Topic: 16. Myeloproliferative neoplasms - Clinical Background: According to recent real-world evidence, patients with high-risk polycythemia vera (PV) receiving standard care spend <30% of time in response for blood count targets recommended by European LeukemiaNet (ELN) (Carpenter et al 2022; eJHaem). Individual responses fluctuated considerably; a novel observation not detectable by conventional evaluation at predefined timepoints. Ropeginterferon alfa-2b induces higher response rates than standard treatment (hydroxyurea [HU]/best available treatment [BAT]) after long-term therapy, but whether this corresponds with cumulative time in response is unknown. Therefore, final PROUD-PV/CONTINUATION-PV data were evaluated regarding time in peripheral blood count remission. Aims: To assess the cumulative proportion of time in response for blood counts according to ELN targets in patients treated with ropeginterferon alfa-2b vs HU/ BAT over a period of ≥6 years. Methods: Patients with PV (WHO 2008 criteria) who were HU-naïve/pre-treated and gave informed consent were randomized 1:1 to ropeginterferon alpha-2b or control (HU) for one year in PROUD-PV (EudraCT: 2012-005259-18). Dosing was optimized per protocol in both arms. In the extension CONTINUATION-PV (2014-001357-17), patients in the control arm could switch from HU to BAT. Hematology was evaluated at intervals of 2-12 weeks for 5 years, and 6-monthly in the final year. Complete hematologic response (CHR) was defined per modified ELN criteria (hematocrit <45% with no phlebotomy for ≥3 months, PLT<400x109/L and WBC<10x109/L). Cumulative time in CHR and in response for individual parameters were assessed in the CONTINUATION-PV full analysis set based on the last response at each assessment, up to study completion/discontinuation. All safety data were analyzed. Results: The full analysis set comprised 169 patients: 95 in the ropeginterferon alfa-2b arm and 74 in the control arm. Individual patient data for time spent in CHR over ≥6 years demonstrate more consistent blood count responses among patients treated with ropeginterferon alfa-2b than in the standard treatment arm, in which 88% received HU as of the last assessment (Figure 1). Despite a more gradual onset of response in the ropeginterferon alfa-2b arm, on average, patients spent 60.9% of time in CHR vs. 41.2% for patients in the control arm (p=0.0437). These findings align with results of log-binomial modelling of longitudinal blood count assessments over the entire 6 years, indicating a higher CHR rate for ropeginterferon alfa-2b vs. standard treatment (RR: 1.27 [95% C.I. 1.05 to 1.53; p=0.0152]). Differences were also observed for individual parameters, with significantly more time spent with WBC counts on target in the ropeginterferon alfa-2b arm vs. control (mean: 93.7% vs. 80.9% p=0.0249). The respective mean proportion of time in response was 65.1% vs 57.0% (p=0.4501) for hematocrit and 87.7% vs 75.6% (p=0.0875) for PLT counts. Including PROUD-PV (N=254), 5 thromboembolic events occurred in the ropeginterferon alfa-2b arm; CHR was recorded at the preceding visit in only 1 case. On standard treatment, 7 thromboembolic events occurred, 3/7 preceded by CHR. Statistical correlation with CHR was precluded by the low incidence of events. Summary/Conclusion: These results underscore the difficulty of maintaining PV patients within peripheral blood count targets during standard treatment and indicate that more consistent control of these parameters can be achieved with ropeginterferon alfa-2b. Thromboembolic events were rare during ropeginterferon alfa-2b therapy and largely occurred during periods of non-response, in agreement with current response criteria.Keywords: Myeloproliferative disorder, Interferon alpha, Polycythemia vera

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

Introduction: Ropeginterferon alfa-2b at a fixed dose of 100 µg/2 weeks was efficacious in patients with low-risk polycythemia vera (PV) in the Low-PV trial, but the response rate was lower in a group of patients who switched to ropeginterferon alfa-2b after failing to respond to phlebotomy alone (Barbui et al., 2023). The finding that this group had a higher proportion of males and higher baseline values for body-mass index, phlebotomy demand, blood counts and JAK2V617F allele burden suggests that these characteristics might predict a higher dose requirement of ropeginterferon alfa-2b. We analyzed low-risk PV patients from the PROUD-PV/CONTINUATION-PV (NCT01949805/NCT02218047) cohort to examine the impact of baseline characteristics and individually optimized dose levels of ropeginterferon alfa-2b on response status at 12, 24 and 72 months. Methods: Patients diagnosed with PV (WHO 2008 criteria) were randomized 1:1 and received ropeginterferon alfa-2b or standard care for a total of ≥6 years during the 12-month PROUD-PV study and its extension CONTINUATION-PV. Low-risk patients (aged ≤60 years with no history of thrombosis) allocated to the ropeginterferon alfa-2b arm were analyzed. Ropeginterferon alfa-2b was started at a dose of 100 µg/2 weeks (50 µg if transitioning from hydroxyurea) and escalated by 50 µg/2 weeks until blood counts normalized to a maximum of 500 µg/2 weeks. Grade 2-3 drug-related toxicity mandated dose reduction/interruption. During maintenance treatment the dosing interval could be extended to 3-4 weeks. Complete hematologic response (CHR) defined by modified ELN criteria (without the spleen criterion) and safety data at 12, 24 and 72 months were assessed. Results: In the setting of individualized dosing, 33/56 (58.9%) low-risk PV patients allocated to ropeginterferon alfa-2b in PROUD-PV achieved a CHR at month 12. Response rates increased with longer treatment duration; of the 46 low-risk patients enrolled in CONTINUATION-PV; 80.4% and 73.2% of patients with available data achieved a CHR at months 24 and 72, respectively. Baseline characteristics by response status at month 12 indicated that males were overrepresented among non-responders (15/23 non-responders [65.2%] were male vs 11/33 responders [33.3%] [p=0.0291]), and baseline median JAK2V617F allele burden was non-significantly higher in non-responders at 12 months (45.6% vs 35.5%: p=0.1860). However, no significant differences in these baseline parameters were observed by long-term response status (24 months or 72 months), nor were there consistent differences in baseline body mass index or blood counts according to response status at any time point evaluated. The most frequent reason for non-response was failure to meet the CHR criterion hematocrit <45% without phlebotomy in the past 3 months, accounting for the majority of non-responders at months 12, 24 and 72 (13/23 [56.5%], 6/9 [66.7%], and 6/11 [54.5%], respectively), followed by discontinuation for any reason, which accounted for 30.4% of non-responders at month 12 and 36.4% at month 72. Only one low-risk patient discontinued due to ropeginterferon alfa-2b-related toxicity. Despite response-driven dosing, the median 4-weekly derived dose of ropeginterferon alfa-2b in the first year was only somewhat higher in non-responders compared with responders (809 µg [range: 209-898] vs 717 µg [188-898]; p=0.6954); 10/23 of non-responders at month 12 did not escalate the dose immediately according to protocol on ≥1 occasion during the first year, e.g. due to responses already observed for leukocyte or platelet counts. In the second year, the median 4-weekly doses were 997 µg (range: 211-997) vs 690 µg (88-1036) respectively (p=0.2024), indicating that non-responders received and tolerated the maximum dose (500 µg/2 weeks). Conclusions: High long-term response rates (80.4% at 24 months; 73.2% at 72 months) were achieved with ropeginterferon alfa-2b treatment in the low-risk PV population when the dose was optimized on an individual basis. No specific baseline characteristics among low-risk PV patients appear to be associated with long-term response to ropeginterferon alfa-2b. However, the PROUD-PV/CONTINUATION-PV studies show that - as hypothesized based on the Low-PV trial data - some low-risk patients require and can tolerate high doses, and that the optimal dose of ropeginterferon alfa-2b varies substantially between patients.

Interferon alfa not only restores normal blood cell counts in patients with polycythemia vera (PV) but can diminish the mutant JAK2V617F allele burden [1][2][3].After discontinuing long-term interferon therapy, hematologic responses may persist [4,5], which is more likely in patients achieving JAK2V617F allele burden <10% before stopping treatment [6].Allele burden declines gradually during interferon treatment [7]; however, no data from large, prospective, clinical studies of long-term treatment with pegylated alfa interferons are available.Results from 3 years' treatment in the phase 3, open-label, randomized clinical trial PROUD-PV and its phase 3b extension trial CONTINUATION-PV [8] led to regulatory approval of ropeginterferon alfa-2b (BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval of 2-4 weeks, in the European Union.The compound was subsequently approved by the US FDA for first-line treatment of PV.Here we report hematologic and molecular responses and safety results after 5 years' treatment in PROUD-PV and CONTINUATION-PV, which compared the efficacy and safety of ropeginterferon alfa-2b with hydroxyurea in the first year, and with best available treatment (BAT) thereafter.Study design and methods were published previously [8]; selection criteria, dosing and endpoints are described in the supplement (Supplementary Tables 1-3 and Supplementary Fig. 1).JAK2V617F-positive patients with PV who were hydroxyurea naïve or hydroxyurea pre-treated for <3 years without complete response, resistance or intolerance were randomized 1:1 (stratified by age, history of thromboembolic events and hydroxyurea pretreatment) in PROUD-PV to receive ropeginterferon alfa-2b or hydroxyurea for 12 months.Dosing increased until blood counts

Introduction: Patients with "low-risk” (LR) PV are managed conservatively despite higher risk of vascular events and impaired quality of life compared to a population without PV. Acknowledging new evidence (LOW-PV study, Barbui et al 2021), recent treatment guidelines (European LeukemiaNet [ELN] 2021) recommend ropeginterferon alfa-2b (BESREMi®) as a cytoreductive treatment in LR PV patients meeting specific criteria as well as in high-risk (HR) PV patients. Final data from the phase 3 PROUD-PV and CONTINUATION-PV trials (NCT01949805; NCT02218047) demonstrated the long-term efficacy and safety of ropeginterferon alfa-2b compared with hydroxyurea/best available treatment (HU/BAT); here we report results in the ropeginterferon alfa-2b arm by risk stratum. Methods: PV patients were randomized 1:1 and received ropeginterferon alfa-2b or HU/BAT for ≥6 years. In the ropeginterferon alfa-2b arm, subgroup analyses were performed post-hoc by risk stratum (LR: age ≤60 years and no history of thrombosis; all others HR). Complete hematologic response (CHemR) and molecular response defined by modified ELN criteria were assessed in the full analysis set for CONTINUATION-PV (N=95); safety analyses included all data regardless of roll-over (N=127). Results: CONTINUATION-PV enrolled 46 LR and 49 HR patients in the ropeginterferon alfa-2b arm. At baseline, mean age was 50.7 vs 63.7 years respectively, and median duration since PV diagnosis was 1.9 months vs 1.5 months. HR patients had higher platelet and leukocyte counts at baseline and more frequently presented with clinically significant splenomegaly or PV-related symptoms. Median JAK2V617F allele burden was similar for LR and HR patients (37.0% vs 39.4%), however LR patients were less likely to harbor additional non-driver mutations (11.4% vs 24.4%). The median 4-weekly ropeginterferon alfa-2b dose was comparable in LR and HR patients throughout the study (in the 6th year, 499 µg and 489µg respectively) as was the use of an extended 3-4 weekly dose regimen (6th year: 59.5% vs 65.4%). LR patients achieved a significantly higher CHemR rate than HR patients during long-term treatment (Month 72: 73.2% vs 38.3% in LR and HR respectively [RR: 2.41; 95% CI: 1.50 to 3.90; p=0.0003]). Higher CHemR among LR patients was confirmed in a sensitivity analysis including discontinued patients (last observation carried forward [LOCF]; 80.4% in LR vs 65.3% in HR patients at Month 72) indicating that in the HR group, more patients discontinued despite CHemR. In general, discontinued patients were older than those who completed the study (mean age 62.8 years vs 55.2 years) but did not have a longer duration of PV or markedly greater symptom burden at baseline. Importantly, regardless of risk stratum, most patients receiving ropeginterferon alfa-2b did not require any phlebotomy for the entire 6th year (85.7% of LR patients and 75.0% of HR patients entering the 6th year [p=0.3]). LR patients had a higher molecular response rate than HR patients (LOCF at Month 72: 84.4% vs 49.0% respectively, RR: 2.15 [95% CI: 1.37 to 3.37]; p=0.0009) and achieved molecular response more rapidly (median time to first response: 12 months [95% CI: 12 to 18] vs 18 months [95% CI: 12 to 24]; Log-rank test p=0.03). The median JAK2V617F allele burden was 5.6% for LR and 17.9% for HR patients at Month 72 (p<0.0001). During the entire PROUD-PV/CONTINUATION-PV studies (≥6 years exposure), adverse drug reactions (ADRs) to ropeginterferon alfa-2b led to withdrawal of treatment in 1 (1.8%) LR patient (due to sarcoidosis), and in 13 (18.3%) HR patients (due to thrombocytopenia [n=1], elevated transaminases [n=1], psychiatric disorders [n=2], autoimmune disorders [n=6], hypothyroidism [n=2] and dyspnea/pneumonitis [n=1]). LR patients were also less likely than HR patients to experience ADRS of grade ≥3 severity (5.4% vs 23.9%). Conclusion: These results demonstrate the benefit of ropeginterferon alfa-2b therapy in both HR and LR patient populations. LR patients may have a greater potential benefit: higher hematologic and molecular response rates can be safely achieved, and the patients are more likely to remain on long-term treatment. These data provide further evidence for an early treatment start as recently outlined by the updated ELN guidelines.

Patients with hematological malignancies, particularly multiple myeloma (MM), typically have a high prevalence of renal impairment (RI). When combined with the nephrotoxic risk of anticancer drugs, especially with an older patient population like that frequently observed in MM, optimizing treatment regimens that are both safe and efficacious is difficult.1 Taken together, there is a need to identify effective therapeutic options that can be used in patients with RI and do not pose or induce additional renal toxicity in patients with MM. Selinexor is an oral selective inhibitor of nuclear export (SINE) compound, which specifically blocks exportin 1 (XPO1). By inhibiting XPO1, SINE compounds force the nuclear retention of tumor suppressor proteins (TSPs), leading to their functional activation, which is followed by induction of apoptosis in myeloma and other cancer cells, while largely sparing normal cells.2 Selinexor has good oral bioavailability, and is metabolized primarily by multiple hepatic routes without significant renal metabolism.3 In addition, it does not directly affect creatinine clearance (CrCl), though it can be associated with asymptomatic hyponatremia, which may be due to increased sodium loss from the kidney.2 Selinexor is approved by the United States Food and Drug Administration for patients with MM after at least one prior therapy based on the BOSTON study,4 with no contraindications based on renal dysfunction. The combination of selinexor, bortezomib, and dexamethasone (XVd) conferred a significant improvement in progression-free survival (PFS), overall response rate (ORR), and time to next therapy (TTNT), and showed a trend toward improved overall survival (OS),5 while rates of peripheral neuropathy (PN) were lower in the XVd than the Vd arm.4 Here, we present data on the efficacy and safety of selinexor in MM patients with and without RI (additional details in Supplemental Methods). The BOSTON study enrolled a total of 402 patients, of which 195 were randomized to XVd and 207 were assigned to Vd. Among these, 56 patients in the XVd arm and 70 in the Vd arm had RI (CrCl < 40 or 40–60 mL/min), while 139 and 137 had normal renal function, respectively. Baseline patient characteristics are shown in Table S1. The median PFS of patients with CrCl 40–60 mL/min was significantly improved with XVd compared to Vd (16.62 vs 7.26 months) (p = .028) (Figure S1A, Table 1). A similar significant improvement was observed in patients with normal kidney function: 13.24 months with XVd and 9.66 months with Vd (p = .019). In patients with CrCl < 40 mL/min, the median PFS was 7.62 months with XVd and 4.30 months with Vd (p = .129). Patients with RI treated with XVd had a significantly higher ORR than patients who received Vd (< 40 mL/min, 81.0% vs. 53.8%, respectively, p = .027; and 40–60 mL/min 80.0% vs. 59.1%, respectively, p = .024). Rates of very good partial response (VGPR) or better were higher with XVd in patients with 40–60 mL/min (48.6% XVd vs. 27.3% Vd, p = .026). In patients with normal renal function, the ORR was also significantly higher with XVd (p = .037) (Table 1). OS in patients with RI trended in favor of XVd (median not reached in both < 40 mL/min and 40–60 mL/min) versus Vd (median, < 40 mL/min 19.06 months and 40–60 mL/min 21.22 months) (< 40 mL/min HR, 0.74 [95% CI, 0.29–1.88], p = .263; 40–60 mL/min HR, 0.55 [95% CI, 0.23–1.29], p = .080) (Figure S1B, Table 1). The median TTNT was significantly improved in patients with CrCl 40–60 mL/min with XVd compared to Vd (p = .040). Patients with normal renal function also showed significantly improved TNNT with XVd compared to Vd (p = .007) (Table 1). Treatment-emergent adverse events (TEAEs) were similar between patients with CrCl > 60 mL/min with XVd (99.3%) and Vd (97.1%), and patients with RI (< 40 mL/min 100.0% XVd, 96.0% Vd; 40–60 mL/min 100.0% XVd, 97.6% Vd). Despite the higher rate of thrombocytopenia on the XVd arm, there was no difference in the rate of clinically significant (Grade ≥ 3) bleeding on the XVd arm, even in patients with RI, with a single case of clinically significant bleeding in each arm. Serious AEs (SAEs) were similar between treatment arms and subgroups (< 40 mL/min XVd 66.7% vs. Vd 40.0%; 40–60 mL/min XVd 42.9% vs. Vd 47.6%; > 60 mL/min XVd 51.8% vs. Vd 34.3%). The percentage of patients with dose reductions was numerically higher with XVd than Vd, regardless of CrCl levels. Treatment discontinuation due to AEs was similar in both arms for patients with CrCl 40–60 and >60 mL/min. Although a smaller number, those in the <40 mL/min group trended toward a lower rate of discontinuation with XVd (Table S2). Overall, grade 2 or greater AEs related to PN in patients with RI (< 40) was lower in the XVd arm compared to the Vd arm (< 40: XVd 4.8% vs. Vd 36.0%) and similar in the 40–60 subgroup (40–60: XVd 34.3% vs. Vd 35.7%). A trend of lower grade 2 or greater PN AEs were observed in patients with CrCl > 60 mL/min (XVd 20.1% vs. Vd 33.6%) (Table S2). The BOSTON study in patients with previously treated MM evaluated the standard twice-weekly Vd regimen versus the once-weekly XVd regimen, which utilizes 40% less bortezomib and 25% less dexamethasone in the first 24 weeks, compared with Vd. The study showed that XVd was superior to Vd on the primary endpoint of PFS, and several secondary endpoints, with adequate tolerability.4 Here we have assessed the impact of baseline calculated CrCl as an indicator of RI on efficacy and tolerability between the two regimens. Patients with RI in the BOSTON study that were treated with XVd had a 44% improvement in median PFS compared to the Vd arm. KM-curves of PFS (Figure S1) demonstrated that despite the median age being 73 years and 53.6% having high-risk cytogenetics, this patient population had early and sustained separation of XVd from Vd treatment arms, similar to the entire intention-to-treat (ITT) population. Among patients with RI, and specifically those with CrCl 40–60 mL/min, however, there appeared to be more pronounced improvements in ORR, deep (≥ VGPR) responses, and a trend toward improved OS for XVd versus Vd, as compared with patients with normal renal function. Thus, there was a significant increase in ORR in patients with RI treated with XVd, as compared to those treated with Vd, with significantly more ≥VGPR with XVd. In patients who had normal renal function (defined as CrCl > 60 mL/min), similar, but often less marked, differences were observed. Overall, these results demonstrate that the simple, once-weekly XVd regimen clearly benefited patients with baseline RI, with no dose adjustments required for renal function levels. The increased risk of toxic side effects and fatalities in patients with RI can require a dose reduction, or administration of a less effective treatment, which reduces efficacy and can cause a failure in therapy, andultimately reduce survival time.6 Many aggressive therapeutics, such as those in second or third or more lines of therapy, require a minimum kidney function threshold, which leaves a population of patients who cannot benefit from a more aggressive treatment.6 Lenalidomide, which is renally excreted, demonstrated a median PFS of 7.8 months and a 50% ORR in phase 3 studies in patients who had severe RI (CrCl of < 30 mL/min).7 Although about 2% of pomalidomide is excreted in the kidneys,8 treatment with pomalidomide plus dexamethasone demonstrated an ORR under 40% (39.4% in moderate RI, 32.4% in severe RI, and 14.3% in severe RI that requires hemodialysis) in heavily pre-treated patients.9 While we cannot make a direct comparison, the ORR of 80.4% overall observed in patients with RI treated with XVd, and the PFS of 16.62 months in patients with CrCl 40–60 mL/min, demonstrates a robust and durable potential option for MM patients with RI. The incidence of AEs was comparable between groups within treatment arms, notably grade 3 PN in the XVd arm versus the Vd arm (normal: 3.6% vs 5.8%; RI: 5.4% vs 14.9%), which is improved over other MM treatments. For example, our results are significantly improved compared to results of the OPTMIUM phase 3 study with thalidomide as a monotherapy, which demonstrated an incidence of grade 2 or more PN that increased with dosage 12%–22%.10 Taken together, these results present a case for the ability to more safely treat a larger population of patients, even those with RI and aggressive disease that have limited options, with better safety and efficacy, placing less importance on renal function and more importance on patient needs. Renal insufficiency is common in patients with MM and limits the opportunity to be treated with optimally effective therapeutics. Our data demonstrates that the once-weekly XVd regimen conferred improved clinical outcomes and good tolerability in patients with MM who have RI, as compared with standard twice-weekly Vd. The XVd regimen induced deep and durable responses in patients with RI, despite the fact that these patients were older and had more high-risk cytogenetics than those with normal renal function. In conclusion, the use of selinexor may provide improved, durable outcomes, and reduced incidence of PN in patients with previously treated MM and RI. This study was supported by research funding from Karyopharm Therapeutics, Inc. JetPub Scientific Communications LLC, supported by Karyopharm Therapeutics, Inc., assisted in the preparation of this manuscript, in accordance with Good Publication Practice (GPP3) guidelines. SD has received honoraria from Janssen, Takeda, Amgen, and Celgene. MVM has served as member of advisory boards or received honoraria from Janssen, BMS-Celgene, Takeda, Amgen, Sanofi, Oncopeptides, GSK, Adaptive, Pfizer, Regeneron, Roche, and Sea-Gen. RH has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. HWA reports an advisory role for Takeda and Karyopharm; grant from Amgen; and a speaker's bureau role for Janssen. MG reports (Maria Gavriatopoulou) receiving honoraria from Amgen, Karyopharm Therapeutics, Takeda, Genesis Pharma, and Janssen-Cilag. HQ reports grants from and an advisory board role for Amgen, Celgene, Karyopharm, GlaxoSmithKline; non-financial support and research drug supply from Sanofi; an advisory board role for Janssen Cilag and Specialized therapeutics. CPV has received honoraria from BMS/Celgene, Janssen, Sanofi, Amgen, GSK, and Takeda. MG (Mamta Garg) reports support for attending conferences from Takeda; an advisory role for Amgen, Takeda, Jansen, Novartis, and Celgene; and a speaker's bureau role for Janssen. PM reports honoraria from Celgene/BMS, Amgen, Janssen, Sanofi, Abbvie. ML reports receiving consulting fees and lecture fees from Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals, and Janssen. YC, JJ, MA, JS, and MGK are employees of and stockholders of Karyopharm. SS reports being employed by and owning stock in Karyopharm Therapeutics, holding patents (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide-containing nuclear transport modulators and uses, and holding pending patents (PCT/US12/048319, 499/2012, PI20102724, and 2 012 000 928) on hydrazide-containing nuclear transport modulators and uses. PGR reports receiving grant support and honoraria from Oncopeptides, Celgene, and Takeda, grant support from Bristol-Myers Squibb, and honoraria from Amgen, Janssen, and Karyopharm Therapeutics. All other authors declare no competing interests. Karyopharm Therapeutics agrees to share individual participant data that underlie the results reported in this article (after deidentification), including the study protocol and statistical analysis plan. Data availability will begin 9 months after publication and will be available 36 months after publication. To gain access, data requestors should submit a proposal to [email protected] Proposals will be reviewed by an independent review committee identified for this purpose. Appendix S1 Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background: BCL-2 inhibition with venetoclax has proved to be highly effective treatment for patients with CLL. However, when administered to patients with CLL who have a high tumor burden, venetoclax is associated with an elevated risk of tumor lysis syndrome (TLS). Because of this risk, venetoclax is initiated with a gradual, 5-week dose ramp-up, requiring close laboratory monitoring over an extended period. Lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor under clinical development for hematologic malignancies (HMs). Preliminary data in 18 patients with CLL treated in a first-in-human study suggested the feasibility of an abbreviated ramp-up of lisaftoclax that might also result in a lower incidence of neutropenia (Ailawadhi et al, J Clin Oncol 39, 2021; abstr 7502).

8019 Background: Multiple myeloma (MM) typically affects older populations, which are more vulnerable to toxicity with anti-MM treatments. These patients (pts) have significant morbidity and mortality, resulting in a need for dose modifications or alternative suboptimal treatment options. Significant improvements were observed in the BOSTON study with XVd vs Vd in median progression-free survival (PFS), overall response rate (ORR), and rates of peripheral neuropathy (PN); median overall survival (OS) trended in favor of XVd. Methods: The phase 3 randomized BOSTON trial (NCT03110562) is a controlled, open-label study of once weekly XVd vs. twice weekly standard Vd in pts with MM and 1-3 prior treatment regimens. We performed post-hoc analyses to compare survival benefits in pts ≥65 vs < 65 years of age. Results: The BOSTON study enrolled a total of 402 pts between June 2017 and February 2019 that were randomized into XVd or Vd arms. The numbers of pts treated with XVd or Vd who were ≥65 were 109/132 and 86/75 who were < 65, respectively. Baseline characteristics were similar by age although pts ≥65 years were less likely to have received ASCT than those < 65 years (48.4% vs. 25.3%). Median PFS was prolonged with XVd compared with Vd, across both age groups: ≥65 (HR, 0.55 [95% CI, 0.37-0.83] P = 0.002) and < 65, (HR, 0. 74 [95% CI, 0.49-1.11], P = 0.07). Vd was associated with a lower ORR (64.4%) than treatment with XVd (76.1%) (OR, 1.77 [95% CI, 1.00-3.11], P = 0.024) in pts ≥65, while the ORR in those < 65 was 76.7% with XVd and 58.7% (OR, 2.33 [95% CI, 1.18-4.59], P = 0.007) with Vd. As of Jan 2021, the median OS for the overall population was not reached for both arms (HR = 0.86; p = 0.193), with 61 and 75 deaths in the XVd and Vd arms, respectively. Median OS was not reached in pts ≥65 with XVd and was 28.6 months with Vd (HR = 0.60; 95% CI, 0.38-0.94; p = 0.012), while there was no difference in the OS for pts < 65 (HR = 1.52; 95% CI, 0.86-2.68; p = 0.926). Pts ≥65 had a lower incidence of death with XVd as compared to Vd (29 vs 56) and there were 32 deaths with XVd and 19 with Vd in pts < 65. Grade ≥3 treatment-emergent adverse events were not observed more often in older compared to younger pts. Amongst pts ≥65, PN of any grade was lower with XVd (32.1%) compared to Vd (46.5%); (OR 0.57 [95% CI 0.34-0.97], p = 0.017), including a lower incidence of grade ≥3 PN (XVd 4.6% vs. Vd 11.6%). Pts < 65 followed a similar trend of PN AEs of any grade: XVd, 32.6%; Vd, 48.0% (OR 0.42 [95% CI 0.21-0.82], p = 0.006). Conclusions: In an older patient population with a poor prognosis, XVd was associated with a significant survival benefit, improved PFS and OR with reduced PN, and requires relatively short and infrequent clinic visits. XVd may be a simple, effective regimen for pts ≥65 years of age. Clinical trial information: NCT03110562.

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.

8024 Background: Lenalidomide (LEN) is typically a frontline therapy for newly diagnosed MM. Patients (pts) with MM refractory to LEN are less likely to repond to other IMiDs and represent a signification area of unmet medical need. In the BOSTON study in the ITT population, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. Methods: The BOSTON trial (NCT03110562) is a Phase 3 randomized, controlled, open-label study of once weekly XVd vs twice weekly Vd in pts with MM and 1-3 prior therapies. We performed post-hoc analyses on two different subgroups to compare outcomes based on refractory status to LEN and immunomodulatory drug (IMiD) therapy. These post hoc analyses evaluated if PFS, overall response rate (ORR), time to next treatment (TTNT) and safety was influenced by prior treatment with LEN when comparing XVd with Vd. Results: Amongst the 402 pts in BOSTON, 160 had MM refractory to any IMiD (XVd = 74, Vd = 86). Of those, 106 were documented to be refractory to LEN (XVd = 53, Vd = 53) and 296 were not refractory to LEN (XVd = 142, Vd = 154). Baseline characteristics were generally well balanced between subgroups. In these subgroups based on refractory status to IMiD or LEN, median PFS was significantly longer in the XVd arm as compared to Vd (IMiD refractory, 13.9 vs. 8.4 months (mo), p = 0.005; LEN refractory, 10.2 vs. 7.1 mo, p = 0.012; not LEN refractory, 15.4 vs 9.6 mo, p = 0.014). Significant increases in TTNT were observed with XVd treatment in pts that were IMiD refractory (14.8 vs. 10.2 mo, p = 0.003), LEN refractory (13.0 vs. 7.6 mo, p = 0.015), and not refractory to LEN (19.1 vs 12.9 mo, p = 0.005). ORR was improved with XVd compared to Vd regardless of refractory status (IMiD refractory, 68.9% vs 55.8%, p = 0.045; LEN refractory, 67.9% vs. 47.2%, p = 0.016; and not refractory to LEN, 79.6% vs 67.5%, p = 0.010). The most common treatment-emergent AEs for the XVd/Vd arms for all subgroups were thrombocytopenia (66.2/30.6%; 71.7/40.4%; 55.6/22.4%), nausea (48.6/11.8%; 50.9/11.5%; 50.0/9.2%), and fatigue (40.5/20.0%; 45.3/21.2%; 40.8/17.1%) for IMiD, LEN, and not LEN refractory, respectively. Incidence of PN AEs of any grade were reduced compared to pts treated with Vd (IMiD refractory, 27% vs. 42.4%; LEN refractory, 30.2% vs 36.5%; not refractory, LEN 33.1% vs 50.7%). Conclusions: In pts with previously treated MM, PFS, ORR, and TTNT were significantly improved regardless of documented refractory status to any IMiD or to LEN-specifically. These analyses support the use of the XVd combination for pts with disease refractory to LEN and likely to any IMiD. Clinical trial information: NCT03110562.

Background: Naratuximab emtansine (nara, Debio 1562, formerly IMGN529) is an antibody-drug conjugate (ADC) consisting of a humanized anti-CD37 antibody, K7153A, conjugated via a thioether-based linker to a cytotoxic maytansinoid, DM1. CD37, a lymphocyte surface marker, is highly expressed in B-NHL. A Phase 1 monotherapy study of nara revealed a good safety profile and promising efficacy (22% overall response rate [ORR] in DLBCL at all doses). In preclinical models of B-NHL, nara demonstrated synergistic antitumor activity when combined with rituximab (RTX). Aim: The aim of thisopen-label Phase 2 study was to evaluate the safety and efficacy of nara + RTX and to characterize pharmacokinetics (PK) and pharmacodynamics (PDy) in patients (pts) with relapsed and/or refractory (R/R) B-NHL. Methods: R/R B-NHL pts who were not candidates for stem cell transplant, with 1-6 prior lines of treatment, were recruited to two study parts. In Part 1, which included a safety run-in followed by an expansion, pts received 0.7 mg/kg nara in combination with 375 mg/m 2 RTX every 3 weeks (Q3W). In Part 2, only R/R DLBCL pts were included. Pts were assigned either to the Q3W regimen (cohort A), or to a weekly regimen of 0.4, 0.2, and 0.2 mg/kg nara administered on days 1, 8 and 15 of 21-day cycles combined with 375 mg/m 2 RTX on day 1 (cohort B). Six cycles of treatment were administered with possible extension. Primary endpoints were safety and ORR. PK and PDy evaluations included ADC and DM1 catabolites' systemic levels and receptor occupancy on peripheral blood mononuclear cells (PBMCs), to investigate CD37 target engagement. Pts from cohorts A and B were requested to fill in the FACTLym quality of life questionnaire (QoL). Pts with double/triple hit lymphoma, bulky disease, and up to 6 prior lines of treatment for DLBCL were allowed. There was no limit on life expectancy. Pts were considered efficacy evaluable (EE) if they had one baseline and at least one post-baseline tumor assessment or an assessment of clinical progression. Tumor assessment by CT was acceptable. The follow-up period was up to 1 year after last pt first dose (NCT02564744). Results: 100 pts were enrolled in the study: 80 DLBCL, 14 follicular lymphoma (FL) and 6 mantle cell lymphoma (MCL) pts; 81 pts (81%) experienced grade ≥ 3 treatment emergent adverse events, the most common being neutropenia 54 (54%), leukopenia 19 (19%), lymphopenia 17 (17%), and thrombocytopenia 12 (12%). Of the 80 DLBCL pts, 10 (12.5%) were primary refractory, 24 (30%) were refractory to last line, 62 (78%) had Ann Arbor stage III/IV, and 35 (44%) had received at least 2 prior systemic cancer therapies. The ORR in the 76 EE DLBCL pts was 44.7%, with 24 (31.6%) complete responses (CR) and 10 (13.2%) partial responses (PR). In addition, 9 (11.8%) stable disease (SD) and 33 (43.4%) progressive disease (PD) were observed. 30 pts were efficacy evaluable in each of the two major cohorts (A and B) of Part 2, enrolling mainly relapsed pts. ORR was 50% in each cohort (CR rate: 43.3% in cohort A; 33.3% in cohort B). In Part 1, 16 DLBCL pts were EE, of which 6 were primary refractory and 10 were refractory to last line. ORR in this group was 25%. Median duration of response (mDoR) in the 76 evaluable DLBCL pts was not reached (lower 95% confidence interval [CI] 12 months). Median duration of follow-up in responders was 15 months (95% CI 9-18 months). In the 14 FL pts, the ORR was 57%: 5 CR, 3 PR, 3 SD, and 3 PD; the mDoR in this population was not reached (lower 95% CI: 19 months), with a median duration of follow-up of 21.8 months (95% CI 19.1 - not reached). Of the 6 MCL pts, 4 were efficacy evaluable: 2 CR and 2 PD. Due to the low number of pts, the DoR curves are not presented. PK levels were sufficient to fully engage the CD37 target on PBMCs. A relationship between PK exposure and efficacy was identified. Data showed acceptable systemic release of cytotoxic DM1 and catabolites. DLBCL responders in cohorts A and B demonstrated on average a clinically meaningful improvement of 3 points (standard deviation: 6.6) in the Lymphoma Subscale of the FACT-Lym QoL. Summary/Conclusion: The combination of nara + RTX resulted in good OR and CR rates, durable responses, a manageable safety profile, and full CD37 target engagement. Consequently, nara + RTX could be considered an attractive option for the treatment of R/R B-NHL. The treatment was well tolerated and contributed to the pts' well-being, as demonstrated by the QoL results. Figure 1 Figure 1. Levy: Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Grudeva-Popova: University Hospital St George: Current Employment; Roche: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Portola: 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; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Jurczak: Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. André: Johnson & Johnson: Research Funding; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Roche: Other: Travel/accomodation/expenses, Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding; Pharmacyclics: Research Funding; Millenium: Research Funding; ATARA: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data safety monitoring board; Rafael: Research Funding; Debiopharm: Research Funding. Rechavi-Robinson: Debiopharm International SA: Current Employment. Toffanin: Debiopharm International SA: Current Employment. Micallef: F. Hoffmann La Roche: Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Attinger: Debiopharm International SA: Current Employment. Rouits: Debiopharm International SA: Current Employment, Patents & Royalties. Roubaudi-Fraschini: Debiopharm International SA: Current Employment. Orfanos: Debiopharm International SA: Current Employment; F. Hoffmann La Roche: Ended employment in the past 24 months. Dymkowska: CANTARGIA AB: Consultancy; AUREALIS OY: Consultancy; Debiopharm International SA: Consultancy; Morphosys AG: Consultancy. Nauwelaerts: Novartis Pharmaceuticals AG, Basel: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Woei-a-Jin: University Hospitals Leuven, Belgium: Current

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT. Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562 .

Abstract Introduction: Treatment of multiple myeloma (MM) has greatly improved over the last two decades. However, most pts will relapse and develop refractory disease. Most anti-cancer regimens require dose modifications (interruption, reduction, or discontinuation) during the treatment course in order to optimize the therapeutic window; appropriate modifications improve tolerability while maintaining anti-cancer activity. Selinexor, an oral selective inhibitor of XPO1-mediated nuclear export (SINE) compound, enforces the nuclear retention and functional activation of tumor suppressor proteins within the nucleus and prevents the translation of oncoproteins. The combination of once weekly (QW) selinexor, QW bortezomib, and dexamethasone (XVd) is FDA approved for previously treated MM. Compared to standard twice weekly (BIW) bortezomib plus dexamethasone (Vd) and using 40% less bortezomib and 25% less dexamethasone, XVd demonstrated significantly prolonged median progression-free survival (PFS) and time-to-next-treatment (TTNT), increased the overall response rate (ORR), reduced rates of peripheral neuropathy, and showed a trend towards improved overall survival (OS) in the Phase 3 randomized BOSTON study (NCT03110562). The recommended starting dose of selinexor in XVd is 100mg QW, but the median dose administered in BOSTON was 80 mg QW. Here, we analyzed the efficacy outcomes and adverse events (AEs) in pts whose dose was reduced compared to those where it was not. Methods: The BOSTON study consisted of two arms: pts treated with selinexor QW (100mg), bortezomib QW (1.3mg/m 2) and dexamethasone BIW (20 mg) (XVd; n=195 in the intention-to-treat [ITT] population) compared to standard BIW Vd. Results: Of the XVd pts in the BOSTON study, 126 had a dose reduction of selinexor and 69 did not. The median age was 66.0 in both groups (range: with reduction, 47-87; without, 40-84) and the median number of prior therapies was 1.0 (range, 1-3) for both groups (Table 1). The median time to dose reduction in these pts was 68 days (range, 8-561 days). The median duration of study treatment for these pts was 34.5 weeks (range, 3-120 weeks) compared to 20.0 weeks (range, 1-118) in pts with no dose reduction. In the group with dose reduction, the median dose of selinexor received per week was 71.3 mg (range, 29.7, 101.4) compared to 100 mg (range, 33.3, 136.7) in pts with no reduction. Pts who dose reduced had a median PFS of 16.6 months compared to 9.2 months in pts who did not (one-sided p value, <0.01), with a median follow up of 14.1 months with reduction and 10.6 months without. The ORR in the dose reduced group compared to pts who did not dose reduce was 81.7% vs 66.7% (one-sided p value, <0.01), and the rate of VGPR or better was 51.6% vs 31.8% (Table 2). Duration of response (DOR) was NR in the dose reduced group and was 12.0 months in the group without reduction. TTNT was 22.6 months in the dose reduced group and 10.5 months in pts with no dose reductions (one-sided p value, <0.001). The most common adverse events (AEs; dose reduction and without dose reduction) of any grade were thrombocytopenia (69.8% and 42.0%), nausea (55.6% and 40.6%), and fatigue (49.2% and 29.0%). The rate of treatment discontinuation in the dose reduced group was 24.6% and 14.5% without dose reductions. In the dose reduced group, there were 6 (4.8%) deaths and 6 (8.7%) in the group with no dose reduction. As pts with a dose reduction stayed on therapy for a prolonged period of time, to best understand the impact of dose reduction on the AE, we present the duration-adjusted incidence rates of AEs of clinical interest. The duration-adjusted incidence rates of AE were considerably lower after dose reduction of selinexor compared to the rates on or before dose reduction: thrombocytopenia (62.5% vs 47.6%), nausea (31.6% vs 7.3%), fatigue (28.1% vs 9.9%), decreased appetite (21.5% vs 6.4%), anemia (17.9% vs 10.3%), and diarrhea (12.9% vs 5.2) (Table 3). Conclusions: While all pts on XVd initiated therapy at 100mg selinexor QW, and it was associated with very low rates of progressive disease (1 in 195 pts), appropriate dose reductions of selinexor were associated with a longer PFS, DOR, and TTNT, and significantly reduced AE with improved tolerability, highlighting dose reductions as an important tool to personalize and optimize the therapeutic window for pts with RRMM. Figure 1 Figure 1. Disclosures Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Badros: Janssen: Research Funding; GlaxoSmithKline: Research Funding; J&J: Research Funding; BMS: Research Funding. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Moreau: Celgene BMS: Honoraria; Oncopeptides: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Gavriatopoulou: Takeda: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Garg: University Hospital Leicester: Current Employment; Amgen Janssen Novartis Sanofi Takeda: Honoraria; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses. Gironella Mesa: BMS, Janssen: Honoraria. Jurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Radinoff: Janssen, Pfizer, Novartis, Servier etc.: Consultancy, Honoraria; Amgen, Bayer, Takeda, etc.: Research Funding; the Bulgarian Minister of Health: Membership on an entity's Board of Directors or advisory committees. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Quach: Amgen: 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; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bila: Takeda, AMGEN, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Richardson: GlaxoSmithKline: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n = 70; Vd, n = 71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n = 125; Vd, n = 136). Among patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p = 0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p = 0.004). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p = 0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p = 0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.

Abstract Introduction: Patients with multiple myeloma (MM) have a high rate of relapse resulting in a need for multiple lines of therapy. In contrast to MM with standard risk cytogenetics (SR-Cyto), high-risk cytogenetics (HR-Cyto) in MM such as del(17p), t(4;14), t(14;16), and gain(1q) (≥3 copies), can result in shorter progression-free survival (PFS) and overall survival (OS) with less durable responses. Treatment regimens that can overcome the negative effect of HR-Cyto abnormalities are required to address this area of unmet medical need. Exportin 1 (XPO1), is overexpressed in many hematologic and solid tumor malignancies including MM, and exports tumor suppressor proteins from the nucleus to the cytoplasm, leading to their inactivation. Elevated levels of XPO1 are correlated with more aggressive MM and resistance to therapy and confers a poor prognosis. The potent oral XPO1 inhibitor, selinexor, has been approved as a triplet combination with bortezomib and dexamethasone for previously-treated MM. In the Phase 3 BOSTON study, treatment with XVd in patients with previously treated MM significantly prolonged median PFS and improved the overall response rate (ORR), with a trend towards a prolonged OS amongst all patients as well as those with HR cytogenetics. Methods: We performed post hoc analyses on patients with previously-treated MM from the XVd arm of the Phase 1b/2 study STOMP (NCT02343042) and the Phase 3 BOSTON (NCT03110562) study to determine the effects of cytogenetic abnormalities on outcomes. The HR-Cyto group included patients with at least one of the following cytogenetic abnormalities at initial diagnosis or screening: del(17p), t(4;14), t(14;16), or gain(1q) (≥3 copies). Efficacy was based on independent review committee. Results: A total of 106 patients with HR-Cyto were identified, including del(17p) (n=25), t(4;14) (n=25), t(14;16) (n=10), and gain(1q) (n=80). There were 131 patients classified as SR-Cyto including those with unknown cytogenetics. Baseline demographics were similar between groups with median age of 66 years old (range 40-87). Patients with HR-Cyto had a median PFS of 12.9 months and patients with SR-Cyto had a median PFS of 16.6 months; PFS on the BOSTON Vd control arm were 8.6 and 9.5 months with HR- and SR-Cyto, respectively. Of the individual abnormalities, a PFS of 13.2 and 13.9 months was observed in the t(4;14) and gain1q subgroups, respectively. Of the HR-Cyto subgroups with more than 10 patients, a similar median OS was observed in comparison to SR-Cyto and ranged from 20.4 months to not reached. The response of XVd treatment was maintained across HR-Cyto risk subgroups, with an ORR of 76.4% overall and the following values for subgroups: del(17p) (72.0%), t(4;14) (88.0%), and gain1q (73.8%). The ORR of the SR group was 69.5%. Of all patients that received XVd, there were 6 CRs (5.7%) and 32 VGPRs (30.2%) in the HR group and 9 CRs (6.9%) and 29 VGPRs (22.1%) in the SR group. The ORRs on the BOSTON Vd control arm were 57.7% and 64.7% for HR- and SR-Cyto, respectively. The rates of the most common treatment emergent adverse events (TEAEs) of any grade were similar across risk groups (HR- vs SR-Cyto): thrombocytopenia (65.1% vs. 54.2%), nausea (53.8% vs. 53.4%), fatigue (47.2% vs. 45.0%) decreased appetite (37.7% vs. 42.0%) and anemia (34.6% vs 40.5%). Rates of AEs of any grade peripheral neuropathy (PN) were 35.8% overall, 40.0% in del(17p), t(4;14) (40.0%), t(14;16) (30.0%), gain(1q) (38.8%), and 23.7% in the SR group. The rates of PN in the HR and SR groups of the XVd arm of the BOSTON and STOMP studies were 37.1% and 29.6% and 11.1% and 15.2%, respectively. The corresponding rates for Vd alone in the BOSTON study were 48.6% and 47.0%. Conclusions: Patients with MM with HR-Cyto treated with XVd demonstrated a comparable ORR and PFS, with a manageable safety profile compared to patients with SR-Cyto, supporting the use of XVd in patients with any cytogenetic profile. These results are consistent with the distinct and broad mechanism of action associated with XPO1 inhibition and the use of the agent in earlier lines of therapy. Further assessment of selinexor in combination with other therapies in patients with MM across the entire cytogenetic spectrum is warranted. Figure 1 Figure 1. Disclosures Bahlis: Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Richard: Karyopharm, Janssen: Honoraria. White: Amgen, Antengene, BMS/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: Consultancy, Honoraria. Chen: Gilead: Research Funding; BMS, Janssen, Abbvie, Novartis, Gilead, AstraZeneca: Consultancy. Delimpasi: Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Sutherland: Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Celgene: Consultancy; Karyopharm: Research Funding. Sebag: Janssen: Research Funding; Bristol Myers-Squibb: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Gavriatopoulou: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria. Lentzsch: Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; Janssen: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kriachok: Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau; Takeda, Roche, Abbivie, Janssen, MSD: Consultancy. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Beigene: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Garg: Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria; University Hospital Leicester: Current Employment. Quach: Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jagannath: Karyopharm Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Badros: J&J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos: Oncopeptides: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Bluebird bio: Honoraria; AbbVie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Richardson: Secura Bio: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

Abstract Introduction: Ropeginterferon alfa-2b (BESREMi®), a novel pegylated interferon with an extended half-life, was approved in Europe for treatment of patients with PV based on results from the phase 3 PROUD-PV and CONTINUATION-PV trials. Ropeginterferon alfa-2b treatment is recommended in hydroxyurea (HU) naïve patients as well as in those who have previously received HU. Therefore, treatment response was analyzed by prior HU treatment status, and the influence of baseline JAK2V617F allele burden and additional mutations - which may increase over time during non-disease modifying treatment - was explored. Methods: In PROUD-PV, patients aged ≥18 years, diagnosed with PV according to WHO 2008 criteria, and either cytoreduction-naïve or HU-pre-treated (for <3 years, without intolerance or resistance) were randomized 1:1 to receive ropeg or HU at individualized doses. After 12 months' treatment, patients could roll over into CONTINUATION-PV and patients in the HU arm were permitted to switch to best available treatment (BAT). After 5 years' treatment, complete hematologic response (CHR) and molecular response defined by modified ELN criteria were assessed in patients enrolled in the extension study CONTINUATION-PV (N=171). Sub-group analyses were performed by prior HU treatment, JAK2V617F allele burden category (≤50% or>50%), and in patients with available data (N=159), by the presence of non-driver mutations (TruSight™ Myeloid Panel, Illumina) or chromosomal aberrations (Affymetrix SNP6.0 array) at baseline. Results: After 5 years of treatment with ropeginterferon alfa-2b, high rates of CHR were sustained in both HU-naïve and HU pre-treated patients (53.1% and 61.3%, respectively), whereas in the control arm, the CHR rate was lower among HU pre-treated patients (36.0% compared to 48.0% for HU-naïve patients). Molecular response rates at 5 years in HU naïve and pre-treated patients were 71.4% and 64.5% respectively in the ropeginterferon alfa-2b arm and 26.0% versus 12.5% respectively in the control arm. Rates of adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to discontinuation were similar between the subgroups regardless of HU pre-treatment. Similar CHR rates were observed at 5 years irrespective of baseline JAK2V617F allele burden category (ropeginterferon alfa-2b arm: 57.1% versus 53.1% for allele burden ≤50% or >50%, respectively; control: 46.9% versus 38.5%, respectively). The molecular response rate in the ropeginterferon alfa-2b arm was higher among patients with baseline allele burden >50% (84.4% versus 61.3% for allele burden ≤50%); in the control arm there was no difference in molecular response rates between the allele burden subgroups (23.1% versus 20.8%, respectively). Of interest, the presence of non-driver mutations or chromosomal aberrations at baseline had no apparent influence on molecular response rates to ropeginterferon alfa-2b (64.5% compared with 70.7% in patients without these genetic abnormalities). Conclusion: High hematologic and molecular response rates in both HU-pretreated and HU-naïve patients and in those with more advanced JAK2V617F burden suggest that ropeginterferon alfa-2b is also a suitable treatment option in patients switching from HU. Disclosures Gisslinger: AOP Orphan Pharmaceuticals GmbH: Other: Personal fees, Research Funding; Novartis: Other: Personal fees, Research Funding; PharmaEssentia: Other: Personal fees; MyeloPro Diagnostics and Research: Other: Personal fees; Janssen-Cilag: Other: Personal fees; Roche: Other: Personal fees; Celgene: Other: Personal fees. Klade: AOP Orphan Pharmaceuticals GmbH: Current Employment. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Mayer: AOP Orphan Pharmaceuticals GmbH: Research Funding. Krejcy: AOP Orphan Pharmaceuticals GmbH: Current Employment. Empson: AOP Orphan Pharmaceuticals GmbH: Current Employment. Hasselbalch: Novartis, AOP Orphan: Consultancy, Other: Advisory Board. Kralovics: AOP Orphan Pharmaceuticals GmbH: Other: Personal fees; PharmaEssentia: Other: Personal fees; Qiagen: Other: Personal fees; Novartis: Other: Personal fees; MyeloPro Diagnostics and Research: Current holder of individual stocks in a privately-held company. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; Taiho Oncology, Inc.: Research Funding.

8501 Background: Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, leading to the reactivation of tumor suppressor proteins. In a phase 1b/2 study, the combination of once weekly (QW) selinexor with bortezomib and dexamethasone (SVd) was well tolerated with anti-MM activity in patients (pts) with PI-sensitive and PI-refractory disease. While twice weekly (BIW) bortezomib in combination therapy is efficacious, prolonged use is limited due to peripheral neuropathy (PN, 50-60%). The BOSTON study was designed to determine if SVd improves progression free survival (PFS), overall response rates (ORR) and reduces the rate of PN vs Vd. Methods: BOSTON is a global, phase 3, randomized study of QW SVd vs BIW Vd after 1-3 prior anti-MM regimens. The primary endpoint is PFS. Secondary endpoints include ORR, overall survival (OS) and PN (rates and EORTC QLQ-CIPN20 outcomes). Randomization is stratified by treatment with prior PI therapies, number of prior anti-MM regimens (1 vs > 1), and Revised International Staging System (R-ISS; Stage III vs I or II). Following confirmation of progressive disease, pts on Vd could cross over to either: 1) SVd for pts able to tolerate continued bortezomib or 2) selinexor and dexamethasone for pts with bortezomib intolerance. Results:402 pts were enrolled; 195 and 207 to SVd and Vd, respectively. Median age was 67 (range: 38-90). Most (59.6%) pts were > 65 years and 57.1% were male. R-ISS stage at the time of MM diagnosis was III for 18.5% of pts. Baseline characteristics were balanced across the 2 arms. SVd significantly prolonged PFS vs Vd (median 13.93 vs 9.46 months, HR = 0.70, P = 0.0066). SVd was associated with a significantly higher ORR (76.4% vs 62.3%, P = 0.0012). Median OS was not reached on SVd vs 25 months on Vd (P = 0.28). Most frequent treatment-related adverse events (grade ≥3) for SVd vs Vd were thrombocytopenia (35.9% vs 15.2%), fatigue (11.3% vs 0.5%) and nausea (7.7% vs 0%). Clinically important differences were reported on the motor, autonomic and sensory scales on CIPN20. PN rates (grade ≥2) were significantly lower with SVd vs Vd (21.0% vs 34.3%, P = 0.0013). Conclusions: BOSTON is the first phase 3 study to evaluate the clinical benefit of SVd for relapsed/refractory MM. The study met the primary endpoint: once weekly SVd significantly improved PFS and ORR compared to twice weekly Vd. Rates of PN were significantly reduced with numerically fewer deaths on SVd vs Vd. Full dataset will be presented at the meeting. Clinical trial information: NCT03110562 .

Introduction Selinexor is a first-in-class, oral, potent selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, leading to cancer cell apoptosis. Selinexor has demonstrated antimyeloma activity in triple class refractory multiple myeloma (MM) [Chari et al. NEJM 2019]. Selinexor synergizes with proteasome inhibitors (PIs) in PI-sensitive and -resistant cell lines and produces high response rates in patients with PI refractory and non-refractory MM. (Bahlis et al. Blood 2018). In the phase 3 BOSTON study, the combination of once weekly (QW) selinexor, QW bortezomib and dexamethasone (SVd) in patients who had received 1-3 prior therapies led to a significantly (47%) longer median progression-free survival (PFS) of 13.93 versus 9.46 months (HR 0.70; P=0.0075) compared to standard twice weekly bortezomib and dexamethasone (Vd). In addition, SVd regimen produced higher response rates and deeper responses (ORR: 76.4% vs 62.3% and ≥CR 16.9% vs 10.2%) compared with Vd. The benefit with SVd was observed across all efficacy endpoints and was associated with lower incidence and severity of bortezomib-induced peripheral neuropathy. Here we present subgroup analyses according to number of prior lines of therapy and prior treatment with lenalidomide (LEN). Methods BOSTON is an open-label, randomized phase 3 study in patients with MM comparing SVd (QW selinexor 100 mg, QW subcutaneous bortezomib 1.3 mg/m2, and 20 mg twice weekly [BIW] dexamethasone), versus Vd (1.3 mg/m2 bortezomib BIW and dexamethasone 20 mg 4 x weekly [QIW]). Patients previously treated with a PI must have had at least a partial response (PR) to the PI and 6 months since the last PI regimen. The study primary end point was PFS. Results Of the 402 patients in the BOSTON study, 198 (49%) had 1 prior line versus 204 (51%) with 2-3 prior lines. In addition, 154 (38%) comprised the LEN treated subgroup, versus 248 (62%) in the LEN naïve subgroup. Of note, 41% patients received prior thalidomide, which is consistent with most of the BOSTON study patients being treated in the EU. Baseline demographic and disease characteristics were well balanced between treatment arms across subgroups. A very good partial response (VGPR) or better to most recent prior line anti-MM therapy was more frequent in patients with 1 prior line of therapy (63% vs 41%) versus those with 2-3 prior lines of therapy. Patients with prior LEN therapy were more likely to have had 2-3 prior therapies (72.1%) compared with LEN naive patients (37.5%). As shown in the table, SVd was associated with longer PFS compared with Vd in all subgroups. Overall response rates (ORR) and times-to-next-treatment (TTNT) were statistically greater with SVd compared with Vd in all subgroups. Rates of very good partial response or better (VGPR) were statistically greater for SVd vs Vd in the LEN-naïve group and 1 prior treatment group. Grade ≥2 peripheral neuropathy (a key secondary endpoint prespecified in the study) occurred less frequently across all SVd subgroups compared with Vd: LEN treated (21% SVd, 37% Vd, P=0.0166); LEN-naïve (21% SVd, 33% Vd, P=0.0252), 1 prior line (21% SVd, 33% Vd, P=0.0501); 2-3 prior lines (21% SVd, 36% Vd, P=0.0107). Adverse events of ≥grade 3 were more commonly reported in the SVd treatment arm than in the Vd arm, LEN treated (83% SVd, 57% Vd), LEN-naïve (76% SVd, 55% Vd), 1 prior line (77% SVd, 56% Vd), 2-3 prior lines (81% SVd, 56% Vd), and were mostly managed with dose modification and/or supportive treatment. Pneumonia occurred at comparable rates between treatment arms. There were no differences between subgroups in grade 3 adverse events. Conclusions In the BOSTON study, once-weekly SVd significantly improved PFS, ORR, TTNT and reduced rates of ≥grade 2 peripheral neuropathy compared with Vd regardless of number of prior treatments or whether patients were previously treated with LEN. Adverse events were managed with dose modification and treatment-related discontinuation rates did not differ between the 2 regimens for any subgroup. The PFS of 16.6 months with SVd after 1 prior therapy, and the HR of 0.63 in patients with prior LEN treatment support the use of once-weekly SVd for the second line treatment of MM following a LEN-containing regimen. Table Disclosures Mateos: Takeda: Honoraria; Abbvie: Honoraria; GlaxoSmithKline: Honoraria; EDO Mundipharma: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Jagannath:Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria. Delimpasi:GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Kryachok:Takeda, Janssen, Novartis, Roche, MSD, Bayer: Consultancy, Research Funding; Janssen, Bayer, Karyopharm, MSD, Acerta, AvbbVie, Debiopharm: Research Funding; Takeda, MSD, AbbVie, Ro: Other: Travel, accommodations, expenses; Takeda, Janssen: Consultancy. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Auner:Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Leleu:BMS-celgene: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria. Sinha:Dr Reddys Lab, Intas Pharmaceuticals, Karyopharm Therapeutics: Honoraria. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Quach:Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Moreau:Novartis: Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Levy:Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment; Takeda: Consultancy, Honoraria, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Anderson:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Bahlis:Genentech: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Chai:Karyopharm Therapeutics Inc: Current Employment. Arazy:Karyopharm Therapeutics Inc.: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Background: MGD013 is an investigational, first-in-class, Fc-bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells (1). MGD013 demonstrates in vitro ligand blocking properties and improved T-cell responses beyond that observed with anti-PD-1 and anti-LAG-3 benchmark antibodies alone or in combination. PD-1 targeted therapy with nivolumab in patients (pts) with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) has yielded modest efficacy (2). LAG-3, highly expressed in DLBCL (3), has emerged as another therapeutic target of interest in this population with continued unmet need. Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose, PK/PD, and antitumor activity of MGD013 in pts with advanced solid and hematologic malignancies. R/R DLBCL pts are being treated at the recommended Phase 2 dose of 600 mg every two weeks in Cohort Expansion. Results: At data-cutoff, 17 DLBCL pts received MGD013 (2.5 median prior lines of therapy, 41.2% with prior CAR-T therapy). Treatment-related adverse events (TRAEs) occurred in 11/17 (64.7%) pts, with no same TRAE occurring in > 1 patient except pyrexia (n=3). One grade ≥ 3 TRAE occurred (pneumonia), and no events of tumor lysis syndrome were observed. Among 11 response-evaluable pts (i.e. received at least one on-treatment scan), 1 complete response (CR) and 3 partial responses (PRs) per the Lugano Classification were observed. Analyses of available pre-treatment tumor biopsy samples corresponding to responding pts demonstrated relatively high levels of LAG-3, PD-1, and PD-L1 by IHC. More comprehensive translational analyses were undertaken for the pt with CR, observed after a single MGD013 infusion in a 28-year-old male in relapse 6 months after CD19-directed CAR T-cell therapy. In contrast to a pre-CAR T biopsy specimen demonstrating no LAG-3 or PD-1 expression, IHC analysis of a lymph node specimen biopsied post-CAR T and prior to MGD013 treatment revealed high levels of both LAG-3 and PD-1 on both infiltrating T-cells and malignant B-cells. Consistent with CD19 CAR T resistance, no CD19 expression was evident. MHC class II and PD-L1 expression were observed, which when bound to LAG-3 and PD-1, respectively, form immune checkpoints that can decrease T cell function. Following MGD013 treatment, serum IFN-γ markedly increased to >140-fold above baseline. No significant changes were observed for IL-6 or IL-2. Expansion of circulating CD3+CD8+ and CD3+CD4-CD8- T-cell subsets and associated cytolytic markers (i.e., perforin, granzyme B) were observed following MGD013 treatment. The patient underwent allogeneic stem cell transplant (allo-SCT) and remains in remission 14 months post-MGD013 and 12 months post-allo-SCT. Further correlative biomarker analyses are underway in the ongoing clinical trial. Conclusion: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has preliminarily demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity in R/R DLBCL pts with and without prior treatment with CAR T. Biomarker analyses confirmed expression of both PD-1 and LAG-3 axes in responding pts with evidence of pharmacodynamic responses consistent with the ability of MGD013 to enhance T-cell function. References: 1. Luke JJ, Patel MR, Hamilton E, et al. A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms. J Clin Oncol 38: 2020 (suppl; abstr 3004). 2. Keane C, Law SC, Gould C, et al. LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood Adv. 2020;4(7):1367-1377. doi:10.1182/bloodadvances.2019001390 3. Ansell SM, Minnema MC, Johnson P, et al., Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. J Clin Oncol, 2019. 37(6): p. 481-489. Disclosures Wang: Verastem Oncology: Membership on an entity's Board of Directors or advisory committees; Curio Science: Honoraria; Putnam LLC: Honoraria. Asch:Astellas Pharma: Research Funding; Cartesian: Research Funding; Forty Seven: Research Funding; Juno: Research Funding; MacroGenics: Research Funding; MEI Pharma: Patents & Royalties: Provisional patent submitted (I), Research Funding. Hamad:Novartis: Honoraria; Abbvie: Honoraria. Weickhardt:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ulahannan:Merck Co. Inc: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics, Inc.: Research Funding; ArQule, Inc.: Research Funding; Evelo Biosciences, Inc.: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Klus Pharma, Inc.: Research Funding; Isofol: Research Funding; GlaxoSmithKline GSK: Research Funding; Mersana Therapeutics: Research Funding; Macrogenics: Research Funding; Celgene Corporation: Research Funding; Boehringer Ingelheim: Research Funding; Array: Membership on an entity's Board of Directors or advisory committees; Ciclomed LLC: Research Funding; AbbVie, Inc.: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Exelxis: Membership on an entity's Board of Directors or advisory committees. Koucheki:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sun:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Li:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Chen:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Moore:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumrow:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company.