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Abstract Abstract 596 Background Large population-based studies have demonstrated a significant improvement in survival (OS) for patients (pts) with multiple myeloma (MM) over time since the mid-1990s. The improvement has mostly affected younger patients suggesting a beneficial impact of AHCT. The availability of novel drugs within the last decade and their impact on the utilization and outcomes of AHCT recipients is unknown. Methods We retrospectively reviewed the characteristics and outcomes of 20,278 patients undergoing AHCT within 12 months of diagnosis in USA and Canada and reported to CIBMTR in the periods of 1995–1999 (n=2226), 2000–2004 (n=6408) and 2005–2010 (n=11644) including a subgroup of 4373 individuals with detailed patient, disease and treatment information. We subsequently compared survival and analyzed patient, disease and treatment characteristics across the three periods with the time period serving as a surrogate for pre- and post-transplant exposure to novel agents. Results Across the 3 time periods, there was a marked increase in the number of upfront transplants across all age groups (Figure 1a). Patients receiving upfront HSCT in the more recent period were older, less likely to have stage 3 MM at diagnosis and more likely to have received thalidomide (<1 % vs. 22% vs. 52%), lenalidomide (0% vs. <1% vs. 21%) or bortezomib (0% vs. 2% vs. 35%) and have chemosensitive disease at the time of AHCT. The proportion of African-American patients remained low and stable across the three periods (14 vs. 13 vs. 15%). Over the 3 periods, there was a decrease in chemotherapy based stem cell mobilization and increase of single agent G-CSF based mobilization (24% vs. 24% vs. 41%). The use of single agent Melphalan conditioning increased from 54% in 1995–1999 to nearly 100% in the latest period concomitant with near disappearance of total body irradiation-based and multi-drug conditioning regimens. Compared with 1995–99 cohort, survival was superior in the 2000–04 and 2005–09 cohorts at 24 (72% vs. 79% vs. 84%, P<0.001), 48 (54% vs. 60% vs. 64%, P<0.001) and 60 months (47% vs. 52% vs. 55%, P<0.001) (Figure 1b). In multivariate analysis, we found that transplant in the 2000–04 period (HR=0.77, 95% C.I. 0.67–0.89) or in the 2005–10 period (HR=0.68, 95% C.I. 0.59–0.79) along with Karnofsky performance score of 80–100 (HR=0.59, 95% CI 0.51–0.70) and chemosensitivity (HR= 0.76, 95% C.I. 0.66–0.87) were associated with lower risk of death. Factors associated with higher risk of death were age 50–65 (HR=1.29 95% 1.13–1.47), age 65–80 (HR=1.45, 1.23–1.72), Durie-Salmon or ISS stage III at diagnosis (HR 1.56, 95% C.I. 1.39–1.76) and more than one prior line of therapy (HR=1.15, 95% C.I. 1.03–1.28). In comparison to patients transplanted in 1995–99, post relapse survival was superior for patients transplanted in 2000–04 and 2005–10 at 24 months (58% vs. 65% vs. 72%, P=0.005 and <0.001 respectively) and 48 months (33% vs. 39% vs. 40%, P=0.023 and 0.033 respectively). The use of maintenance therapy has changed with 27% in 1995–99 receiving planned interferon vs. 23% in 2005–09 receiving planned thalidomide, lenalidomide or bortezomib maintenance. Conclusions Utilization of upfront AHCT is increasing in the USA, particularly in older patients. Improvement in survival for MM patients seen in population studies results not only from greater utilization of AHCT but also from the improvement in outcomes after AHCT and a significant recent improvement in post-relapse survival. Pre- and post-transplant exposure to novel agents likely contributes to survival. AHCT and novel agents are complementary and should be combined for the optimal management of newly diagnosed MM. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1827 Poster Board I-853 Background It is now well established that cytogenetic abnormalities can affect the responses to therapies in multiple myeloma (MM) patients. Bortezomib, used alone or in combination with other agents, has been shown to overcome the adverse impact of several common unfavorable cytogenetic features. More recently, responses with lenalidomide and dexamethasone have been reported in patients with some types of unfavorable cytogenetics. Carfilzomib (CFZ) is a novel proteasome inhibitor that has demonstrated single agent activity in relapsed and/or refractory MM patients. The objective of this analysis was to provide the first preliminary information on the influence of cytogenetics in patients (pts) with relapsed and/or refractory MM treated with CFZ. Methods We evaluated 79 pts treated on two single agent CFZ studies (PX-171-003 and PX-171-004) in relapsed and/or refractory myeloma in which metaphase cytogenetics and/or FISH analysis for del 13q, t(4:14), and t(14;16) chromosomal abnormalities were available. Metaphase cytogenetics was conducted for all pts in the analysis; fluorescence in situ hybridization (FISH) results were available for 28 of the 79 pts. Twenty-one pts with relapsed and refratory MM (PX-171-003) and 58 pts with relapsed or refractory MM (PX-171-004) received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles. For this analysis, responders were defined as pts who achieved at least a Minor Response (MR) [MR + Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR)] by IMWG and EBMT criteria. Results The median age of analysed pts was 63 yrs and 100% of pts were relapsed, with 70% refractory to their last therapy. Analysis of their histories demonstrated prior thalidomide treatment in 75% of pts, prior lenalidomide treatment in 57%, prior bortezomib treatment in 55%, and prior stem cell transplantation in 84%. The response rate (≥MR) for the entire group of patients was 40.5%. Twenty three of 79 pts had at least one of the abnormalities. The presence of del 13q, t(4;14), or t(14;16) did not significantly change the response rates, with 43.5% of pts with one or more abnormalities responding compared to 39.3% with none. The median time to progression (TTP) for all patients in this analysis was 203 days. The TTP for pts with one or more of the abnormalities was 195 days and was not significantly different from the TTP of 208 days for pts with none of the abnormalities (Figure; P > 0.05). Conclusion In this preliminary analysis, CFZ showed comparable activity in relapsed and relapsed/refractory MM with del 13q and/or t(4:14), and/or t(14;16) versus none of these abnormalities, with ≥MR in 43.5% vs. 39.3% of patients, and a TTP of 195 vs. 208 days, respectively. Updated efficacy data and TTP data will be presented at the meeting. Disclosures Jakubowiak: Millennium: 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; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang:Proteolix, Inc.: Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Kukreti:Celgene: Honoraria. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. McDonagh:Proteolix: Research Funding. Vallone:Proteolix, Inc.: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix: Research Funding.

Abstract Abstract 1516 Background: MM is generally considered incurable, but the rapid integration of IMiDs.. and proteasome inhibitors into systemic anticancer treatment (SAT) has resulted in clinically important improvements in response rates, disease control and overall survival. A number of factors — including age and comorbidities — influence selection of an initial SAT and whether autologous stem cell transplant (ASCT) is planned. A paucity of information exists on selection of specific SATs for patients in different age groups and resultant outcomes. We attempted to address this issue by aggregating and examining clinical information on individual patients receiving initial treatment for MM. Methods: US community-based MOs were recruited from a database of past participants in our CME activities to provide anonymous information on the presenting symptoms, diagnostic workup, treatment selection, side effects and clinical antitumor response for all patients in their practices with a new diagnosis of MM since January 1, 2008. Modest, per-patient honoraria were provided to each MO for this work. Results: From April 14 to July 9, 2010, 43 MOs entered a total of 276 cases of MM into a web-based data bank (minimum 1 case, maximum 14, median 6). 54% of the patients were men. The median age was 68, with 34% under age 65, 36% from 65 to 74 and 30% age 75 or older. 88% of patients had their tumors evaluated by FISH and/or metaphase cytogenetics. 73% of the evaluated specimens were considered to be “standard risk” and 27% were determined to be “poor risk.” 67% of patients were considered very or moderately symptomatic from the disease at the time treatment was initiated (Table 1), and similar fractions of patients presented with various levels of symptomology across the three age groups. 128 patients (46%) were deemed eligible for ASCT (maximum age 78), and 59 of these patients had already received ASCT after induction treatment. The median age of patients eligible for ASCT was 62, and the most common induction SATs for these patients were Rd or RD (29%), RVD (26%) and VD (23%). The median age of patients considered ineligible for transplant was 76.5, and the most common induction SATs were VD (22%) Rd or RD (21%) MPT (17%) and MPV (17%). Overall, these treatments resulted in CR and PR rates of 22% and 64% respectively, and “things went very well with expected or fewer toxicities” in 38% and minor or moderate toxicity in 44%. These outcomes are similar to what has been reported in published trial data from randomized Phase III studies of these regimens. No major differences were observed in reported levels of efficacy and side effects among the three age groups (Table 1). Conclusions: This unselected case series produced, in a rapid manner, useful information addressing a variety of clinical issues in newly diagnosed MM, including the impact of age and transplant status on treatment selection and outcomes. These data suggest that MOs are able to individualize SATs for older patients and match the short-term outcomes of the therapies they select for younger patients. This risk-benefit differential is of particular palliative importance as these data demonstrate that at diagnosis most patients present with tumor-related symptoms. Additional work of this kind is needed to better understand how physicians adjust doses and schedules of SATs to prevent and ameliorate toxicity, particularly in older patients. Disclosures: Lonial: Bristo-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onxy Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fonseca:Amgen Inc: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy, Research Funding; Genzyme Corporation: Consultancy; Medtronic Inc: Consultancy; Otsuka Pharmaceutical Co Ltd: Consultancy; Onyx Pharmaceuticals: Research Funding.

Background:IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and dexamethasone (DEX).Aims:This phase 1b/2a multicenter, open‐label, dose‐escalation study (NCT02773030) was conducted to evaluate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary efficacy of IBER in combination with DEX, in patients with relapsed/refractory multiple myeloma (RRMM).Methods:Eligible patients had RRMM and must have received ≥2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All patients had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in patients aged >75 years) on days 1, 8, 15, and 22, of each 28‐day cycle. Dose escalation was reviewed by a dose escalation committee.Results:As of January 2019, 58 patients had received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplantation (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) patients and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% patients, respectively. Three patients discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table 1); 20 of 51 patients remain on treatment (2–27+ cycles).Summary/Conclusion:IBER + DEX showed favorable efficacy and safety in heavily pretreated patients with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT.image

Background:Iberdomide (IBER) is a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that is being investigated as monotherapy, in combination with dexamethasone (DEX), and in combination with DEX and daratumumab or bortezomib in a phase 1b/2a dose‐escalation study in relapsed/refractory multiple myeloma (RRMM). IBER modulates CRBN, which induces ubiquitination of Aiolos, Ikaros and ZFP91, increases their proteasome‐dependent degradation, and thereby inhibits myeloma cell growth. IBER binds more potently to CRBN and is more efficient at degrading Aiolos and Ikaros than the immunomodulatory agents (IMiDs) lenalidomide (LEN) and pomalidomide (POM) and it can overcome IMiD drug resistance in pre‐clinical models.Aims:To determine if IBER is pharmacodynamically (PD) active in multiple myeloma patients refractory to POM and/or LEN, and to establish pharmacokinetic (PK)/PD and PD/dose relationships.Methods:As of Jan 11, 2019, 83 patients received IBER as monotherapy or in combination with DEX; 61 (74%) were LEN refractory and 47 (57%) were POM refractory. Longitudinal immunohistochemistry (IHC) data on CRBN, Aiolos, Ikaros and ZFP91 expression was obtained from bone marrow samples from 14 patients dosed with 0.3–0.9 mg IBER daily ± DEX. PD analysis of immune activity by TruCulture® (n = 45) and by peripheral blood flow cytometry (n = 60) was completed on a subset of patients dosed up to 1.0 mg IBER ± DEX. A population PK approach was used to estimate exposure (area under the concentration curve over the 24 hr dosing interval [AUCτ]) on 59 patients dosed up to 1.0 mg IBER ± DEX.Results:IBER AUCτ increased in a dose‐proportional manner in RRMM patients over the dose range 0.3–1.0 mg (22.4–65.31 ng∗hr/mL, respectively). In patient biopsies analyzed to date, CRBN expression was observed in all tumors by IHC at baseline and did not significantly change while on‐treatment. Furthermore, no significant decrease in baseline CRBN expression was observed in patients refractory to POM. In MM cells, significant decreases in Aiolos (median 37% decrease, P < 0.001), Ikaros (median 12% decrease, P = 0.006), and ZFP91 (median 47% decrease, P < 0.001) protein expression were observed on‐treatment across all dose levels; these decreases were unrelated to levels of CRBN expression at screening or prior LEN or POM refractoriness. In TruCulture® samples, dose‐dependent increases were observed in IL‐2 and IFN‐γ, with median increases of 78% and 66%, respectively, 5 hours post 0.9 mg dose of IBER. A dose‐ and exposure‐dependent decrease in B‐cells was detected (median 74% decrease at cycle 2 day 15, IBER 0.9 mg). These observations are consistent with the proposed IBER mechanism of action. Immunoprofiling showed significant increases in total and proliferating NK cells in RRMM patients treated with IBER, and a dose‐dependent increase in proliferating, activated, and effector memory T‐cells. These trends were consistent in RRMM patients treated with IBER monotherapy and in combination with DEX.Summary/Conclusion:These translational analyses from IBER treated RRMM patients indicate it is pharmacodynamically active at the lowest dose (0.3 mg) and exhibits dose‐ and exposure‐dependent immunostimulatory activity, supporting further dose‐escalation beyond 1.0 mg, which is currently ongoing. These results also suggest that prior refractoriness to LEN or POM is not associated with significant loss of CRBN or IBER PD activity, supporting continued investigation of IBER in RRMM patients refractory to IMiD drugs.

Background:The treatment paradigm for multiple myeloma (MM) has evolved rapidly following new drug approvals and combinations. These improvements have the potential to improve outcomes for patients, but only if specialists in hematology/oncology (hem/oncs) have up‐to‐date knowledge on selection of treatments, prevention and management of adverse events (AEs), and comfort with emerging clinical trial data.Aims:We sought to determine if a curriculum of online continuing medical education (CME) activities could improve hem/onc knowledge and competence in treating patients with MM.MethodsThis analysis included hem/onc data from a MM curriculum spanning over 4 years, with 54 activities. For each year of the curriculum, an expert panel identified knowledge/competence gaps to be addressed through CME. Within the analysis, assessment questions were grouped into learning topics and the average for pre and post‐education was calculated for 2016‐2018 of the curriculum for each topic. The analysis elucidated the impact of the curriculum on narrowing gaps in knowledge/competence using a pre/post design. Statistical significance was assessed using a chi‐square statistic (P < .05 level).Results:As of December 2018, the curriculum had reached 33,699 US hem/onc learners and 2144 participated in the outcomes assessment. Treatment Selection: The curriculum significantly improved hem/onc knowledge/competence over time for selecting treatment for patients with relapsed/refractory (R/R) MM (pre/post: 2016, 41%/51%, P < .001; 2018, 48%/64%, P < .001). Managing AEs: The curriculum led to sustained knowledge gains for hem/oncs over time related to managing treatment‐related AEs in patients with MM (pre/post: 2016, 39%/53%, P < .001; 2018, 80%/84%, P = .427). Knowledge of Clinical Trial Data: Activities within the curriculum also significantly improved hem/onc knowledge of clinical trial data for consolidation and maintenance therapy (pre/post: 2016, 63%/76%, P < .001; 2017, 68%/74%, P < .05; 2018, 62%/76%, P < .001). Potential Patient Impact: The reach of Medscape Oncology CME has a large impact on how US hem/oncs treat patients with MM. Of all hem/onc specialists with MM diagnostic encounters, 64% are members of Medscape. Additionally, 70% of all high decile (deciles 7‐10) hem/onc specialists with MM diagnostic encounters are members of Medscape. Based on the number of learners for the curriculum and the average number of patient encounters, this education has the potential to impact 33,894 MM patient encounters.[IQVIA Data]Summary/Conclusion:This analysis shows that online CME, as part of a sustained educational curriculum, using various formats (video, text, panel discussion, case‐based) can significantly improve the knowledge and competence of hem/oncs in multiple areas related to MM. Statistically significant gains in knowledge and competence selecting treatment for R/R MM were seen even with the introduction of new clinical evidence in this area. The analysis also shows the potential impact on patients and the large reach that is achievable with online education. As new therapies and combinations of treatments continue to change practice, additional education is needed to aid hem/oncs in staying abreast of new data, managing AEs, and tailoring therapy selection for individual patients with MM.