Usmani, Saad Z.

Abstract Introduction Lenalidomide-based therapies are a standard of care for patients with newly diagnosed, transplant-ineligible MM. Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody which has single-agent activity in heavily pretreated MM patients. As previously reported in 3 phase 3 studies, the addition of DARA to standards of care in both relapsed refractory (D-Rd, DARA plus bortezomib and dexamethasone [D-Vd]) or transplant-ineligible NDMM (DARA plus bortezomib, melphalan, and prednisone [D-VMP]) resulted in a ≥50% reduction in the risk of disease progression or death (Palumbo A, et al. N Engl J Med 2016;375:754-766; Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331; Mateos MV, et al. N Engl J Med 2018;378:518-528). Of these, the POLLUX study with D-Rd showed the greatest benefit with a 63% reduction in risk of disease progression or death in patients with MM who had at least one prior line of therapy. Based on the efficacy and tolerable safety profile of D-Rd, we conducted a phase 3 study (MAIA) to evaluate D-Rd vs Rd in transplant-ineligible NDMM. Here we report the prespecified interim analysis of the MAIA study. Methods Patients ineligible for high-dose chemotherapy with autologous stem cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to Rd ± DARA. Stratification was based on International Staging System stage (ISS [I, II, III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of treatment with Rd ± DARA. R: 25 mg (oral) QD on Days 1-21; d: 40 mg (oral) on Days 1, 8, 15 and 22. In the D-Rd arm, DARA was given at 16 mg/kg (intravenously) QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. In both arms, patients were treated until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), minimal residual disease (MRD)-negativity rate (10-5 sensitivity, clonoSEQ® version 2.0), and safety. Results This international study randomized 737 patients (368 to D-Rd; 369 to Rd) from 14 countries. Key baseline characteristics were well balanced between the two arms. The median (range) age was 73 (45-90) years with 44% of patients ≥75 years, and 52% were male. Two thirds of patients had ECOG scores ≥1: ECOG score 0, 34%; 1, 50%; ≥2, 17%. Overall, 27%, 43%, and 29% were ISS stage I, II, and III, respectively. Of 642 patients evaluable for FISH/karyotyping analysis, 86% and 14% were standard and high cytogenetic risk, respectively. The prespecified interim analysis occurred after 239 PFS events on 24 September 2018 with a median follow up of 28 months. For the primary endpoint, the hazard ratio was 0.55 (95% CI, 0.43 to 0.72; P <0.0001), representing a 45% reduction in the risk of progression or death in patients treated with D-Rd (Figure). The median PFS for the Rd arm was 31.9 months and not reached for the D-Rd arm. Adding DARA to Rd resulted in deeper responses with a complete response (CR) or better rate of 47.6% in the D-Rd arm compared with 24.7% in the Rd arm (odds ratio [OR] 2.75, 95% CI, 2.01 to 3.76; P <0.0001). The very good partial response (VGPR) or better rate was 79.3% in the D-Rd arm compared with 53.1% in the Rd arm (OR 3.4, 95% CI, 2.45 to 4.72; P <0.0001). A total of 19% of patients have died and the HR for OS was 0.78 (95% CI, 0.56 to 1.1); follow-up is ongoing. Higher rates (5% or more difference) of grade 3/4 pneumonia, neutropenia, and leukopenia were observed in the D-Rd arm. The safety profile is consistent with previously reported DARA studies. The complete topline data set will be presented with additional efficacy endpoints, including MRD negativity rate. Conclusion The addition of DARA to Rd in patients with transplant-ineligible NDMM significantly reduced the risk of progression or death by 45%. There are no new safety signals using DARA plus Rd in NDMM. These data together with the phase 3 ALCYONE study (D-VMP vs VMP) support the addition of DARA to standard of care combinations in patients with NDMM ineligible for transplant. Disclosures Facon: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner:Celgene: Other: Independent Response Assessment Comittee; Janssen: Consultancy. Orlowski:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioTheryX: Research Funding; Spectrum Pharma: Research Funding. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hulin:Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Adaptive Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria. O'Dwyer:Janssen: Consultancy. Perrot:Janssen: Consultancy, Equity Ownership, Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Weisel:Celgene: Consultancy; Angeb: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding; Bristol Myers SquibbMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ahmadi:Genmab: Employment, Equity Ownership. Chiu:Janssen Research & Development, LLC: Employment, Equity Ownership. Wang:Janssen Research & Development, LLC: Employment. Van Rampelbergh:Janssen: Employment. Uhlar:Janssen: Employment. Kobos:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.

Background:MAIA, an ongoing phase 3 trial of transplant‐ineligible patients with NDMM, demonstrated significant improvement in progression‐free survival with D‐Rd vs Rd alone. Assessment of patient‐reported outcomes (PRO) alongside efficacy endpoints provides patient perspective on their quality of survival and overall value of health‐related quality of life (HRQoL) while on treatments.Aims:To utilize PRO assessments as a tool in capturing the patient perspective on quality of survival and HRQoL changes in MAIA.Methods:The EORTC QLQ‐C30 and EQ‐5D‐5L questionnaires were completed by patients using an electronic device at baseline and every 3 months during treatment; interim results are presented for first 12 months. Treatment effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature.Results:Compliance rates in completing the assessment tools were high and comparable at baseline (>90%) and through month 12 (>80%) for both groups (D‐Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D‐Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D‐Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: −0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D‐Rd was also observed in EQ‐5D‐5L Visual Analog Scale (VAS) scores (LS mean change; D‐Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D‐Rd. Of note, meaningful differences were observed between the treatment groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D‐Rd (LS mean change at cycle 3; D‐Rd: −17.9 [95% CI: −20.7, −15.0], Rd: −11.0 [95% CI: −14.0, −8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D‐Rd. There was a decline in cognitive functioning through Cycle 12 in both treatment arms with the peak difference occurring at Cycle 9, but mean differences between groups were not statistically significant.Summary/Conclusion:Faster and sustained improvement in patients treated with D‐Rd was observed using HRQoL assessments compared with Rd, with similar findings reflected across the pain subscale.

BACKGROUNDRace/ethnicity remains an important barrier in clinical care. The authors investigated differences in the receipt of autologous hematopoietic cell transplantation (AHCT) among patients with multiple myeloma (MM) and outcomes based on race/ethnicity in the United States.METHODSThe Center for International Blood and Marrow Transplant Research database was used to identify 28,450 patients who underwent AHCT for MM from 2008 through 2014. By using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registries, the incidence of MM was calculated, and a stem cell transplantation utilization rate (STUR) was derived. Post‐AHCT outcomes were analyzed among patients ages 18 to 75 years who underwent melphalan‐conditioned peripheral cell grafts (N = 24,102).RESULTSThe STUR increased across all groups from 2008 to 2014. The increase was substantially lower among Hispanics (range, 8.6%‐16.9%) and non‐Hispanic blacks (range, 12.2%‐20.5%) compared with non‐Hispanic whites (range, 22.6%‐37.8%). There were 18,046 non‐Hispanic whites, 4123 non‐Hispanic blacks, and 1933 Hispanic patients. The Hispanic group was younger (P < .001). Fewer patients older than 60 years underwent transplantation among Hispanics (39%) and non‐Hispanic blacks (42%) compared with non‐Hispanic whites (56%). A Karnofsky score <90% and a hematopoietic cell transplantation comorbidity index score >3 were more common in non‐Hispanic blacks compared with Hispanic and non‐Hispanic whites (P < .001). More Hispanics (57%) versus non‐Hispanic blacks (54%) and non‐Hispanic whites (52%; P < .001) had stage III disease. More Hispanics (48%) versus non‐Hispanic blacks (45%) and non‐Hispanic whites (44%) had a very good partial response or better before transplantation (P = .005). Race/ethnicity did not impact post‐AHCT outcomes.CONCLUSIONSAlthough the STUR increased, it remained low and was significantly lower among Hispanics followed by non‐Hispanic blacks compared with non‐Hispanic whites. Race/ethnicity did not impact transplantation outcomes. Efforts to increase the rates of transplantation for eligible patients who have MM, with an emphasis on groups that underuse transplantation, are warranted. Cancer 2017;123:3141–9. © 2017 American Cancer Society.

AbstractThe International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.

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).