Citations

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract INTRODUCTION POEMS syndrome is a paraneoplastic disorder that results in multi-organ disease, and Vascular endothelial growth factor (VEGF) is associated with disease activity. There is evidence that the cytokine Interleukin- 6 (IL-6) stimulates VEGF production in several cancer cell lines. It has also been suggested that patients with POEMS syndrome experience symptoms improvement when IL-6 levels are low. Our study aims to understand the role of IL-6 and whether it is a contributor to disease activity in POEMS syndrome. METHODS We conducted a retrospective study of patients (pts) seen at Mayo Clinic within 1 year of diagnosis for POEMS syndrome with an IL-6 level within 3 months of diagnosis between 01/01/2011-05/31/2021 were included. Our database comprised 358 pts,7 were excluded because did not have official diagnosis of POEMS syndrome. Two hundred and ninety-nine pts did not have IL-6 testing within 90 days of diagnosis and were excluded. Clinical data was abstracted from our electronic medical record. Descriptive statistics were used for IL-6 levels. The majority of IL-6 laboratory testing for pts utilized the same reference range. A minority of pts had alternate reference ranges; thus, all IL-6 values and reference ranges were fold-corrected to have a unified reference to determine elevation in IL-6. High IL-6 was considered any value above the normal range, also analyzed pts in quartiles and deciles. Hematologic, VEGF and PET response criteria were utilized to group pts into responders or non-responders. Time to progression (TTP) and overall survival (OS) was calculated using the Kaplan Meier method. Differences between curves were by log rank. Statistical analysis was conducted via JMP software package (SAS, Cary, NC, USA). Univariate analysis was done to determine the prognostic value of IL-6. Statistical significance is considered with p-values <0.05. RESULTS 52 patients from among 352 met criteria and were included for analysis. Twenty-one patients (40%) had elevated IL-6 levels (IQR 5.67, 22.6) at the time of diagnosis. The fold elevation about normal was typically not very high, with a median of 3.1-fold elevation (IQR 1.3, 4.4; and range 1.0, 8.3). The percentage of males in the high IL-6 versus the normal Il-6 group were 90% versus 65%, p=0.03. Compared to normal IL-6, those with elevated IL-6 values had more instances of hepatomegaly (43% vs 16%, p=0.03), ascites (28% vs 6%, p=0 .04), abnormal DLCO (26% vs 3%, p=0.03), mixed bone lesions (57% vs 29%, p= 0.04), and lower serum albumin (range 2.3-3.5 vs 2.5-4.5 g/dL, p=0.0008).There was a trend for lower VEGF values among the high IL-6 group, but this did not meet statistical significance (median 250 vs 438 pg/mL). There was no significant difference in the time to progression between pts with high versus normal IL-6 levels (HR 1.36; p=0.456). Overall survival was significantly longer in pts with normal IL-6 compared to pts with high IL-6 levels (Median OS 67.4 vs 47.8 months, p=0.02). Forty-two pts were evaluated for VEGF response after treatment; there was a significant improvement in time to progression (85.5 vs 14.9 months, p=0.03) in pts who were VEGF responders. Among pts evaluable for a hematologic response (n=15), time to progression in pts with baseline high IL6 was longer in hematologic responders compared to non-responders (p=0.02). Conclusion Although OS was longer for pts with normal IL-6, elevated IL-6 at the time of diagnosis does not prevent pts from achieving disease remission. The study demonstrates that response to treatment rather than interleukin-6 levels in pts with POEMS syndrome is more prognostic. This study is an important initial step into understanding the utility of IL-6 in POEMS syndrome. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Kumar: Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dingli: GSK: Consultancy; Novartis: Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Apellis: Consultancy; Alexion: Consultancy. Lin: Janssen: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy; Legend: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy; Gamida Cell: Consultancy; Takeda: Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.

Abstract Introduction: Smoldering multiple myeloma (SMM) prognostication models routinely used in clinical practice were developed for use at diagnosis. However, retrospective studies have shown that in SMM patients the risk of progression to multiple myeloma (MM) decreases over time. Therefore, this study assessed whether the Mayo 2018 and IMWG 2020 scores could be used dynamically to risk stratify patients post-diagnosis, and whether they could identify SMM patients with evolving disease. Methods: We retrospectively studied 704 SMM patients diagnosed between January 2000 to January 2020. Patients with a baseline FLCr ≥100 and involved FLC ≥10 mg/dL or baseline bone marrow plasma cells ≥60% were excluded. We collected serial laboratory data and available pathology data and re-applied the Mayo 2018 and IMWG 2020 SMM risk stratification models at annual landmark timepoints up to 5 years post SMM diagnosis. Survival analyses were performed using the Kaplan-Meier method. Time to progression (TTP) was defined as time from diagnosis or landmark timepoint to treatment initiation for MM or systemic AL amyloidosis. Cox proportional hazards models were used to estimate hazard ratios. A two-sided p-value <0.05 was considered statistically significant. Results: At SMM diagnosis, 271 (38%) patients were low risk, 228 (32%) were intermediate risk, and 205 (29%) were high risk per the Mayo 2018 score. Applying the IMWG 2020 score at diagnosis, 90 (34%) of patients were low risk, 111 (42%) were low-intermediate risk, 54 (21%) were intermediate risk, and 9 (3%) were high risk. The Mayo 2018 and IMWG 2020 risk scores was re-assessed annually post-diagnosis in patients without progression (respective sample sizes: n=430 and n=197 at year 1 landmark, n=326 and n=143 at year 2 landmark, n=260 and n=106 at year 3 landmark, n=203 and n=73 patients at year 4 landmark). The Mayo 2018 and IMWG 2020 models reliably stratified patients based on progression risk post diagnosis (as shown in Figure 1 and Figure 2, respectively). As shown in Figure 1, if only diagnostic values were used in risk categorization with the Mayo 2018 model, the TTP between risk categories became less distinct over time. However, when follow-up laboratory values were used to re-stratify patients, the TTP between risk categories was more consistent over time. The respective 2-year progression risk in Mayo 2018 high-risk versus IMWG 2020 intermediate-high risk patients was 51% versus 62% at the 1-year landmark, 60% versus 65% at the 2-year landmark, 47% versus 62% at the 3-year landmark, and 47% versus 45% at the 4-year landmark. To assess the prognostic significance of an increase in SMM risk category, we stratified patients based on whether the SMM risk category at follow-up had increased versus was stable or decreased compared to the baseline SMM risk stratification. We found that patients evolving to a risk category during follow up consistently had an increased risk of progression compared to patients with a stable/decreased risk categorization using both the Mayo 2018 (HR 3.34, 95% CI 2.04-5.48, p<0.001 at 2-year landmark; HR 3.41, 95% CI 2.05-5.68, p<0.001 at 3-year landmark; HR 2.69, 95% CI 1.34-5.38, p=0.005 at 4-year landmark) and IMWG 2020 (HR 2.32, 95% CI 1.42-3.77, p<0.001 at 1-year landmark; HR 3.10, 95% CI 1.69-5.70, p<0.001 at 2-year landmark; HR 2.50, 95% CI 1.30-4.78, p=0.004 at 3-year landmark; HR 2.26, 95% CI 0.91-5.60, p=0.072 at 4-year landmark) risk models. However, patients categorized as Mayo 2018 high-risk at follow-up had a similar risk of progression regardless of whether the baseline risk categorization was low-intermediate versus high-risk (HR 0.87, 95% CI 0.51-1.48, p=0.606 at 2-year landmark; HR 1.01, 95% CI 0.59-1.73, p=0.972 at 3-year landmark; HR 0.75, 95% CI 0.34-1.65, p=0.467 at 4-year landmark). Conclusions: Our findings support the use of the Mayo 2018 and IMWG 2020 scores post-diagnosis. We showed that patients migrating to a higher risk category have an increased risk of progression. This suggests that if patients evolve to a high-risk score during follow-up, they should be considered for an early intervention treatment approach. Figure 1 Figure 1. Disclosures Kapoor: Sanofi: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Karyopharm: Consultancy; Cellectar: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy. Gertz: Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Janssen: Consultancy; Sanofi: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy; GSK: Consultancy. Kumar: Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract Background Multiple Myeloma (MM) remains incurable with current approaches and eventually relapses in nearly all patients. At relapse, patients may present with increasing serum and/or urine monoclonal (M) protein or with clinical features suggestive of progression. The outcomes of different progression patterns need to be better understood to provide insight about the optimal time to intervene with salvage therapy. This study aimed to describe the prevalence and outcome of biochemical (BP) versus clinical progression (CP) in a real-world setting. Methods We retrospectively assessed 1347 relapsed MM patients seen at Mayo Clinic between February 2001 and December 2018. CP was defined as per IMWG criteria (increase ≥50% in size or new plasmacytomas/bone lesions, hypercalcemia ≥11.5 mg/dl, decrease in hemoglobin ≥2 g/dl or to ≤10 g/dl, rise in serum creatinine ≥2g/dl, hyperviscosity), while BP was defined as increase in serum or urine M protein leading to initiation of a new line of therapy without meeting criteria for CP. Aggressive relapse was defined as new extramedullary disease (EMD), plasma cell leukemia or hyperviscosity requiring plasmapheresis. The overall survival (OS) was defined as the time from 1 st relapse to last follow-up or death. Time to next treatment (TTNT) was defined as the time between initiation of 2 nd and 3 rd line therapy. Results Prevalence of different patterns of relapse is presented in Table 1. The majority of progressions were BP (60.4%); among the CP (39.6%), the most common presentation was a new bone lesion. Similar proportions of BP and CP patients were diagnosed before 2013 (70% and 73%; p=0.2). The median time from diagnosis to 1 st relapse was 22.8 months (range, 0.4-154.7) and was shorter in the CP group in comparison to BP (20.8 [range, 1.0-152.1] vs 23.7 [range, 0.4-154.7] months, p=0.001). With the exception of ISS stage, patients in the CP group had higher risk features at MM diagnosis including: high-risk (HR) FISH ([4;14], t[14;16], t[14;20], deletion 17p or p53 mutation; 29% vs 20%, p=0.01); elevated LDH (23% vs 17%, p=0.03); and EMD (19% vs 10%, p<0.001). CP patients more often had non-secretory disease at baseline (6% vs 2%, p<0.001). At 1 st line, patients with eventual CP were less likely to have received novel agents (78% vs 85%, p<0.001), upfront autologous stem cell transplantation (ASCT, 43% vs 51%, p=0.004), and lenalidomide-based maintenance (11% vs 16%, p=0.01). While patients in the CP group were less likely to have achieved very good partial remission (VGPR) or better to the 1 st line therapy (53% vs 60%, p=0.01), the percentage of patients who achieved CR was similar between the groups (22% vs 24%, p=0.4). Relapse while on primary treatment/maintenance was more prevalent in the CP (46% vs 40%, p=0.04). On multivariable logistic regression model male sex, plasma cell labeling index (PCLI) ≥2% and EMD at diagnosis were associated with higher risk of CP, whereas achieving VGPR or better after 1 st line treatment was associated with decreased risk of CP. Patients with CP had shorter median TTNT from 2 nd line therapy compared to BP (9.6 vs 17.0 months, p<0.001) as well as shorter median OS from 1 st relapse (26.2 vs 59.4 months, p<0.001; Figure 1). Amongst patients with CP, those presenting with typical "aggressive" versus "CRAB" features at relapse had a significantly shorter median TTNT (6.0 vs 11.0 months, p<0.001) and OS (17.2 vs 28.1 months, p<0.001). Using a multivariable Cox proportional hazard model, CP (vs BP) was a predictor of shorter TTNT from 2 nd line therapy (HR 1.40, 95% CI 1.20-1.62, p<0.001), along with ISS stage III, HR FISH at diagnosis and relapse while on primary treatment/maintenance, whereas the use of upfront ASCT was a predictor of longer TTNT from 2 nd line therapy. CP was also a predictor of shorter OS from 1 st relapse (HR 1.53, 95% CI 1.29-1.81, p<0.001) along with age >65 years, male sex, ISS stage III, HR FISH at diagnosis, EMD at diagnosis and relapse while on primary treatment/maintenance. Conclusions Patients with clinical features at relapse have a worse prognosis after 1 st relapse than patients who relapsed solely biochemically. Approximately half of CP presented while on active treatment, which suggests that even patients monitored closely may develop CRAB features at relapse. Factors that help predict the occurrence of CP include male sex, PCLI ≥2% and EMD at diagnosis. Patients with deeper response to 1 st line treatment are less likely to develop CP. Figure 1 Figure 1. Disclosures Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Pfizer: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Alnylam: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Dingli: Apellis: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Janssen: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Sanofi: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Carsgen: Research Funding; Oncopeptides: Consultancy; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding.

Abstract Background Multiple myeloma (MM) is an incurable disease, and its prognosis is largely influenced by clinicopathological features, response to therapy, and relapse characteristics. Despite novel agents and the attempts to individualize treatment strategies based on baseline risk stratification, significant variations in progression-free survivals (PFS) and overall survivals (OS) are observed between patients. We examined the outcomes of MM patients stratified according to timing of first relapse into early (<2 years) and late (>5 years). Methods We retrospectively assessed 1441 MM patients seen at Mayo Clinic between 2003 and 2018. Patients were 18 years or older and had at least one disease relapse that required an additional line of treatment. The study cohort was divided into three groups based on time of first relapse: early relapse (<2 years from diagnosis), relapse between 2 to 5 years from diagnosis, and late relapse (>5 years from diagnosis). The independent predictors of early/late relapse were identified using a forward stepwise multivariate logistic regression. Odds ratios in multivariate models were adjusted for age and sex. Results Early relapse has been recognized in 758 patients (52.6%), relapse between 2-5 years in 561 patients (38.9%), late relapse in 122 patients (8.5%). Six patients had a PFS >10 years. In comparison to patients with late relapse, patients with early relapse were older (median 63 vs 61 years, p=0.04), more frequently ISS stage III (40% vs 20%, p<0.001) had higher bone marrow plasma cell infiltration (median 60% vs 40%, p<0.001), and were more likely to have high-risk (HR) FISH (defined as translocation t[4;14], t[14;16], t[14;20], deletion 17p or p53 mutation; 28% vs 11%, p<0.001). At diagnosis, early relapse group more often presented with anemia (35% vs 21%, p=0.004), hypercalcemia (15% vs 5%, p<0.001), renal insufficiency (19% vs 5%, p<0.001) and higher serum beta-2-microglobulin (median 4.4 vs 3.4 mg/l, p<0.001). In terms of first line treatment, novel agents use was higher in early relapse group in comparison to late relapse group (82% vs 72%, p=0.007). Early relapse patients more often received PI-based therapy (30% vs 10%, p<0.001) or PI+IMID-based therapy (22% vs 12%, p=0.01), whereas late relapse patients received more often IMID-based therapy (63% vs 37%, p<0.001). No differences in the maintenance therapy were observed. Early relapse patients were less frequently treated with upfront autologous stem cell transplantation (ASCT, 35% vs 60%, p<0.001). Progression on active treatment/maintenance was observed more often in the early relapse group (55% vs 18%, p<0.001). On multivariable logistic regression model early relapse (vs all remaining patients) was predicted by HR cytogenetic features (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.71-5.46, p<0.001), non-IgG isotype disease (OR 2.17, 95% CI 1.33-3.54, p=0.02), a non-ASCT pathway (OR 2.78, 95% CI 1.71-4.52, p<0.01), and by achieving less than a very good partial remission (VGPR; OR 3.23, 95% CI 1.96-5.35, p<0.01). The only factor associated with decreased chances of late relapse (vs all remaining patients) on multivariate logistic regression model was the presence of HR FISH features (OR 0.18, 95% CI 0.04-0.82, p=0.03). Median PFS from first relapse for the whole population was 13.9 months (95% CI 12.9-15.1), median OS from first relapse - 44.6 months (95% CI 41.7-183.0). Early relapse group exhibited worse median PFS and OS from first relapse (median PFS 9.1 months; median OS 26.6 months) than patients who relapsed 2-5 years after diagnosis (median PFS 18.5 months; OS 71.9 months), or late relapse group (median PFS 31.6 months; median OS 87.8 months; p<0.001) (Figure 1). Conclusions Early relapse (<2 years) is an indicator for shorter duration of response to subsequent treatments, and worse OS. Treatment with upfront ASCT and achieving VGPR or better after first line therapy lower the risk of early relapse. The only parameter that is predictive for both early and late relapse is HR FISH features. Although factors that predict worse survival in MM are well defined, further studies are needed to identify predictors of a more indolent disease course so that future therapeutic approaches can be tailored to each individual. Figure 1 Figure 1. Disclosures Kapoor: AbbVie: Research Funding; Glaxo SmithKline: Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Dingli: Alexion: Consultancy; Janssen: Consultancy; Novartis: Research Funding; GSK: Consultancy; Sanofi: Consultancy; Apellis: Consultancy. Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Tenebio: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Antengene: Consultancy, Honoraria; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract Background: Despite many treatment options, multiple myeloma (MM) remains largely incurable with poor outcomes among patients who progress after treatment with a protease inhibitor, immunomodulatory imide drugs (IMiDs), and/or an anti-CD38 antibody. Multiple targeted therapies have been developed for different subtypes of non-Hodgkin lymphoma (NHL); however, these therapies are typically not curative for patients with relapsed/refractory (R/R) disease. IMiDs are a standard of care for treatment of MM and have shown activity in some NHL subtypes. However, given that many patients treated with these agents frequently develop disease progression, an unmet need remains. CFT7455 is a next-generation IKZF1/3 degrader, which is more potent and catalytically active than other approved agents targeting the cereblon E3 ligase complex that degrade IKZF1/3. CFT7455 is orally bioavailable and selective for IKZF1 (Ikaros) and IKZF3 (Aiolos). Depletion of these targets from malignant B cells result in tumor cell death, and depletion from the tumor microenvironment results in T-cell activation. In i n vitro and in vivo models of MM and NHL, including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma (MCL), CFT7455 demonstrated greater activity than other agents in similar classes. These results provided rationale for a first-in-human, phase 1 study to evaluate CFT7455. Study Design: This is an open-label, multicenter, phase 1 clinical trial with dose escalation and dose expansion phases. The dose escalation phase, beginning with a starting dose of 50 mcg daily, may include single-participant cohorts at initial dose levels, after which 3-6 patients are enrolled per cohort using a Bayesian logistic regression model. After initial exploration of single-agent CFT7455 in a mixed cohort of patients with R/R MM or select NHLs, dose escalation is split to perform dose determination in R/R MM separate NHL. Once a safe dose of CFT7455 in R/R MM is determined, the combination of CFT7455 with dexamethasone will be explored in R/R MM. CFT7455 is dosed orally in 28-day cycles, on a 21-day on, 7-day off schedule, until disease progression or intolerable toxicity. Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned. Primary objectives include: safety and tolerability, randomized phase 2 dose (RP2D)/maximum tolerated dose (MTD) of CFT7455, and estimation of antitumor activity of CFT7455. Secondary objectives include assessment of pharmacokinetics. Exploratory objectives include characterization of target engagement and IKZF1/3 degradation and assessing the immunomodulatory effects of CFT7455. For MM patients, key inclusion criteria include histologically/cytologically-confirmed MM that is R/R. Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Plasma cell leukemia is excluded. For NHL patients, key inclusion criteria include histologically/cytologically-confirmed NHL that is R/R. Patients mustn't be candidates for regimens known to provide clinical benefit, defined as the requisite prior lines of therapy according to an indication-specific basis. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Several lymphoma subtypes less likely to benefit are excluded (eg, Richter transformation, Burkitt lymphoma, Sezary syndrome, and lymphoblastic lymphoma). Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726, enrollment is ongoing. Disclosures Berdeja: Legend Biotech: Consultancy; Incyte: Research Funding; Ichnos Sciences: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Lilly: Research Funding; SecuraBio: Consultancy; EMD Serono: Research Funding; Janssen: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Astex Pharmaceuticals: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Takeda: Consultancy. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Xencor: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy; Medimmune: Research Funding. Horwitz: Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Tubulis: Consultancy; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Vividion Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Celgene: Research Funding; Acrotech Biopharma: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Shoreline Biosciences, Inc.: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Verastem: Research Funding. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Martin: GlaxoSmithKline: Consultancy; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; Janssen: Research Funding. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Richard: Karyopharm, Janssen: Honoraria. Bhutani: Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Yee: Takeda: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Palmer: C4 Therapeutics: Current Employment. Gorman: C4 Therapeutics: Current Employment. Schoenborn-Kellenberger: C4 Therapeutics: Current Employment. Bilic: C4 Therapeutics: Current Employment. Crystal: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mahler: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lonial: Merck: Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding.

Abstract Background: Treatment for multiple myeloma (MM) patients refractory to proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies remains an unmet need. Belantamab mafodotin is a first in class antibody drug conjugates (ADCs) in MM utilizing a humanized monoclonal antibody targeting B cell maturation antigen (BCMA) conjugated to a microtubule-disrupting monomethyl auristatin F. The efficacy of belantamab in relapsed refractory MM (RRMM) patients has been reported in several randomized clinical trials. However, clinical trials have restricted patients' eligibilty. We report the "real world" efficacy and safety of belanatmab in patients treated at all three Mayo Clinic sites. Methods: We retrospectively reviewed all consecutive MM patients that received at least one dose of belantamab outside a clinical trial. The primary endpoints were PFS and OS, and the secondary endpoints included overall response rates (ORR) and safety. Results: Thirty-seven RRMM patients were treated with belantamab between September 2020 and June 2021. The median age at diagnosis was 61 (range 37-83) and 64% were male. The median age at belantamab administration was 67 (IQR 59-74) and 14 patients (38%) were 70 years or older. Fifteen of 34 patients (44%) had high-risk FISH and 13 patients of 33 (39%) had ISS 3. Two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three received full dose belantmab (2.5 mg/kg). The median time from diagnosis to belantamab initiation was 7 years (IQR 4-11), and the median prior lines of therapy was 8 (IQR 7-11). Twenty-seven patients (73%) underwent an autologous stem cell transplantation prior to belantamab therapy, and all patients were penta refractory (IMiD, PI, and anti CD38). Seven patients (19%) received CAR-T therapy prior to belantamab. The median number of belantamab doses administered was 3 (range 1-6). Thirty-one (84%) received belantamab monotherapy and 6 patients (16%) received belantamab in combination [pomalidomide (n=3), cyclophosphamide (n=2), or thalidomide (n=1)]. The overall response (ORR) rate to belantamab was 33% (out of 36 evaluable patients). Two patients (6%) achieved complete response (CR), 3 patients (8%) achieved very good partial response (VGPR), and 7 patients (19%) achieved partial response (PR). At data cutoff 20 patients (54%) are alive. Seventeen patients died of MM complications. The median follow-up was 6 months (IQR 3.5-7). The median PFS and OS for the whole cohort was 2 months (95% CI 1-3) and 7 months (95% CI 3--NR), respectively. Two patients died within the first cycle of belantamab (due to PD), and overall, 12 died within 100 days of belantamab therapy, all due to disease progression. Eleven patients (30%) were hospitalized during belantamab therapy. The reasons for hospitalization were related to MM in 4 patients (one patient with malignant ascites, one with hypercalcemia, 2 patients for pain management). Three patients were hospitalized due to thrombocytopenia (related to disease), and one due to an infusion-related reaction (IRR). Other reasons for hospitalization were infection (soft tissue abscess, n=1), proctitis (n=1) and tumor lysis (n=1). Keratopathy developed in 16 patients (43%). Keratopathy was grade 1 in 6 patients, grade 2 in 7 patients, and grade 3 in 3 patients. Only one patient had corneal erosions and 6 patients reported decreased visual acuity, (1 grade 3 keratopathy, 4 had grade 2 keratopathy, and 1 had grade 1 keratopathy). Two patients had IRR. Two patients reported gaining 3.5 kg each after therapy with belantamab was discontinued. Conclusions: The response rates are similar to those reported in randomized clinical trials. The role of belantamab in the era of other BCMA directed therapy (CAR-T, BiTEs) remains unclear. Disclosures Dispenzieri: Janssen: Consultancy, Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Alnylam: Research Funding; Takeda: Research Funding. Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dingli: Novartis: Research Funding; GSK: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Alexion: Consultancy; Apellis: Consultancy. Kapoor: Cellectar: Consultancy; BeiGene: Consultancy; Sanofi: Consultancy; Ichnos Sciences: Research Funding; Karyopharm: Consultancy; Amgen: Research Funding; Pharmacyclics: Consultancy; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option.

Abstract Background Recommendations for 2 nd line treatment for relapsed multiple myeloma (MM) patients have been changing over the past two decades, given the introduction of novel agents, different side-effect profiles, and attempts at more individualized treatment approaches. We designed this study to characterize how 2 nd line treatment strategies have evolved over the last two decades for MM patients. Methods Patients with MM with at least one relapse treated with a 2 nd line regimen, seen at Mayo Clinic between 2003-2021, were included. To visualize trends in treatment choices we divided the study period into 2-year intervals and for descriptive purpose the period was divided into three 6-year intervals. We used "100% stacked area" charts to show how the constituent parts of the whole have changed over time. The height of each colored stack represents the proportion of patients in that category at a given point in time. Results A total of 1439 patients were included. Patients were diagnosed between 2001 and 2018, the initiation of 2 nd line treatment occurred between June 2003 and February 2021. Median age at diagnosis was 62.7 years (interquartile range, 55.8-69.3), 60.0% were male. International Staging System stage I was present in 23.5% of patients, stage II in 32.9% and stage III in 28.8%. In the 1 st line therapy novel agents were used in 82.8% of cases, regimens based on proteasome inhibitors (PI) in 26.5%, immunomodulatory drugs (IMID) in 42.0% and combination of PI+IMID in 21.1%. Upfront autologous stem cell transplantation (ASCT) was performed in 50.1% of patients, and maintenance after 1 st line was used in 25.2%. For 2 nd line treatment, during 2003-2008 the majority were treated with doublets (70.5%), followed by triplets (14.8%) and salvage ASCT (7.7%) (Figure 1A). Patients were treated with IMID or PI-based therapy (50.7% and 21.8%, respectively); only 3.7% received PI+IMID and 20.1% of patients received alkylating agents/anthracyclines. The most frequently used regimens were lenalidomide-dexamethasone (RD, 32.2%) and bortezomib-dexamethasone (VD, 18.1%, Figure 1B). Between 2009-2014, the use of triplets in 2 nd line increased (43.0%), although doublets were still more common (50.9%). Like previous years, IMID-based therapy was most frequently used (37.3%), however, the use of PI-based therapy increased (36.0%). PI+IMID-based therapy was implemented in 17.9% of patient, and 27.3% received alkylating agents/anthracyclines. Most frequently used regimens included: RD (29.4%), bortezomib-cyclophosphamide-dexamethasone (CYBORD, 17.4%), bortezomib-lenalidomide-dexamethasone (VRD, 13.4%) and VD (13.3%). Finally, during 2015-2021, triplets were most common (68.9%), followed by doublets (23.0%). IMID- and PI+IMID-based therapies were most often implemented (34.2% and 31.1%, respectively), followed by PI-based therapy (26.8%). 28.1% of patients received monoclonal antibodies; only 15.9% received alkylating agents/anthracyclines. Most frequently used regimens include RD (13.8%), carfilzomib-RD (11.6%), daratumumab-RD (9.8%), CYBORD (9.3%), VRD (8.8%), daratumumab-pomalidomide-dexamethasone (5.9%) and daratumumab-VD (5.2%). Median time to next treatment (TTNT) from 2 nd line therapy has improved over the course of the three time periods (p<0.01; Figure 1C): years 2003-2008, 10.4 months; years 2009-2014, 13.2 months; and years 2014-2021, 16.6 months. Similarly, the median overall survival from 1 st relapse has increased over the three intervals: 30.9 months, 48.4 months, and 65.8 months, respectively. Conclusions Over the past two decades, the effectiveness of 2 nd line treatment has improved, reflected by improved TTNT from 2 nd line therapy. With the introduction of new agents in 2012-2015 (carfilzomib, pomalidomide and daratumumab) and favorable results for triplets demonstrated in randomized trials, the triplet therapies started to be used more frequently. Over time, the landscape of 2 nd line therapies has become more diverse, which may reflect a more individualized approach to each patient. Moreover, the large variety of treatment strategies makes comparisons more and more challenging. Figure 1 Figure 1. Disclosures Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Sanofi: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Janssen: Consultancy; GSK: Consultancy. Kumar: Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Tenebio: Research Funding; Carsgen: Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy.

Abstract Introduction: Factors contributing to the antitumor activity of systemic oncolytic virotherapy (OV) include (i) generalized innate immune activation due to virus infusion; (ii) direct oncolytic and/or immune-mediated destruction of OV infected tumor cells due to intratumoral spread of the virus infection; (iii) collateral boosting of tumor antigen-specific T cell responses that target uninfected tumor cells. We investigated the relative contributions of these 3 factors T cell lymphoma (TCL) patients (pts) responding to a single intravenous infusion of Voyager-V1, an oncolytic vesicular stomatitis virus (VSV) encoding IFNβ and sodium iodide symporter (NIS) on NCT03017820. Of relevance, the virally encoded IFNβ enhances tumor specificity, boosts proinflammatory activity & serves as a convenient serum biomarker of infection. Methods: In a first in human trial, a single infusion of Voyager-V1 was administered to 15 pts with relapsed refractory hematologic cancers; 4 dose levels (DL) were tested (5x10 9, 1.7x10 10, 5x10 10, 1.7x10 11 TCID50); 7 pts had TCL. Cytokine levels and CRS symptoms were determined as a measure of generalized immune activation; serum IFNβ levels were monitored as a pharmacodynamic biomarker of virus infection; antitumor T cell responses were measured using ELISPOT assays. Results: Of 8 TCL pts, 3 had RECIST responses: PR at DL 2, a CR & PR at DL 4. Most pts experience short lived CRS typically resolving within 24 hours of virus infusion. Serum IFNβ levels increased post-therapy in all pts, typically peaking by 24 hours post virus infusion and returning to baseline by median day 10. T cell responses could not be accurately determined in most cases due to suboptimal T cell viability and/or function after thawing of frozen PBMC. Factors contributing to tumor regression in each of the responding pts appeared to differ significantly, as exemplified by the case reports below. Pt (I) with CTCL experienced grade 1 CRS followed by brisk regression of multiple cutaneous lesions. The PR lasted 3 mo, after relapse of an eye lesion, but responses at other sites deepened after the relapsed lesion was irradiated; pt remained off active therapy for the next 2 yrs. Peak serum IFNβ 4 hours post infusion was only 182 pg/ml suggesting that disease response may have been driven by nonspecific innate immune activation associated with the virus infusion. Pt (IV) (CD30+ PTCL/ cutaneous relapse) had short lived grade 2 CRS, then developed signs of IFNβ toxicity with AST elevation and thrombocytopenia. Oral ruxolitinib was administered for 5 days as IFNβ toxicity mitigation leading to normalization of AST and platelets. All PET-avid tumors regressed completely. This CR continues 16 months post virus infusion. Peak serum IFNβ was 18,213 pg/ml strongly suggesting that response was driven by extensive intratumoral amplification of the virus and oncolytic tumor destruction. Robust CTL responses to tumor neoantigens were detected in this pt at baseline indicating that collateral boosting of tumor-specific T cells may have been responsible for the long term maintenance of this CR Pt (V) (CD30+ PTCL) had short lived grade 2 CRS followed by response at all disease sites (including complete normalization of an enlarged FDG-avid spleen). Her PR ended after 6 months due to relapse in cervical lymph nodes. Peak serum IFNβ level was modest, 600 pg/ml & sustained over 48 hours suggesting slower intratumoral spread of the virus infection. The deepening of the response long after resolution of the oncolytic phase points strongly to a contribution from antitumor CTL but the assay was technically unsatisfactory in this pt. Conclusion: Analysis of the correlative data supports that intravenous Voyager-V1 therapy can recruit diverse antitumor effector mechanisms to impact tumor response in pts with heavily pretreated TCL. Importantly, intratumoral virus amplification, which results in high circulating concentrations of IFNβ, does not necessarily lead to tumor regression perhaps because of defective immune cell recruitment and/or activation in some tumors but not in others. This will be further evaluated in future study participants by performing CTL assays on fresh, rather than frozen PBMC. In conclusion, a single IV infusion of Voyager-V1 shows highly promising activity against treatment refractory TCL and should be further advanced as a new single-shot or combination therapy for this therapeutically challenging indication. Figure 1 Figure 1. Disclosures Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Paludo: Karyopharm: Research Funding. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Gertz: Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy. Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Roche-Genentech: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Bergsagel: Oncopeptides: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Janssen: Consultancy, Honoraria. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Lin: Sorrento: Consultancy; Vineti: Consultancy; Legend: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Merck: Research Funding; Juno: Consultancy; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding. OffLabel Disclosure: VSV-IFNβ-NIS is an oncolytic virus in clinical trial for systemic administration in hematologic malignancies

Abstract INTRODUCTION Sparse data exist regarding I+V in an off-trial setting, particularly in patients (pts) with progression of disease on either I or V as single agent treatment. The 1-year overall survival (OS) rates with V monotherapy following I range from 75%-91% (Eyre et al, BJH 2019; Jones et al, Lancet Oncol 2018); however, longer-term follow-up of these or other patient cohorts treated with V after I has not yet been reported. Effective options in double-refractory pts are lacking when a clinical trial is not feasible. Here, we report our experience with I+V in these patient groups. METHODS After IRB approval, we reviewed the records of pts seen at Mayo Clinic (between 4/2012-1/2021) who received I+V therapy off-trial for CLL progression. Pts treated with I+V for Richter's transformation were excluded. Time to next treatment (TTNT) was measured from I+V treatment start date to the date of next treatment start or last known treatment status with death as a competing risk. OS was measured from I+V start date until date of death or when the patient was last known alive; OS was analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS Thirty-three pts with progressive CLL were treated with I+V (median duration 13.3 months [95% CI: 7.1 months-not estimable (NE)]). The median age was 70 years (range 47-86), 6 (18%) were women, and 20 (65%) had del(17p) or TP53 mutation. The median number of prior lines of therapy was 3 (range 1-15). Additional characteristics at the time of I+V start are shown in Table 1. Median follow-up from start of I+V was 23.8 months. Among 22 pts with prior progression on I only (V-naïve), the median duration of I+V was 14.8 months (95% CI 7.6 months-NE). The median duration on either I or V from the start of combination was 20.3 months (95% CI 8.3 months-NE). The median TTNT was 25.1 months (Figure 1A). Four pts proceeded to cellular therapy (alloSCT [n=3], CAR-T [n=1]) while on I+V. Next therapy (n=9) consisted of Richter transformation treatment (n=2), chemotherapy plus continued I+V (n=1), anti-CD20 plus continued I+V (n=1), duvelisib + I (n=1), TP-0903 + I (n=1), reintroduction of I at disease progression after previously stopping I during I+V therapy (n=1), and reintroduction of I (n=1) or V (n=1) at disease progression after previously stopping I+V. Of 9 pts who did not receive subsequent therapy, 4 pts remain on I+V (median duration 16.4 months), 4 pts continued V after discontinuing I (median duration on V from start of I+V was 21.5 months), and 1 pt discontinued I+V following a second cancer diagnosis and died without receiving additional CLL-directed treatment. Eleven pts received I+V in the double-refractory setting; 9 pts had prior disease progression on sequential I then V and 2 pts had prior disease progression on sequential V then I. The median duration of I+V was 7.5 months (95% CI 4.3 months-NE), and the median duration of either agent from I+V start was 10.8 months (95% CI 7.1 months-NE). The median TTNT was 14.0 months (Figure 1A). Eight pts required additional treatment, consisting of PI3K inhibitor (n=2), anti-CD20 added to I+V (n=1), CAR-T (n=1), anti-CD20 with (n=1) or without (n=1) bendamustine added to continued I, and Richter transformation treatment (n=2). One pt continues I+V (17.4 months ongoing) without further treatment. Two pts died from disease progression without receiving additional treatment. The median OS of all 33 pts was 27.4 months (95% CI 25.9 months-NE; Figure 1B). The median OS of the 22 pts with prior progression on I (V-naïve) was 47.1 months (95% CI 27.7 months-NE), and the median OS of the 11 pts with prior progression on I and V separately was 27.0 months (95% CI 15.5 months-NE). In univariate analyses, prior progression on V was a predictor of shorter OS (HR=3.9; 95% CI 1.4-11.2; p=0.01). CONCLUSIONS Combination I+V therapy in heavily pre-treated CLL pts who have disease progression after I provides durable benefit with a median OS approaching 4 years. In the double-refractory setting, repurposing both drugs as combination I+V therapy can be a useful strategy, despite the short-term disease control, for pts where clinical trial options are limited or not available. Further examination of these approaches in larger cohorts and understanding the operative resistance mechanisms in pts with double-refractory disease are key next studies. Figure 1 Figure 1. Disclosures Ding: Octapharma: Membership on an entity's Board of Directors or advisory committees; DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chanan-Khan: BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage: Research Funding; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BieGene, Jansen, Ascentage: Consultancy. Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Novartis: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees. Ailawadhi: Pharmacyclics: Consultancy, Research Funding; Xencor: Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Sanofi: Consultancy; BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Ascentage: Research Funding; Medimmune: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Research Funding; Beigene: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy. Koehler: AbbVie: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Kay: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Combination ibrutinib and venetoclax in patients with relapsed CLL.