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Abstract We and others previously demonstrated an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of multiple myeloma (MM) and MGUS patients, underscoring a familial component to this disease. However, MM is known to be a collection of cytogenetically distinct diseases, with 40-50% of MM cases having a reciprocal translocation involving the IgH locus on chromosome 14q32 and in many of the remaining patients, trisomies. In a small proportion of cases, both IgH abnormalities and trisomies are found in the same clone. These MM cytogenetic subtypes are associated with differential prognosis. Whether there are differences in familial risk by cytogenetic subtypes is not known. Patients with MM were recruited from the Mayo Clinic Hematology practice in Rochester, Minnesota (MN) between 2005 and 2015. Serum samples were collected from first-degree relatives and subjected to electrophoresis and immunofixation for MGUS determination. Age- and sex-specific rates of MGUS from the population-based Olmsted County, MN, prevalence study were used as expected rates for the calculation of risk ratios (RRs) for comparisons of first-degree relatives. Cytogenetic subtypes were classified by FISH testing performed in the clinic and categorized into groups defined by IgH translocation , trisomy, intermediate/ high-risk disease (t(4;14), t(14;16), t(14;20), and del17p). Further, the distribution of cytogenetic subtypes was compared between MM cases with and without evidence of MGUS in first degree relatives using Chi square tests. Analyses were also subset to MM probands diagnosed in MN. There were a total of 442 MM probands, with 1235 first-degree relatives recruited and eligible for the study. MGUS was detected in 78 relatives, for an age- and sex-adjusted prevalence of 6.1% (4.7%-7.5%). Analyses comparing prevalence of MGUS in first degree relatives to population-based rates from Olmsted County showed a 2.5-fold (95% CI=1.9-3.0) increased prevalence. When performing analyses among MN probands only (RR=2.9; 95% CI=2.1-3.8), results were similar. Of the 442 probands, 310 had FISH performed on plasma cells (identified by cIG staining; cIg-FISH) at diagnosis. Of these cases, 49% had a trisomy, 23% had an IgH translocation, and 9% had both. Although the proportion of trisomies and IgH translocations were 4-6% higher among MM probands with a relative with MGUS compared to those without, these differences were not statistically significant (Table 1). MM probands with a first degree relative with MGUS also had a similar proportion of cytogenetic subtypes that are considered of intermediate or high risk compared to those MM without a family history (26.9% vs 25.2%) (p=0.79) (Table 1). When restricted to MM probands from MN, results remained non-statistically significant (Table 1). We showed an increased risk of MGUS in first-degree relatives of MM cases, implying shared environment and/or genetics underlying this malignancy. However, we did not find an association between family history of MGUS in MM probands and the cytogenetic subtypes examined. Larger cohorts are needed to examine if a relationship exists between cytogenetic subtypes of MM and familial risk. Disclosures Kumar: Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; Janssen: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; BMS: Consultancy.

Abstract Background Ixazomib, the first oral proteasome inhibitor (PI), is approved by the US FDA, in combination with lenalidomide-dexamethasone (Rd), for the treatment of pts who have received at least 1 prior therapy. Lenalidomide is a common partner agent in regimens for RRMM; however, due to increasing use of lenalidomide treatment to progression as a standard of care in the first-line setting, novel PI-based combinations without lenalidomide are needed for RRMM. Combinations of a PI, an alkylating agent, and dexamethasone have been shown to be active, with manageable side effects, in RRMM patients (e.g. VCD - bortezomib, cyclophosphamide, dexamethasone), but require SC or IV administration of the PI. The all-oral combination of ICd may offer activity, tolerability, and more convenient administration. This open-label, multicenter phase 2 study (NCT02046070) assessed the safety and efficacy of ICd in pts with RRMM. Methods Adult pts with RRMM after 1-3 prior lines of therapy, who had ECOG performance status 0-2, were not PI-refractory, had adequate hematologic, renal, cardiac, and hepatic function, and did not have grade ≥2 peripheral neuropathy (PN) or grade 1 PN with pain, were eligible. Pts received oral ixazomib 4.0 mg and oral cyclophosphamide 300 mg/m2 on days 1, 8, and 15, plus oral dexamethasone 40 mg (20 mg for pts aged >75 yrs) on days 1, 8, 15, and 22, in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥partial response [PR]); secondary endpoints included safety, pharmacokinetics (PK), complete response (CR) plus very good PR (VGPR) rate, CR rate, time to response (TTR), duration of response (DOR), and progression-free survival (PFS). Results 78 pts were enrolled; median age was 64 yrs (40% aged >65 yrs), 53% were male, median time from initial diagnosis was 53.4 months (range, 12.9-142.7), and 24%/27% had ISS stage II/III disease at diagnosis. Median number of prior therapies was 2, including prior bortezomib, lenalidomide, and stem cell transplant (SCT) in 45 (58%), 38 (49%), and 50 (64%) pts, respectively; 17% were immunomodulatory-drug-naive. At data cut-off (June 20, 2016), pts had received a median of 12 treatment cycles (range, 1-22). A total of 51 (65%) pts had discontinued treatment, primarily due to disease progression (26 pts, 33%) and AEs (13 pts, 17%). Overall, 92% of pts reported AEs, including 59% with grade ≥3 AEs (51%/71% in pts aged ≤65/>65 yrs), and 29% with serious AEs (30%/29%). Common AEs are listed in Table 1. AEs resulted in dose reductions of any study drug in 28 (36%) pts (28%/48% of pts aged ≤65/>65 yrs) and treatment discontinuation in 11 (14%) pts (15%/13% aged ≤65/>65 yrs). Ixazomib, cyclophosphamide, and dexamethasone were dose modified in 83%, 85%, and 87% of pts, respectively. Median ixazomib relative dose intensity was 96%. There were 3 on-study deaths: cardiac arrest, severe pulmonary edema, and cerebral hemorrhage secondary to thrombocytopenia, with the latter considered treatment-related. PK data showed that ixazomib exposures were comparable to those in pts treated with IRd in the TOURMALINE-MM1 study, suggesting no PK interaction with Cd. ORR was 49%, including 16% CR+VGPR (Table 2); in pts with/without prior SCT, ORR was 41%/61% (15%/18% CR+VGPR). Median TTR in responding pts was 2.14 months; median DOR was not reached, with response durations of up to 17 months. After a median follow-up of 12.5 months, median PFS was not reached; 12-month PFS rate estimate was 57.5%. Subgroup analysis showed a higher ORR (68% vs 35%), a higher CR+VGPR rate (23% vs 12%), and a significant PFS improvement in pts aged >65 yrs vs pts aged ≤65 yrs (12-month PFS rate estimate 67.2% vs 50.7%; HR=0.43, p=0.028) (Figure). Although pts aged >65 yrs were less likely to have had prior SCT than those aged ≤65 yrs (22% vs 78%), this did not appear to account fully for the difference in outcomes (PFS in pts without vs with prior SCT, HR=0.82, p=0.6). Conclusions All-oral triplet therapy with ICd appears to have activity in RRMM pts, with a toxicity profile consistent with that seen with ixazomib in combination with Rd (Moreau, et al; N Engl J Med 2016). Preliminary best response and PFS data suggest there may be preferential benefit in elderly pts compared to younger patients (possibly related in part to more limited use of prior high-dose alkylator [melphalan] exposure associated with SCT in elderly pts) albeit with additional toxicity. Disclosures Kumar: Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Grzasko:Celgene: Honoraria; Munipharma: Honoraria; Janssen: Honoraria. Jędrzejczak:Novartis: Consultancy, Research Funding; BMS: Research Funding; Janssen-Cilag: Consultancy; Celgene: Consultancy; Angelini: Consultancy; Roche: Consultancy, Research Funding; Amgen: Research Funding; Sandoz: Consultancy. Kyrtsonis:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gupta:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Array: Equity Ownership. Byrne:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets >400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), >600 x 109/L (3.7%, 8.9%); WBC >10 and ≤15 x 109/L (16.7%, 16.1%), >15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

Abstract HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

PURPOSE: To describe the frequency, content, dynamics, and patterns of cost conversations in academic medical oncology across tumor types. PATIENTS AND METHODS: We reviewed 529 audio recordings between May 3, 2012, to September 23, 2014, from a prospective three-site communication study in which patients at any stage of management for any solid tumor malignancy were seen in routine oncology appointments. Recordings were deidentified, transcribed, and flagged for any mention of cost. We coded encounters and used qualitative thematic analysis. RESULTS: Financial issues were discussed in 151 (28%) of 529 recordings. Conversations lasted shorter than 2 minutes on average. Patients/caregivers raised a majority of discussions (106 of 151), and 40% of cost concerns raised by patients/caregivers were not verbally acknowledged by clinicians. Social service referrals were made only six times. Themes from content analysis were related to insurance eligibility/process, work insecurity, cost of drugs, cost used as tool to influence medical decision making, health care–specific costs, and basic needs. Financial concerns influenced oncology work processes via test or medication coverage denials, creating paperwork for clinicians, potentially influencing patient involvement in trials, and leading to medication self-rationing or similar behaviors. Typically, financial concerns were associated with negative emotions. CONCLUSION: Financial issues were raised in approximately one in four academic oncology visits. These brief conversations were usually initiated by patients/caregivers, went frequently unaddressed by clinicians, and seemed to influence medical decision making and work processes and contribute to distress. Themes identified shed light on the kinds of gaps that must be addressed to help patients with cancer cope with the rising cost of care.

Abstract Background Little is known about how complementary and alternative medicine (CAM) is discussed in cancer care across varied settings in the U.S. Methods In two practices affiliated with one academic medical center in southern California (SoCal), and one in the upper Midwest (UM), we audio-recorded patient-clinician interactions in medical oncology outpatient practices. We counted the frequency and duration of CAM-related conversations. We coded recordings using the Roter Interaction Analysis System. We used chi-square tests for bivariate analysis of categorical variables and generalized linear models for continuous variables to examine associations between dialogue characteristics, practice setting, and population characteristics with the occurrence of CAM discussion in each setting followed by multivariate models adjusting for clinician clustering. Results Sixty-one clinicians and 529 patients participated. Sixty-two of 529 (12%) interactions included CAM discussions, with significantly more observed in the SoCal university practice than in the other settings. Visits that included CAM were on average 6 minutes longer, with CAM content lasting an average of 78 seconds. In bivariate tests of association, conversations containing CAM included more psychosocial statements from both clinicians and patients, higher patient-centeredness, more positive patient and clinician affect, and greater patient engagement. In a multivariable model including significant bivariate terms, conversations containing CAM were independently associated with higher patient-centeredness, slightly longer visits, and being at the SoCal university site. Conclusion The frequency of CAM-related discussion in oncology varied substantially across sites. Visits that included CAM discussion were longer and more patient centered. Implications for Practice The Institute of Medicine and the American Society of Clinical Oncology have called for more open discussions of complementary and alternative medicine (CAM). But little is known about the role population characteristics and care contexts may play in the frequency and nature of those discussions. The present data characterizing actual conversations in practice complements a much larger literature based on patient and clinician self-report about CAM disclosure and use. It was found that CAM discussions in academic oncology visits varied significantly by practice context, that the majority were initiated by the patient, and that they may occur more when visit time exists for lifestyle, self-care, and psychosocial concerns.

Background: Spontaneous coronary artery dissection (SCAD) is an uncommon idiopathic disorder predominantly affecting young, otherwise healthy women. Rare familial cases reveal a genetic predisposition to disease. The aim of this study was to identify a novel susceptibility gene for SCAD. Methods: Whole-exome sequencing was performed in a family comprised of 3 affected individuals and filtered to identify rare, predicted deleterious, segregating variants. Immunohistochemical staining was used to evaluate protein expression of the identified candidate gene. The prevalence and spectrum of rare (<0.1%) variants within binding domains was determined by next-generation sequencing or denaturing high-performance liquid chromatography in a sporadic SCAD cohort of 675 unrelated individuals. Results: We identified a rare heterozygous missense variant within a highly conserved β-integrin–binding domain of TLN1 segregating with familial SCAD. TLN1 encodes talin 1—a large cytoplasmic protein of the integrin adhesion complex that links the actin cytoskeleton and extracellular matrix. Consistent with high mRNA expression in arterial tissues, robust immunohistochemical staining of talin 1 was demonstrated in coronary arteries. Nine additional rare heterozygous missense variants in TLN1 were identified in 10 sporadic cases. Incomplete penetrance, suggesting genetic or environmental modifiers of this episodic disorder, was evident in the familial case and 5 individuals with sporadic SCAD from whom parental DNA was available. Conclusions: Our findings reveal TLN1 as a disease-associated gene in familial and sporadic SCAD and, together with abnormal vascular phenotypes reported in animal models of talin 1 disruption, implicate impaired structural integrity of the coronary artery cytoskeleton in SCAD susceptibility.

AbstractObjectivesTo evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation.MethodsData were pooled from four NDMM phase I/II studies; patients received induction therapy with once‐ or twice‐weekly ixazomib plus lenalidomide‐dexamethasone (IRd), melphalan‐prednisone (IMP), or cyclophosphamide‐dexamethasone (ICd), followed by single‐agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity.ResultsA total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice‐weekly IRd, n = 18; weekly or twice‐weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug‐related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance.ConclusionsIxazomib maintenance following ixazomib‐based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long‐term administration. Phase III investigation of ixazomib maintenance is ongoing.