 4 or more lines. Patients completed validated questionnaires to assess their QOL, fatigue, psychological distress, and perceptions of prognosis. RESULTS: A total of 180 patients with MM were enrolled (newly diagnosed [n = 60], 2 to 3 lines [n = 60], and ≥4 lines of therapy [n = 60]). QOL, symptom burden, and fatigue scores did not differ by lines of therapy. There were no statistically significant differences in psychological distress by line of therapy. The rates of clinically significant depression, anxiety, and post-traumatic stress disorder symptoms were 23.9% (43 of 180), 23.9% (43 of 180), and 24.4% (44 of 180), respectively. Most patients (84.7%, 149 of 176) reported that their oncologist told them their cancer was incurable, but only 30.6% (53 of 173) acknowledged that they were terminally ill, and 42.0% (73 of 174) reported that they thought their cancer was incurable. CONCLUSIONS: Patients with MM undergoing treatment experience impaired QOL and elevated psychological distress across the disease continuum, regardless of line of therapy. A substantial proportion of patients with MM have significant misperceptions about their prognosis and the curability of their illness despite reporting being informed of the prognosis by their oncologist.

Introduction Anemia and bone disease are hallmarks of multiple myeloma (MM). Sotatercept (ACE-011) is a novel, first-in-class activin type IIA receptor fusion protein that binds with high affinity to activin A and GDF11, and it acts during late-stage erythropoiesis to increase the production of mature erythrocytes through a mechanism independent of erythropoietin. Sotatercept has shown promising activity in clinical trials for anemia in myelodysplastic syndromes (Komrokji et al., ASH 2014) and in thalassemia (Cappellini et al., EHA 2015). Additionally, we have shown that targeting activin A through an analog of sotatercept reverses osteoblast inhibition and improves MM bone disease in a mouse model (Vallet et al., PNAS 2010). Lenalidomide increases activin A secretion with consequent inhibition of osteoblastogeneis, and this can be abrogated by treatment with an activin A neutralizing antibody (Scullen et al., Leukemia 2013). Sotatercept has been previously studied with melphalan, prednisolone, and thalidomide in MM (Abdulkadyrov et al., Br J Haematol 2014). Based on these findings, we evaluated sotatercept in combination with lenalidomide and dexamethasone in MM (NCT01562405). Methods Patient with relapsed and/or refractory MM with at least one prior line of therapy, anemia with hemoglobin <13 g/dL, lytic bone disease, and otherwise adequate organ function were eligible to participate. Sotatercept 10, 15, 30, or 45 mg was given s.c. q28 days along with lenalidomide and weekly dexamethasone on a standard 28 day schedule, with dose escalation following a 3 + 3 design. Sotatercept was held for hemoglobin ≥13 g/dL or for ≥ grade 3 hypertension. Bone mineral density by DEXA was assessed after four cycles. Bisphosphonates were not permitted during the study; prior bisphosphonate therapy was allowed. Results Thirteen patients with a median age of 62 years (range 49-77) and a median of 2 prior lines (range 1-5) of therapy have been enrolled to date (July 31, 2015). Median duration of treatment is 8.1 months (range 0.5, 27 months); five patients continue on study. The MTD has not been reached, and the current dosing level is sotatercept 45 mg with lenalidomide 25 mg. Grade 3-4 adverse events included anemia (38%), diarrhea (15%), fatigue (15%), hypophosphatemia (15%), and thrombocytopenia (38%). Grade 3 hypertension occurred in one patient receiving sotatercept 15 mg (hemoglobin at the time, 11.5 g/dL). There was one death on study that was unrelated to treatment. In patients who completed at least two cycles of treatment, there was a significant mean increase in hemoglobin on study of 0.94 g/dL (N = 10, p = 0.0048) from a mean starting hemoglobin 10.27 g/dL (range 8.6, 12.2). Mean maximal increase in hemoglobin was 2.11 g/dL (range 1.1, 4). Bone density by DEXA was assessed after four cycles. In patients who received a cumulative dose of sotatercept over 45 mg (N = 6), total lumbar spine BMD increased by a mean of 2.0% after four cycles; 83% had increase in BMD. ORR for this combination was 60% (CR = 1, VGPR = 1, PR = 4, SD = 4) in patients evaluable for response. Conclusion Sotatercept in combination with lenalidomide and dexamethasone is well tolerated with expected toxicities related to lenalidomide in MM. Preliminary data from this ongoing study suggest that sotatercept leads to early increases in both hemoglobin and bone mineral density, and it is the first agent that may address both of these significant causes of morbidity in MM. Disclosures Laubach: Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. O'Donnell:Millennium: Consultancy. Puccio-Pick:Celgene Corp.: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Raje:Acetylon: Research Funding; AstraZeneca: Research Funding; Onyx: Consultancy; Takeda: Consultancy; Eli Lilly: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy.