Mıkhael, Joseph

Abstract Background: Pomalidomide is an immunomodulatory agent (IMiD®) that has been approved for treatment of relapsed and refractory multiple myeloma (MM). Combinations of IMiDs and proteasome inhibitors offer the potential for deeper and more durable responses due to enhanced efficacy. Preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This phase I/II trial was designed to evaluate the maximum tolerated doses (MTD) as well as safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone (PVD) in patients with relapsed, lenalidomide refractory, MM. Patients and methods: We included patients with relapsed MM who had 1-4 prior lines of therapy and were resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15, and 22 IV or SQ and dexamethasone 40 mg days 1,8,15, and 22 PO, given every 28 days. Bortezomib was increased to 1.3mg/m2 for dose level 2 and and was adopted for the phase 2 portion. The primary aim of the phase I cohort was to determine the MTD of the combination, and for the phase II cohort was to evaluate the confirmed response rate (PR, VGPR, or CR) in relapsed refractory MM. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. Results: 50 patients were accrued between March 2012 and July 2014 (dose level (DL)1: 3, DL 2: 6, Phase II: 41). We describe results in 47 patients treated at MTD and phase II. Median age was 66, 51% were female and median time from diagnosis to study was 46 months (15-142). Twenty five percent had mSMART defined high-risk status. Median number of prior regimens was 3. All patients had prior lenalidomide, 68% had stem cell transplant, 17% received thalidomide, 56% had alkylators and 57% had bortezomib. With median follow up of 9 months, 72% remain progression free, 96% are alive and 66% remain on treatment. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. Grade ≥3 AEs (regardless of attribution) that occurred in at least 3 patients included neutropenia (29), leukopenia (15), lung infection (6), lymphopenia (8) dyspnea (3) and syncope (3). DVT/PE occurred in one patient. Among the 42 patients who were evaluable, confirmed responses (PR, VGPR, or CR) were seen in 34 (81%) including sCR (3), CR (5), VGPR (8), PR (18). Confirmed responses were seen in 9 of 11( 82%) high risk patients. Median progression free survival was 17.7 months (95%CI: 9.5-NA). Conclusions: PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80%. Weekly administration of bortezomib enhanced the tolerability and convenience of this regimen. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. PVD is a highly attractive option in patients with relapsed and refractory MM. Disclosures Lacy: Celgene: Research Funding. Lust:Senesco: PI Other. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Stewart:Celgene: Consultancy; Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Abstract Background: In Phase II trials, carfilzomib (Cfz) was associated with dyspnea (34%), hypertension (14%), renal insufficiency (24%), and peripheral edema (24%) with cardiac events reported in 7% of patients (pts). In order to better understand these toxicities, we prospectively instituted detailed cardiac evaluation in 62 Cfz treated multiple myeloma (MM) pts. Methods: Pts received Cfz between 8/11-5/14. Parameters recorded included Cfz dose, concurrent chemotherapy, hydration, blood pressure, day 1 and 2 creatinine, troponin and NT-proBNP, baseline and cycle 4 echocardiograms with EF, strain and compliance. Notable cardiac events were examined for attribution. Results: Median age was 65 years, with 60% male. 20 pts had no prior therapies, 42 were relapsed; mean 4 prior therapies (range 1-10). 20 received induction chemotherapy (Cfz, dex, thalidomide, cyclophosphamide). At relapse, Cfz was given alone in 21 pts, with added cyclophosphamide in 10, and with an IMiD in 10. Cfz dose was 20mg/m2 days 1,2 and ranged from 27-45mg/m2in subsequent treatment days. Dex was given at 20-40mg weekly in 77% pts. Hydration (250-500ml) was delivered in 89% of patients pre and 63% post treatment. Baseline hypertension (>140mmHg) was present in 20% of pts and rose ≥10mmHg in 26% on day 2, but dropped ≥10mmHg in 36%. On day 8, more pts (32%) had hypertension pre-treatment. Baseline creatinine was elevated in 25% pts. 7 of 55 (13%) pts had a creatinine rise (≥0.3 mg/dL) on day 2, 5 of whom had elevation at baseline. Thus, with normal baseline creatinine and pre-treatment hydration 2/45 (4%) pts had a creatinine rise. Troponin levels on day 1 were normal in all 16 tested patients. 2/25 pts had an elevated troponin on day 2, one with associated MI on day 4. In these 2 pts, symptomatic pre-existing ischemic heart disease and severe cardiac amyloid were confounding factors. Mean baseline NT-proBNP (n=22) was elevated at 565 pg/mL (range <50-3666; normal <77) with normal baseline values in only 41%. On day 2 (n=25), the mean was significantly higher at 1580 pg/mL. Between day 1 and 2, 72% of pts had a rise ≥50 pg/mL; mean change 1387 (range 0 to +6187). On day 2, 52% had a NT-proBNP ≥500 pg/mL, while 36% were ≥1000 pg/mL. 30 pts had baseline and post-C4 treatment echocardiograms, all with normal pre-treatment EFs. Three pts (10%) developed impaired systolic function (EF<50%), however, 2 had plausible concurrent alternative etiologies (VTE/PE, hospitalized multilobar pneumonia) while one patient (during C2) had an asymptomatic unexplained decline in EF (56 to 42%) detected pre-op while hospitalized for hip fracture. Thus, 1/30 (3%) had an EF change in absence of concurrent acute illness. A fourth patient had normal echo at C4 but was hospitalized at C10 with severe sepsis and a diminished EF was documented. All 4 pts with low EF were pre-treated (≥2 therapies plus SCT). Changes in cardiac strain often precede an EF fall. Only 14/25 pts had normal baseline cardiac strain (≥ -18%). Post treatment strain measurement significantly improved in 4 pts and worsened in 4 pts, the latter accompanied by EF decline within the normal range in 2 pts (68/60%, 65/58%). 28 pts had E/e’ ratio (LVEDP) reviewed as a marker of ventricular compliance. 46% had abnormal ratios (≥ 15), prior to Cfz treatment. 20% of patients experienced worsening parameters post treatment, however, an equal number of pts demonstrated improvement. There was no consistent correlation with change in EF. Conclusions: MM pts frequently have baseline elevated cardiac peptides (59%) and abnormal cardiac strain (15% of newly diagnosed and 36% at relapse). A frequent, and sometimes dramatic, rise in the NT-proBNP occurs immediately following Cfz based chemotherapy. Acute structural cardiac events were however uncommon (3%) in the absence of confounding illness. Overall 5/62 (8%) patients had serious cardiac events during treatment with Cfz (4 EF decline, 1 MI). These toxicities were considered probably attributable to Cfz in 3/62 (5%) patients. Prospective controlled studies with longer term follow up and bortezomib treated controls are necessary to accurately document the cardiovascular impact of Cfz and the role of proteasome inhibition. Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Stewart:Celgene Novartis Array BioPharma BMS, research funding Millenium: Consultancy, Research Funding.

Abstract Background: A diagnosis of cancer leads to significant information requirements to facilitate health care decision making, understand management options, and health care system navigation. Many patients demonstrate a knowledge deficit that can lead to decreased quality of life and poor health care compliance. This study sought to evaluate the impact of a patient centered cancer symposium on knowledge level, symptom burden, and desired information in a broad population of cancer patients. Methods: Surveys were distributed to attendees of the Mayo Clinic "Living with and Surviving Cancer" patient symposium in January 2015. A follow up survey was sent to participants 3 months after the symposium. Surveys included demographic data, questionnaire evaluating disease comprehension, symptom burden, desired information and quality of life. Results: Demographics: 113 patients completed the pre-intervention survey. Average age of participants was 64.7 years. Disease types represented included hematologic malignancies (N=50), specifically multiple myeloma (N=24), lymphoma (N=17), leukemia (N=6), MPN/MDS (n=3), as well as solid tumor malignancies (N=77). Highest knowledge topics were disease (80%), screening tests (74%), and monitoring tools (72%). Lowest knowledge topics were financial management (13%), legal issues (13%), and pain management (35%). Pre and Post Analysis: Of the 113 initial participants, 79 patients completed the pre- and post-symposium surveys. In the post-symposium setting significant improvement was noted in understanding of disease (pre 80% vs post 92%), treatment options (pre 60% vs post 76%), nutrition (pre 68% vs post 84%) and legal issues (pre 15% vs post 32%). Non-significant knowledge improvement was noted in areas of risk factors and symptoms, screening/monitoring tools, disease side effects, managing stress/fatigue, end of life decision making and health care navigation. Most patients desired increased understanding regarding disease, screening tests, nutrition, and stress and fatigue management. The level of patient reported desire for information of these topics decreased in the post-symposium setting, statistically significant decrease noted in 4 of 5 topics assessed. In hematology patients who completed pre and post surveys (N=36), a higher level of baseline knowledge was reported regarding disease understanding (89%), tools monitoring response (83%) and recurrence (75%), symptoms (83%), relapse symptoms (64%) and treatment options (72%). In this group the decrease in desire for information was less prominent in the post-symposium setting. Discussion: This data demonstrates improved patient reported understanding on a variety of topics with durable response at 3 months. A majority of patients reported adequate baseline knowledge of many topics prior to the symposium but also a desire of increased cancer specific information. Knowledge deficit in cancer care includes disease specific topics, social stressors and health care navigation. The percentage of participants reporting a high desire for more information remained high but did decrease, suggesting decreased knowledge deficit in the post-symposium setting. Patient education should strive to be accessible, all-inclusive and reactive to patient needs. Table 1.Reported "quite a bit" or "very much" understanding and desired information regarding cancer carePrePostP-valueN=79(%)N=79(%)I understand…How to manage financial considerations of my disease/treatment39(51)41(53)0.85How to manage my pain24(34)23(32)0.81Risk factors that can lead to my disease37 (49)42 (56)0.56How to navigate the health care system43(55)47(60)0.56How to manage fatigue38(50)43(56)0.54Process of making end of life decisions33(47)41(53)0.52Screening tests60 (76)63 (81)0.5Symptoms associated with relapse35(45)42(54)0.27Disease symptoms54(70)60(76)0.2Tools monitoring recurrence49(62)56 (72)0.19Tools monitoring response56(71)63(81)0.15How to manage stress46(60)56(71)0.12Legal issues of my disease11(15)24(32)<0.05Treatment options47(60)60(76)<0.05What to eat49(68)66(84)<0.05My disease62(80)71(92)<0.05I desire increased understanding…Of my disease59(77)53(70)0.4Of managing stress50(65)35(51)<0.05Regarding nutrition64(84)54(70)<0.05Of the screening tests62(79)43(57)<0.05How to manage fatigue54(72)42(54)<0.05 Disclosures Tibes: TetraLogic Pharmaceuticals: Research Funding. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Abstract Abstract 201 Background: Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with relapsed multiple myeloma (MM). Between November 2007 and March 2012, we opened 6 sequential phase 2 trials and treated 345 patients with relapsed MM with pomalidomide at differing doses with weekly dexamethasone (Pom/dex). Results of 164 of these patients have been previously published. Here we describe long term follow up of these patients as well as results of an additional 181 patients with relapsed MM treated with the Pom/dex regimen. Methods: The six cohorts consisted of: Cohort 1 (N=60): relapsed MM with 1–3 prior regimens, 2 mg dose; Cohort 2 (N=34): lenalidomide (LEN) refractory, 2 mg dose; Cohort 3 (N=35): BZ)/LEN refractory, 2 mg dose; Cohort 4 (N=35): BZ/LEN refractory, 4 mg dose; Cohort 5 (N=60) LEN refractory, 1–3 prior regimens, 4 mg dose; and Cohort 6 (N=120) LEN refractory, 4 mg dose. Pomalidomide was given orally 2 mg daily or 4mg daily on days 1–28(cohorts 1–5) or 1–21 (cohort 6) of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for deep venous thrombosis (VTE) prophylaxis or full dose anticoagulation. Results: A total of 345 patients were enrolled across all 6 cohorts. One patient was ineligible and excluded from analysis. The median age was 64 years (32–88). The median time since diagnosis was 53 months. The median number of prior therapies was 3 (1–14). 147 (44%) had high-risk molecular markers by mSMART criteria. Prior therapies consisted of thalidomide 52%, lenalidomide 87%, bortezomib 75%, autologous stem cell transplant 70% and allogeneic transplant 3%. The median follow-up is 10.4 months (5.4–34 months). Sixty-seven percent are alive and 32% remain progression free. 46 patients are continuing to receive treatment. The most common toxicities (grade 3 or higher) were neutropenia (31%), anemia (16%), thrombocytopenia (12%), pneumonia (8%) and fatigue (8%). VTE was seen in 10 patients (3%). Outcomes are shown in Table 1. Across all 6 cohorts confirmed responses of partial response (PR) or better were seen in 34%. The response rate in all patients with mSMART high risk status was 30.6%. Responses and duration of response (DOR) in those with high risk molecular markers include: 17p– 19 of 56 (34%) DOR 8.2 months; t(4;14) 6 of 24 (25%) and DOR 4.8 months; t(14;16) 7 of 11(64%) and DOR 9.5 months; deletion 13 by cytogenetics 13 of 37 (35%) with DOR 8.2 months. In a multivariate analysis, only LDH > ULN, number of prior regimens, and prior BZ therapy were predictive of a shorter TTP and factors associated with a poor OS following initiation of pomalidomide therapy included B2M > 5.5, LDH > ULN,number of prior regimens, and prior BZ therapy. Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients and those with high risk molecular markers. Remissions are durable. Response rates and toxicity are similar between the 2 mg and 4 mg doses. Disclosures: Lacy: Celgene: Research Funding. Stewart:Celgene: Consultancy, Honoraria. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding.

Abstract Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that has shown promising antitumor activity in patients (pts) with hematologic malignancies (HM), including WM (Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with WM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, multicenter, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives of the phase 1b portion of the study are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective of the phase 2 portion of the study is to determine the best overall response rate (ORR; ≥minimal response [MR]). In the phase 1b portion, single-agent OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments. In the phase 2 study, pts have received 240 mg/d on the 5/14 schedule, which was the initial phase 2 schedule opened to enrollment. For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 36 pts with WM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with WM are presented in Table 1. For WM patients in the phase 1b portion, median treatment duration was 17.1 weeks (range, 3.1–51.4; 2/7 schedule) and 51.7 weeks (range, 3.9–74.9; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 8.1 weeks (range, 0.7–22.0). In all pts with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. None of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule occurred in patients with WM. Two of the 4 DLTs observed on the 5/14 schedule occurred in pts with WM (grade 4 tumor lysis syndrome [240 mg/d, n=1] and grade 3 vomiting [270 mg/d, n=1]). The most common adverse events (AEs) in pts with WM are shown in Table 2. Grade 4 AEs were thrombocytopenia (n=1; phase 1b; 2/7 schedule) and influenza and tumor lysis syndrome (n=1 each; phase 1b; 5/14 schedule). No on-study deaths occurred in pts with WM. In the phase 1b portion, two pts (25%) in the 2/7 schedule and 1 pt (9%) in the 5/14 schedule discontinued treatment due to an AE; 6 pts (35%) discontinued treatment due to an AE in the phase 2 portion. In the phase 1b portion, 3 pts (38%) (2/7 schedule) and 6 pts (55%) (5/14 schedule) had their dosage reduced at least once due to an AE; 10 pts (59%) in the phase 2 portion had their dosage reduced at least once due to an AE. In the phase 1b portion, all 19 pts were eligible for response and were carfilzomib (CFZ)-naïve. The ORR in 8 pts enrolled on the 2/7 schedule was 38% (3 pts had a partial response [PR]). Among 11 pts enrolled on the 5/14 schedule, the ORR was 73% (1 complete response, 1 very good partial response, 5 PRs, and 1 MR); the ORR for BTZ-refractory pts (n=4) was 75%. All 17 pts enrolled on the phase 2 portion were response-eligible. The ORR in the phase 2 portion was 59% (there were 5 PRs and 5 MRs). The ORR among CFZ-naïve pts (n=16) in the phase 2 portion was 56; the ORR among BTZ-refractory pts (n=3) was 67%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all pts with HM. In pts with WM who received single-agent OPZ, the most common grade 3 AEs were neutropenia and diarrhea; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity in pts with WM. Enrollment of patients on the 2/7 schedule is continuing; the target enrollment for the phase 2 portion of the study is 66 patients. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Disclosures Siegel: Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Off Label Use: Monoclonal antibody/toxin fusion protein. For treatment of multiple myeloma. Kaufman:Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Raje:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; Ely Lilly: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Treon:Onyx: Consultancy, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other.

Abstract Abstract 194 Background: Immunomodulatory drugs (IMiDs) are key components of treatment for hematologic malignancies, especially multiple myeloma (MM). Recently, we demonstrated that CRBN expression is the major mediator of IMiD action operating at least in part via interferon regulatory factor 4 (IRF4), however the clinical significance of this finding remains unclear. Methods: To better understand clinical impact, we retrospectively reviewed 148 MM patients whose tumor cells were tested for CRBN expression by Gene Expression Profiling (GEP) prior to treatment with an IMiD containing therapy. Results: GEP studies show no significant differences in CRBN expression between MGUS, smoldering MM (SMM), untreated symptomatic MM and normal plasma cells. However, differences were observed between MM cell lines of varying drug sensitivity to IMiDs and between other B-cell Neoplasia (eg low grade lymphoma has higher levels). Within the genetic subtypes of MM, levels were significantly higher for hyperdiploid patients (median 1.26) as opposed to significantly lower levels for TC class D2 (median 0.76) and average for the 4p16 (median 0.97). We next screened the University of Arkansas Medical School (UAMS) GEP database of MM patients treated with combination therapies and did not find significant correlation between CRBN expression and survival in this multi-agent regimen. We then focused on patients that received only single agent IMiD therapy with low dose dexamethasone. Review of the twelve lowest expressing patients demonstrated a lack of response to IMiDs in any patient. Finally we analyzed 53 relapsed or relapsed/refractory patients treated homogeneously in a study with pomalidomide 2–4mg daily and weekly dexamethasone 40mg. CRBN levels were assessed prior to therapy initiation. Response rates varied significantly based on gene expression level. The percentage of patients that demonstrated at least a partial response was 0% for CRBN <0.81, 19% for CRBN expression of 0.81–0.90, and 33% for CBN expression >0.9. Significant differences in PFS (3.0 months vs. 8.9 months, p = 0.0006) and in OS (9.1 months vs. 27.2 months, p = 0.01) were observed when the lowest quartile of CRBN expression was compared to the top three quartiles. Values used for the cut offs are as follows: (25%: 0.889687; 50%: 1.026542, 75%: 1.211133). While this study demonstrates a positive correlation between CRBN expression and response to pomalidomide and dexamethasone, an important caveat with respect to PFS and OS is that CRBN mRNA level is primarily a reflection of the number of copies of CRBN. Since focal deletions are uncommon, this mostly reflects chromosome 3p copy number. Since trisomy 3 is common in hyperdiploid, good prognosis disease, CRBN not only is required for IMiD function but higher levels also serve as a surrogate for low risk disease. Optimal gene expression cut offs for survival were determined using the Contal and O'Quigley method. The optimal cut point for PFS was 1.18443 and for OS was 1.17816. Conclusion: In summary, this study demonstrates, for the first time, a clinical correlation between CRBN expression and response to IMiD and dexamethasone therapy. CRBN expression is also predictive of survival outcomes and when quantified prior to therapy could potentially be utilized as a predictive biomarker for response to an IMiD based treatment. Disclosures: Stewart: Celgene: Consultancy, Honoraria.

SummarySelinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non‐clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose‐escalation trial of twice‐weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib‐refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP2D of twice‐weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment‐emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual‐class refractory (PI and immunomodulatory drug)/quad‐exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression‐free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re‐established disease control in RRMM patients, including carfilzomib‐refractory patients.Registered at ClinicalTrials.gov (NCT02199665)

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.