Background: Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) pts, especially those who are not cured with CAR-T, have poor outcome. Targeted agents can disrupt key survival pathways in DLBCL, but rarely induce durable responses as monotherapy. We previously showed combination targeted therapy (ViPOR) is safe and able to induce durable remission in R/R non-GCB DLBCL and HGBCL-DH-BCL2 (Melani. NEJM. 2024). Furthermore, we observed synergistic cytotoxicity with MMAE, the chemotherapy payload of Polatuzumab (POLA), and the ViPOR agents in DLBCL cell lines (Staudt lab, unpublished). We also noted differential sensitivity to POLA in ABC vs GCB DLBCL secondary to CD79B glycosylation and expression (Corcoran. Cancer Discov. 2024). We hypothesized that adding POLA to ViPOR will further improve efficacy, especially in non-GCB DLBCL, and time-limited, cyclic dosing will limit toxicity. Methods: R/R DLBCL pts with adequate organ function are eligible. In Ph 1, a “3+3” design is used to determine the recommended phase 2 dose (RP2D) of POLA IV D2 and venetoclax (VEN) PO D2-14 at 3 dose levels (DLs) (DL1: 1.4 mg/kg + 600 mg, DL2: 1.8 mg/kg + 600 mg, and DL3: 1.8 mg/kg + 800 mg) with fixed-dose ibrutinib, prednisone, obinutuzumab, and lenalidomide as previously published. A Ph 2 expansion cohort, enriched for non-GCB DLBCL, is included at the RP2D. ViPOR-P q21d x 6C is given without maintenance or consolidation. All pts receive TLS, PCP, HSV, and G-CSF prophylaxis (ppx) with VTE ppx per PI discretion. Baseline CT, PET, BM, and tumor biopsy is performed with CT scans after C2, C4, and C6 and PET after C6. Surveillance CT is then performed q3m x 1y, q4m x 1y, q6m x 1y, then annually x 2y. Minimal residual disease (MRD) is assessed in plasma ctDNA using clonoSEQ at baseline, during treatment, and in f/u. Results: 32 DLBCL pts (15 in Ph 1 & 17 in Ph 2) have been enrolled. Median age is 55y (range, 23-83) with 72% male pts. 17 (53%) pts had non-GCB DLBCL, 11 (34%) HGBCL-DH-BCL2, 2 (6%) HGBCL-DH-BCL6, and 1 (3%) pt each with GCB DLBCL and THRLBCL. 7 (22%) pts had transformed lymphoma. Stage III/IV disease was noted in 84% and 56% of pts had an IPI score >3. Median prior therapies was 2 (range, 1-6), with prior CAR-T in 44% and 56% of pts refractory per SCHOLAR-1 criteria. One dose-limiting toxicity (DLT) of G4 thrombocytopenia >7d occurred at DL3 with no other DLTs observed, thus DL3 was identified as the RP2D. Hematologic AEs were most common and included G3-4 (% cycles) thrombocytopenia (27%), neutropenia (21%), and anemia (10%), with 2 events of febrile neutropenia among 126 total cycles. Non-hematologic AEs (% pts) of any grade included hypokalemia (94%), diarrhea (77%), nausea (48%), and elevated LFTs (48%), with the only G3-4 non-hematologic AE in >10% of pts being hypokalemia (26%). G1-2 neuropathy was seen in 9 (29%) pts with no G3-4 neuropathy observed. 1 TLS event occurred and resolved after temporary HD, and there was no treatment-related mortality. Dose reductions and delays occurred in 10% and 8% of cycles, respectively, and 3 pts prematurely stopped therapy due to toxicity or illness. In 28 evaluable DLBCL pts off-treatment, overall response rate was 75% (21/28) with 50% (14/28) complete responses (CR). CR rate was 63% (10/16) in non-GCB and 33% (4/12) in GCB DLBCL by IHC, with GCB CRs only seen in HGBCL-DH-BCL2 (36%, 4/11) and HGBCL-DH-BCL6 (100%, 2/2). By RNA-seq, CR rate was 86% (6/7) in ABC, 45% (5/11) in GCB, and 100% (1/1) in unclassified DLBCL. In refractory and post-CAR-T pts, CR rate was 38% (6/16) and 33% (4/12), respectively. With a median f/u of 22.6m, 57% of CRs are ongoing with a 2y (95% CI) progression-free survival (PFS) and overall survival of 36% (18-54) and 53% (32-71), respectively. 2y PFS was 45% in non-GCB and 25% in GCB DLBCL by IHC, and 71% in ABC and 27% in GCB DLBCL by RNA-seq. In post-CAR-T and refractory pts, 2y PFS was 27% and 22%, respectively. Conclusion: ViPOR-P is safe without notable additional toxicity, especially neutropenia and neuropathy, compared to ViPOR, and DL3 was identified as the RP2D. Most AEs were hematologic and manageable with G-CSF with rare febrile neutropenia observed. Fixed-duration ViPOR-P x 6C without maintenance resulted in durable CRs, especially in pts with non-GCB DLBCL by IHC and ABC DLBCL by RNA-seq, including refractory and post-CAR-T pts. Molecular and MRD analyses are ongoing, and enrollment continues to assess whether ViPOR-P improves CR rate compared to ViPOR alone in R/R non-GCB DLBCL.

Abstract Background: Relapsed/refractory (R/R) aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma double-hit (HGBCL-DH), and peripheral T-cell lymphoma (PTCL), have poor outcomes with standard therapy. VIP152 (enitociclib) leads to rapid depletion of short-lived mRNA transcripts such as MYC and MCL1 through CDK9 inhibition. Preclinical studies have identified BCL2 overexpression as a mechanism of resistance to CDK9 inhibition, and synergistic cytotoxicity has been shown with venetoclax (BCL2 inhibitor), steroids, and CDK9 inhibitors in DLBCL. Based on this preclinical data, we hypothesized that the combination of VIP152 with venetoclax and prednisone (VVIP) would result in acceptable safety and improved efficacy in R/R lymphoid malignancies. Methods: R/R non-GCB DLBCL, MYC-rearranged DLBCL/HGBCL-DH, and PTCL pts after 2 prior systemic therapies are eligible. In phase I, pts are treated at 4 dose levels (DL) of VIP152 and venetoclax in combination with fixed-dose prednisone to identify the recommended phase II dose (RP2D). VIP152 (15mg, 22.5mg, or 30mg) is given IV on days 2 and 9 in combination with venetoclax (600mg or 800mg) PO and prednisone 100 mg PO on days 1-10 every 21 days. Phase II expansion cohorts are included at the RP2D. VVIP x 12 cycles is given for pts who achieve complete response (CR), with a max of 24 cycles for pts not in CR. TLS, G-CSF, and PCP prophylaxis are given to all pts. Baseline CT, PET, and BM are performed with CT after cycles 1 and 2 then every 2 cycles and PET after cycles 6 and 12. CT is then performed q3m x 1y, q4m x 1y, q6m x 1y, then q12m x 2y post-therapy. Results: As of March 26, 2024, 5 pts were enrolled (3 at DL1 and 2 at DL2), including 3 PTCL, 1 non-GCB DLBCL, and 1 HGBCL-DH. Median (range) age was 56 (55-77) yrs, with stage 3/4 disease in 100%, >/=2 extranodal sites in 100%, IPI >/=3 in 80%, and elevated LDH in 40%. Median (range) prior therapies were 3 (3-6), with prior ASCT, allo-HSCT, and CAR-T in 1 (20%) pt each, and 80% of pts refractory per SCHOLAR-1 criteria. All 5 pts completed the dose-limiting toxicity (DLT) window with no DLTs observed. The most common adverse events (AEs) (% pts) included hypokalemia (100%), thrombocytopenia (80%), neutropenia (80%), and anemia (80%). Two (40%) pts had G3-4 neutropenia and 1 (20%) pt had G3 hypokalemia, with no other >/=G3 AEs observed. No dose reductions occurred and only 1 pt required a dose delay due to infection. Tumor reduction was observed in 80% (4/5) of pts, with an overall response rate of 60% (3/5). Partial responses include 1 HGBCL-DH pt refractory to both CAR-T and epcoritamab (71% tumor reduction) and 2 PTCL pts refractory to CHOP and targeted therapy (86% and 91% tumor reduction). Four pts have progressed, and no pts have died. Conclusions: Preliminary results show VVIP to be safe and well tolerated with no DLTs observed. Early activity is noted in pts with HGBCL-DH and PTCL. Enrollment continues to identify the RP2D and to further assess the safety and efficacy of VVIP in R/R aggressive lymphomas. Citation Format: Christopher Melani, Max Gordon, Rahul Lakhotia, Stefania Pittaluga, Jillian Simard, Jagan Muppidi, James D. Phelan, Svetlana Pack, Amynah Pradhan, Candis Morrison, Atekelt Tadese, Anna M. Juanitez, Amy J. Johnson, Melanie M. Frigault, Ahmed Hamdy, Mark Roschewski, Louis M. Staudt, Wyndham H. Wilson. Phase I/II study of VIP152 (enitociclib), venetoclax, and prednisone (VVIP) in relapsed/refractory (R/R) lymphoid malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-008.

Background: Mantle cell lymphoma (MCL) is incurable with standard chemotherapy. Although oral targeted agents are active in MCL, they fail to induce deep responses as monotherapy and are administered chronically. We developed a fixed-duration, multi-agent targeted regimen (ViPOR) and showed it to be safe and able to induce durable complete responses (CRs) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (Melani. NEJM. 2024). We hypothesized that simultaneously targeting multiple survival pathways with ViPOR will improve efficacy and time-limited, cyclic dosing will limit toxicities in MCL. Methods: R/Rand treatment-naïve (TN) MCL pts >18y with adequate organ function are eligible. One prior study agent (excluding prednisone and CD20 Ab) is allowed. In Ph 1b, R/R MCL pts are treated at 2 dose-levels of venetoclax (VEN) (200 & 400 mg) PO D2-14 (starting C2) with fixed-dose ibrutinib 560 mg PO D1-14, prednisone 100 mg PO D1-7, obinutuzumab 1000 mg IV D1-2, and lenalidomide 15 mg PO D1-14 to determine the recommended phase 2 dose (RP2D). In Ph 2, 20 pts each with R/R and TN MCL are treated at the RP2D. ViPOR q21d x 6C is given without maintenance or consolidation. All pts are admitted for a 12d VEN ramp-up on C2 with tumor lysis syndrome (TLS) prophylaxis (ppx) and monitoring. All pts receive PCP ppx with VTE ppx per PI discretion. G-CSF ppx is given in all R/R pts and as needed in TN pts. Baseline CT, PET, and BM is performed with CT scans after C1, C2, C4, and C6 and PET after C6. Surveillance CT is then performed q3m x 1y, q4m x 1y, q6m x 1y, then annually x 2y. Minimal residual disease (MRD) is assessed in plasma ctDNA using clonoSEQ at baseline, during treatment, and in f/u. Results: 36 MCL pts (16 R/R & 20 TN) have been enrolled. Median age is 67y (range, 41-82) with 69% male pts. Blastoid morphology and Ki-67 >30% was seen in 25% and 37% of pts, respectively. TP53 expression >50% was observed in 19% of pts with TP53 mutations and/or deletions in 32%. High-risk MIPI and MCL35 proliferation score was present in 33% and 20% of pts, respectively. Median prior therapies in R/R pts was 3 (range, 1-7), with prior BTKi in 50%. No pts received prior VEN or lenalidomide. No dose-limiting toxicities occurred and VEN 400 mg was identified as the RP2D. G3-4 hematologic adverse events (AEs) (% cycles) included thrombocytopenia (14%), neutropenia (13%), and anemia (10%), with no febrile neutropenia observed across 204 total cycles. Common non-hematologic AEs (% pts) of any grade included hypokalemia (89%), diarrhea (67%), and rash (58%), with the only G3 non-hematologic AEs in >10% pts being hypokalemia (25%) and rash (11%). No TLS or treatment-related mortality occurred. Dose reductions and delays occurred in 5% and 11% of cycles, respectively, and 89% of pts completed all planned 6C of therapy. All 35 (100%) MCL pts who are now off-treatment achieved CR, including 15 R/R and 20 TN pts. Median f/u across all pts was 24.1m. In TN MCL pts, 95% of CRs are ongoing with a 2y (95% CI) time to progression (TTP), progression-free survival (PFS), and overall survival (OS) of 95% (70-99), 95% (70-99), and 100%, respectively. In R/R MCL pts, 73% of CRs are ongoing with a 2y (95% CI) TTP, PFS, and OS of 91% (51-99), 75% (41-91), and 75% (41-91), respectively. 1 R/R pt received consolidative allo-HSCT. 1 TN pt with blastoid MCL relapsed in the skin and 2 R/R pts (1 blastoid & 1 TP53 mutated) relapsed in the CNS and blood, respectively. 2 R/R pts died in remission from COVID-19. 2y TTP was 100% in TP53 mutated/deleted, 81% in Ki-67 >30%, 80% in post-BTKi, and 74% in blastoid pts. In high-risk MIPI and MCL35 pts, 2y TTP was 100% and 80%, respectively. Baseline ctDNA was identified in 97% (31/32) pts, with undetectable MRD (uMRD) after C1, C2, and at end-of-therapy in 13% (4/31), 81% (25/31), and 97% (28/29) of pts, respectively. 95% (18/19) of TN and 83% (10/12) of R/R pts remain in continued uMRD CR, with 1 TN MRD positive CR pt relapsing 1m post-treatment and 2 R/R uMRD CR pts experiencing molecular relapse prior to imaging. Conclusion: Fixed-duration ViPOR x 6C without maintenance achieved CR in 100% and uMRD in 97% of MCL pts, with ongoing CR in 95% and 73% of TN and R/R pts, respectively, and only 1 R/R pt receiving consolidative allo-HSCT. This includes blastoid, TP53 mutated, and post-BTKi high-risk subsets. ViPOR with a 12d VEN ramp-up on C2 is safe in MCL pts of all ages without significant TLS or febrile neutropenia. Enrollment continues to better define the response and durability of ViPOR in MCL.

Background:Follicular lymphoma (FL) shows marked heterogeneity in clinical course including spontaneous regression and histologic transformation (HT). Watchful waiting (W&W) is routinely employed, but monitoring is not standardized. A subset of pts require treatment early after diagnosis, but biologic basis is unclear. Improved classifiers and monitoring tools are needed. Circulating tumor DNA (ctDNA) is a highly tumor-specific biomarker that is prognostic in aggressive B-cell lymphomas. We previously showed that ctDNA in plasma can be identified in >90% FL pts with next-generation sequencing of Ig heavy- and light-chain loci. Here, we present updated results from serial ctDNA monitoring of pts on a prospective clinical trial [NCT03190928]. Methods: Adult pts with grade 1-3A FL were eligible if evaluable disease, no HT, and no prior systemic therapy. Pts underwent W&W until they met uniform protocol-defined treatment criteria and then monitored until 2nd line therapy. Baseline testing included plasma, CT and PET, and biopsy. Clinic visits were every 4m for 2y, every 6m in years 3-5, then annually with CT scans every other clinic visit. PET scans were repeated at 2y, or at suspected disease progression. Cell-stabilizing tubes (plasma) and PBMCs were drawn at each visit. Analysis of ctDNA was performed using the research version of clonoSEQ blinded to clinical outcomes. The primary endpoint was progression requiring treatment within 2 years of enrollment. Pts who required treatment in first 2 years were labeled early progressors and those without treatment were labeled non-progressors. Results: 78 pts enrolled between July 2017 and Aug 2021, of which 77 had baseline plasma samples. Of 58 pts with available FFPE tumor biopsies, all (100%) had ≥1 dominant clonotype(s) identified from tumor. Of 19 pts without FFPE, ≥1 dominant clonotype was identified from plasma in 7 (37%). These 65 pts with trackable clonotype(s) comprised the study population. Median age of the study population was 57y (range 24-84), including 12 (18%) low-risk, 25 (39%) intermediate-risk, and 28 (43%) high-risk by FLIPI. Baseline ctDNA was detectable in 60 (92%) pts with median (interquartile range [IQR]) level of 34 (6-114) lymphoma molecules per mL. Four (80%) pts with undetectable ctDNA at baseline had stage 1-2 disease. Baseline ctDNA levels correlated with both FLIPI (p<0.01) and total metabolic tumor volume (TMTV) on PET (p<0.001). Three pts were unevaluable for progression at 2y due to non-progression events including a second malignancy, sudden death, and hemolytic anemia requiring rituximab. Thirty-three (53%) pts were early progressors and 29 (47%) were non-progressors at 2y. Median time to treatment (TTT) was 20m (95% CI, 10-68). Early progressors had median (IQR) baseline ctDNA level of 38.2 (13-189.4) compared to 18.7 (1.2-56.8) lymphoma molecules per mL for non-progressors. Pts with >median baseline ctDNA levels had median TTT of 9.7m (95% CI, 2.8-NE) compared to 37m (95% CI, 17-NE) for pts with Median (IQR) baseline TMTV was 138 (39-388) cm3. Pts with >median baseline TMTV had median TTT of 5.3m (95% CI, 2.1-28) compared to 54m (95% CI, 26-NE) for pts with Ten (15%) pts had HT. Neither baseline ctDNA levels (p=0.85) nor TMTV (p=0.65) were associated with increased risk of subsequent HT. Twenty-three (39%) pts had spontaneous regression of tumor lesions by ≥25% on CT. Lower baseline ctDNA levels (p=0.02) and TMTV (p<0.01) were associated with subsequent spontaneous regression. Twenty pts with spontaneous regression had serial samples and 13 (65%) had decrease in ctDNA levels corresponding to CTs. Conclusions: Circulating tumor DNA is detectable in baseline plasma of >90% pts with untreated FL. Quantitative ctDNA levels correlate with both FLIPI and TMTV and are associated with earlier need for treatment. Serial ctDNA monitoring shows fluctuating levels that correlate with tumor burden on CT which provides a non-invasive method to monitor disease. Baseline ctDNA levels and TMTV do not predict future histologic transformation.

Background: Primary diffuse large B-cell lymphoma (DLBCL) of the CNS (PCNSL) and secondary CNS involvement with DLBCL (SCNSL) have an overall poor prognosis. High-dose chemotherapy cures a subset of younger patients, but those who relapse after or are ineligible for intensive therapy are rarely cured. The molecular biology of PCNSL and non-GCB SCNSL involves chronic active BCR signaling targetable by BTK-inhibitor (BTKi) based therapy. We developed the multi-targeted therapy combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (VIPOR) and demonstrated curative potential in relapsed and refractory systemic non-GCB DLBCL (Melani et al. N Engl J Med 2024). VIPOR is a synergistic combination that overcomes resistance to both chemotherapy and prior treatment with BTKi. Here, we show results of a pilot study testing VIPOR in pts with CNS lymphoma who have relapsed after or are ineligible for high-dose chemotherapy. Methods: Pts with PCNSL or non-GCB SCNSL, and adequate organ function were eligible. Pts had either relapsed after or were ineligible for high-dose methotrexate (HD-MTX) (advanced age, effusions, renal dysfunction). Prior BTKi was allowed. Staging included baseline MRI brain, CSF flow cytometry, PET/CT brain and body, eye exam, and bone marrow. In the original study design, pts first received nivolumab 200mg IV x 1 and lenalidomide 15mg x 14 days in a 21-day window, followed by up to six 21-day cycles of nivolumab 200mg IV D1, venetoclax 800mg PO D2-14, ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14. No doses were escalated. The study was later amended to remove the 21-day window, and all pts received up to 6 cycles of VIPOR alone without maintenance or planned consolidation. Response assessments with brain MRI and PET/CT scans were done after cycles 1, 3, and 6. All complete responses by brain MRI were confirmed with PET brain and CSF analysis. Surveillance imaging with brain MRI and CT body were performed q3m for 1y, q4m for 1y, q6m for 1y, then annually. The primary objective was to assess the safety and tolerability of VIPOR in CNS lymphomas. Secondary objectives included overall response rate and duration of response. Results: Overall, 14 pts were enrolled, including 9 with PCNSL and 5 with SCNSL. In the PCNSL cohort, 5 (56%) had brain only involvement and 4 (44%) had both brain and CSF involvement. In the SCNSL cohort, 3 (60%) had CNS only involvement and 2 (40%) had both systemic and CNS involvement. Median age was 66 (range 54-86) and 9 (64%) pts were male. Nine (64%) pts were White, 4 (29%) were Black, and 1 (7%) was Asian. Ten (71%) patients had primary refractory disease. Median prior lines of therapy was 2 (range 1-6), including 10 (71%) pts with prior BTKi, 9 (64%) with prior HD-MTX, 4 (29%) with prior autologous stem cell transplant, and 1 (7%) with prior CAR-19. After 4 pts enrolled, a pt developed grade 4 autoimmune hepatitis during window and did not receive VIPOR (response unevaluable). The study was amended to treat with VIPOR only without nivolumab and no window. Of 56 cycles administered, G3-4 thrombocytopenia occurred in 9 (16%), neutropenia in 5 (9%), anemia in 2 (3%), and febrile neutropenia in 1 (2%) pt. Grade 3 or higher non-hematologic toxicities were uncommon and included hypokalemia in 3 (21%) pts. Ten (71%) pts had grade 1 or 2 diarrhea that required anti-diarrheal agents, and 7 (50%) pts required potassium supplements. Eight (57%) pts stopped therapy prematurely due to progression (N=4), myocardial infarction (N=1, unrelated), renal insufficiency (N=1, unrelated), pneumonia (N=1, related), and autoimmune hepatitis (N=1, related). Of 13 evaluable pts, 8 (62%) responded including 4 (31%) who achieved a CR. In 9 pts treated with prior BTKi, 6 (67%) responded including 2 (22%) pts who achieved CR. Two patients who achieved a CR remained free from progression, both of whom had not received prior BTKi. Both patients with concomitant systemic disease and CNS involvement responded in both compartments. Conclusion: VIPOR is safe in CNS lymphoma without any additional toxicities than those observed in systemic DLBCL. VIPOR can overcome treatment resistance to both HD-MTX and BTKi-based therapy, although durable remissions may be more likely in BTKi-naïve patients. Further studies testing multi-targeted combination regimens are warranted in both PCNSL and SCNSL.

Introduction Frontline therapy for pts with follicular lymphoma (FL) is not based on the molecular profile of the tumor. The PI3K pathway is central to FL biology, but the molecular profile of tumors most sensitive to PI3K inhibition (PI3Ki) is unknown. Copanlisib inhibits both PI3Kα and δ isoforms, and we hypothesized that most pts with treatment naïve FL will have PI3Ki-sensitive tumors and durable complete responses (CRs) may be achievable with short durations of targeted therapy. A gene expression profiling (GEP) predictor utilizes a combination of the expression of 45 selected informative genes and an additional 19 housekeeping genes to identify FL pts at high-risk for early progression within 24 months (Wright et al. ASH Annual Meeting2022). We also hypothesized that copanlisib would induce durable CRs in high-risk pts by the GEP assay. Here, we report a preliminary analysis of an ongoing “window of opportunity” study of copanlisib followed by response-adapted copanlisib and rituximab in treatment-naïve pts with FL (NCT03789240). Methods Pts with untreated grade 1-2, 3A FL, ≥stage 2 are eligible if systemic therapy is indicated: symptoms, progressive lymphadenopathy, or organ compromise. Prior radiation is permitted. Eligibility includes age ≥18 and adequate organ function unless due to lymphoma. HIV, CMV, Hep B or C, and autoimmune conditions are excluded. Pts first receive copanlisib 60mg on days 1, 8, and 15 of a 28-day “window of opportunity” to explore the activity of copanlisib. Following the window, pts receive 6 cycles of copanlisib 60mg on days 1, 8, and 15 of a 28-day cycle along with rituximab 375mg weekly x 4 then on day 1 of each cycle and response is assessed with FDG-PET and CT scans. Pts without response after C6 are taken off study and those with a partial response (PR) can continue for an additional 6 cycles and then stop therapy. Pts who achieve a CR after 6 cycles stop therapy. No maintenance is given. Supportive care includesPCP prophylaxis. The primary endpoint is the CR rate with secondary endpoints of safety, duration of CR, and PFS. Exploratory objectives include identification of a predictive signature of PI3Ki response and the response rate in high-risk pts identified by the GEP assay. Results Twenty-eight pts have enrolled. Median age was 56y (range, 24-80). Seventeen (61%) and 12 (43%) pts had high-risk FLIPI and FLIPI-2 scores ≥3, respectively; 6 (21%) pts had Grade 3A FL, and 17 (61%) pts met two or more GELF criteria. After copanlisib monotherapy in the window, 27 (96%) pts had tumor reductions by CT with a median change of -38% (-62% to +16%) (Figure 1). Among 22 pts who completed 6 cycles, 21 (96%) responded, including 9 (41%) pts with PR and 12 (55%) pts with CR. Of 9 pts with PR who received an additional 6 cycles of therapy, only 1 (11%) converted to a CR bringing the overall CR rate to 59% (13/22 pts). After a median follow-up of 25.8 months, the 2-year PFS was 43.2% (95% CI, 20.7-64.0%). The median duration of CR was 29.7 months (95% CI, 6.3 months - not estimable) with 8 (62%) CRs ongoing (Figure 2). Toxicity was evaluated in 28 pts across 220 cycles. Most common were rash (64%), mucositis (50%), and nausea/vomiting (50%), all G1-2 except 1 (4%) pt with G3 mucositis. The most common ≥G3 toxicities were neutropenia and infections in 5 (18%) pts each. ≥G3 neutropenia occurred in 10 (5%) cycles, responded to therapy interruption and/or growth factors, and did not require dose reduction. Two (8%) pts had copanlisib dose reduced, 1 (4%) each due to rash and mucositis. Therapy was prematurely discontinued in 5 pts: 3 due to COVID-19, 1 for hepatotoxicity that resolved, and 1 due to infusion reaction to rituximab. Nine of 24 (38%) pts were poor risk by the GEP assay. Complete responses were observed in 71%, 67%, and 57% of pts categorized as high-risk by FLIPI, FLIPI-2, and GEP assay, respectively. The CR rate was not affected by bulky disease (any LN >7cm; p=1.00), high-risk FLIPI (p=0.19), high-risk FLIPI-2 (p=0.67), poor-risk GEP (p=1.00), or metabolic tumor volume (p=0.33). Conclusion Nearly all pts with treatment naïve FL have PI3Ki-responsive tumors, and the combination of copanlisib with rituximab achieved a CR rate of 59% at the end of induction therapy. The median duration of CR is nearly 30 months, including ongoing remissions without maintenance. CRs were observed in pts deemed high-risk by the GEP assay and FLIPI score. The safety profile is excellent, with mostly G1-2 toxicities manageable with supportive care.

Background: Programmed cell death protein-1 (PD-1) is a signaling molecule on the surface of T-cells that suppresses the cytotoxic effects of T-cells on tumor cells. We previously demonstrated increased PD-1 expression on CD8+ T-cells compared to healthy controls in pts with LYG, which could be reversed with immunotherapy using interferon alpha-2b (Melani et al. Lancet Haematol. 2023). Additionally, elevated expression of programmed death-ligand 1 (PD-L1) has been observed in other EBV-LPDs and NHLs as well as in chronic viral infections, such as EBV. Given this likely shared disease pathobiology, we hypothesized that treatment with the anti-PD-1 antibody, nivolumab, may reverse T-cell exhaustion and result in anti-tumor responses in pts with LYG and other EBV-LPDs and NHLs, including those with systemic and/or CNS involvement. Methods: Relapsed/refractory (R/R) EBV-LPD and NHL pts age ≥ 12y with adequate organ function were eligible. Untreated pts were eligible if EBV-LPD. Exclusions included prior use of PD-1/PD-L1/PD-L2/CD137/CTLA-4 antibodies, solid organ transplant, and HIV infection. Pts with a known immunodeficiency or autoimmune illness were eligible if not requiring steroids or immunosuppression within 14d of study. CNS involvement was permitted if no seizure activity within 4w of study. Nivolumab 480 mg IV was given q4w for up to 2y. Pts who achieved CR discontinued nivolumab after 1y of treatment. Responding patients with relapse or progression within 1y of discontinuing treatment were eligible for retreatment. Baseline evaluation included CT, PET, MRI brain, flow cytometry of peripheral blood and CSF, BM biopsy, and optional tumor biopsy. Restaging CT scans were performed after cycles 3, 6, 13, and 19, and end of treatment (EoT). PET was performed after cycles 1, 3, and EoT. Surveillance CT was performed q3m for 1y, q6m for yrs 2-5, and annually thereafter. Results: 11 pts were enrolled and treated; 6 (55%) with EBV-LPD and 5 (45%) with EBV-NHL (all DLBCL). EBV-LPD subtypes included 4 pts with G1-2 LYG and 1 pt each with EBV B-LPD of the CNS and CAEBV. Median age was 48y (range 20-67), and all pts had stage III/IV disease with extranodal involvement of the lung most common in 64% (7/11) and CNS disease in 18% (2/11). Median baseline absolute CD8 count (cells/mcL) was 86 (range 9-1237; normal: 178-853), CD4 count (cells/mcL) was 255 (range 99-1304; normal: 359-1565), and EBV VL in plasma (Log10 IU/mL) was undetected (range undetected-6.78; normal: <2.3). Median prior therapies were 1 (range 0-6) with 3 previously untreated LPD pts and 50% of previously tx pts were refractory to last tx. In 10 pts evaluable for response(1 came off tx prior to restaging), ORR and CR rate were both 60% (6/10). CR rate was 67% (4/6) in EBV-LPD, including 75% (3/4) with LYG, and 50% (2/4) in EBV-NHL (Fig 1A). One (50%) of 2 EBV-LPD pts with CNS involvement achieved CR after 3C of therapy and remains in ongoing response. Median TTR was 3.0m with 50% (3/6) responses ongoing from 3-56m after first response (Fig 1B). With a median follow up of 32m, 2y PFS and OS was 33% and 72% overall. By cohort, median PFS was 36m in EBV-LPD and 1m in EBV-NHL (p=0.003), with a 2y OS of 100% in EBV-LPD and 40% in EBV-NHL (p=0.04). Three EBV-NHL pts died, all of disease progression. One EBV-NHL pt stopped therapy after 2C due to radiographic disease progression in the kidney, but later developed CR without further therapy and remains in remission 56m after stopping therapy consistent with initial pseudoprogression. Adverse events (AEs) were as expected for nivolumab therapy with the most common AEs (% pts) including maculopapular rash (27%), diarrhea (18%), hypothyroidism (18%), and fatigue (18%). One pt developed an immune-mediated G2 myositis and G3 hepatitis following 3C of therapy which resolved after drug discontinuation and corticosteroids. Conclusion: Nivolumab is well tolerated in pts with LYG and other EBV-LPDs and NHLs without unexpected toxicities. Preliminary activity, including durable CRs, is noted across all pt cohorts, including 1 EBV-LPD pt with CNS involvement. With small numbers, statistically longer PFS and OS was observed with nivolumab in LYG and EBV-LPD compared to EBV-NHL, indicating that monotherapy may be sufficient for LYG and other EBV-LPDs, but combination therapy is likely needed for pts with EBV-NHL. Study enrollment continues to better assess the activity and durability of nivolumab in LYG and other EBV-LPDs and NHLs.

Background: Foundational studies have revealed essential oncogenic pathways in DLBCL, triggering the development of drugs targeting distinct survival pathways in this malignancy. While many of these agents are active in DLBCL as monotherapy, they rarely induce deep responses or cure. Based on our identification of drug synergy in DLBCL models, we hypothesized that targeting multiple survival pathways concurrently could be curative in DLBCL. We developed a 5-drug combination regimen (ViPOR) that targets DLBCL survival sustained by constitutive B-cell receptor (BCR) signaling (ibrutinib, lenalidomide, prednisone) and by BCL2 (venetoclax), and also enlists the innate immune system using obinutuzumab. To maximize drug exposure and minimize toxicity, we administered all agents in non-continuous cycles for fixed duration in R/R DLBCL. Methods: R/R DLBCL pts with adequate organ function were eligible. In Ph I, pts were treated at 4 doses of venetoclax (200-800 mg) PO D2-14 to identify the MTD. An initial 12d venetoclax ramp-up was given in combination with fixed-dose ibrutinib 560 mg PO D1-14, prednisone 100 mg PO D1-7, obinutuzumab 1000 mg IV D1-2, and lenalidomide 15 mg PO D1-14. Ph II expansion cohorts of R/R GCB and non-GCB DLBCL were included at the MTD. Max 6C of ViPOR q21d were given without maintenance. TLS, G-CSF, and PCP prophylaxis were given to all pts. Baseline CT, PET, BM, and tumor biopsies were performed with CT after C1, 2, 4, and 6 and PET after C6. CT was then performed q3m x 1y, q4m x 1y, q6m x 1y, then q12m x 2y. Tumor genomics and ctDNA (clonoSEQ) were studied. Results: 50 DLBCL pts were enrolled (25 DLBCL NOS, 17 HGBCL-DH-BCL2, 3 HGBCL-DH-BCL6, and 5 THRLBCL). 52% and 48% were GCB and non-GCB subtype by IHC, respectively, with transformed lymphoma in 34%. Median age was 61y (range 29-77), with stage 3-4 disease in 92%, elevated LDH in 86%, >2 extranodal sites in 56%, and IPI >3 in 68% of pts. Median prior txs were 3 (range 1-9), with 40% post-CAR-T pts and 58% refractory. A single DLT of G3 intracranial hemorrhage occurred, and venetoclax 800 mg was identified as the MTD. Heme AEs were most common, with G3-4 neutropenia in 24%, thrombocytopenia in 23%, and anemia in 7% of cycles. Febrile neutropenia occurred in 3 (1%) cycles. The only G3-4 non-heme AE in >10% pts was hypokalemia (28%). G3 A.fib occurred in 3 pts, and G4 TLS occurred in 1 pt, which resolved. Other common any grade non-heme AEs (% pts) included diarrhea (68%), hypokalemia (67%), nausea (45%), rash (35%), and fatigue (33%). Dose reductions occurred in 17% of pts, and 8% discontinued tx due to AE. Of 48 evaluable pts (2 came off tx prior to restaging), ORR was 54% (26/48), and CR was 38% (18/48). Responses were observed across all molecular DLBCL subtypes, including a CR rate of 62% (8/13) in non-GCB DLBCL, 53% (8/15) in HGBCL-DH-BCL2, 25% (2/8) in other DLBCL, and a PR rate of 33% (4/12) in GCB DLBCL (non-DH) (Fig. 1A). CR rate was 20% (4/20) and 19% (5/27) in post-CAR-T and refractory pts, respectively. With a median FU of 40m, 72% of CRs are ongoing, with a 2-year PFS and OS of 34% and 36%, respectively. By histology, 2-year PFS was 47%, 38%, 38%, and 8% in HGBCL-DH-BCL2, non-GCB DLBCL, other DLBCL, and GCB DLBCL (non-DH), respectively (Fig. 1B). 2-year PFS was 30% and 21% in post-CAR-T and refractory pts, respectively. MRD was undetectable in 38% (16/42) of pts at end of therapy (EoT), and in 93% (14/15) of pts in PET CR at EoT. Elevated baseline ctDNA or detectable ctDNA during or at EoT were associated with significantly inferior PFS and OS, as were quantitative PET parameters (elevated baseline TMTV and TLG). Two genetic subtypes known to rely on BCR-dependent NF-kB signaling - MCD and N1 - had a significantly higher CR rate (5/6, 83%) than all other genetic subtypes (4/22, 18%; p=0.0066). Conclusions: This is the first study to show the feasibility and curative potential of multi-targeted therapy in R/R DLBCL. ViPOR was well tolerated across all ages in R/R DLBCL with rare febrile neutropenia. ViPOR was most effective in non-GCB DLBCL, as expected from its reliance on BCR signaling and BCL2. ViPOR was also highly active in HGBCL-DH-BCL2, possibly due to inhibition of MYC-driven apoptosis by BCL2 in this subtype. Durable remissions and likely cure were observed in non-GCB DLBCL (38%) and HGBCL-DH-BCL2 (47%), including pts relapsed after or refractory to CAR-T (30%). Multicenter Ph II testing is in development to confirm the activity of ViPOR in R/R non-GCB DLBCL and HGBCL-DH-BCL2.

Background and Significance Targeted agents and immunotherapy have changed the treatment landscape for follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL), but indefinite therapy leads to cumulative toxicity and excessive cost. CD47 is a checkpoint for the innate immune system providing an inhibitory signal to phagocytic macrophages and a rational therapeutic target in B-cell lymphoma. Magrolimab is a fully humanized IgG4 anti-human CD47 antibody, with high activity in FL when combined with rituximab (Advani NEJM 2018). Our objective is to test the safety of adding escalating doses of venetoclax to magrolimab and obinutuzumab in a response-adapted study design with planned dose expansion cohorts (www.clinicaltrials.govidentifier NCT04599634). Study Design and Methods Patients with grade 1-3A FL, MCL, MZL, or CLL relapsed after and/or refractory to ≥2 prior lines of therapy are eligible. Pts with FL are eligible after 1 prior therapy if FLIPI ≥2 or disease progression within 24 months of the end of the last therapy. Pts with MCL are eligible after 1 prior therapy if blastoid histology, 17p deletion, TP53 mutation, Ki67 ≥30%, or received Bruton's tyrosine kinase inhibitor (BTKi) as first-line therapy. Pts with CLL are eligible after 1 prior therapy if 17p deletion, TP53 mutation, or received both a BTKi and a BCL2 inhibitor. Eligibility includes age ≥18 and adequate organ function unless dysfunction secondary to lymphoma. A positive direct antiglobulin test without hemolytic anemia is allowed. Patients with a history of hemolytic anemia or autoimmune thrombocytopenia within 3 months of enrollment are excluded. No washout period is required for prior anti-lymphoma treatment. Active HIV, CMV, and hepatitis B or C are excluded. The safety of venetoclax, obinutuzumab, and magrolimab will first be determined in 2 dose-finding cohorts of up to 24 pts (Cohort 1: 6-12 pts with FL and Cohort 2: 6-12 pts with MZL, MCL, or CLL). During dose-finding, all pts start triplet therapy with venetoclax, obinutuzumab, and magrolimab (Figure 1). Magrolimab IV is administered at a 1mg/kg priming dose on D1 of the first cycle, followed by 30mg/kg x 3 weekly loading doses, then 30 mg/kg on D1 of each 4-wk cycle. Obinutuzumab IV is administered at 100mg on D1, 900mg on D2, and 1000mg on D8 and D15 of the first cycle, followed by 1000mg on D1 of each 4-wk cycle. Pts with FL receive venetoclax 800mg (DL1) daily throughout therapy duration, whereas pts with MZL, MCL, and CLL start venetoclax at 20mg with weekly escalation to 400mg (DL1) over 5 weeks. Dose-limiting toxicity is assessed during the first 4 wks for FL, and the first 5 wks for MZL, MCL, and CLL. If ≥2 of 6 pts in either arm experience DLT, 6 additional pts will be enrolled to the respective arm at DL(-1) of venetoclax (600mg for FL and 200mg for MZL, MCL, and CLL). After dose-finding is completed, expansion cohorts of each histology will first receive magrolimab and obinutuzumab for two 4-wk cycles in a window for translational research. On-treatment tumor biopsies are optional during the window. After the window, venetoclax will be added at the dose determined during dose-finding. FDG-PET and CT scans are performed at baseline, after window, and after cycles 3 and 6 of triplet therapy. During both dose-finding and dose-escalation, pts with complete response (CR) after 6 cycles of triplet therapy will stop therapy. If these pts relapse, they can be retreated with an additional 6 cycles of triplet therapy. Pts with partial response (PR) after 6 cycles of triplet therapy receive an additional 6 cycles of triplet therapy. All pts stop treatment after 12 cycles. The primary objective is safety, with secondary endpoints of overall response rate, duration of response, and PFS. Exploratory objectives include the identification of a molecular signature that predicts response to magrolimab and obinutuzumab, and correlation of response with circulating tumor DNA levels.

As is the case for solid tumors, treatment paradigms have shifted from non-specific chemotherapeutic agents towards novel targeted drugs in the treatment of patients with multiple myeloma (MM). Currently, multiple targeted therapies are available to treat patients augmenting the arsenal of modalities which also includes chemotherapy, immunotherapy, radiation therapy, hematopoietic stem cell transplantation (HSCST) and chimeric antigen T-cell therapy (CAR-T). These novel, targeted agents have dramatically increased optimism for patients, who may now be treated over many years with successive regimens. As fortunate as we are to have these new therapies available for our patients, this advantage is juxtaposed with the challenges involved with delivering them safely. While each class of agents has demonstrated efficacy, in terms of response rates and survival, they also exert class effects which pose risks for toxicity. In addition, newer generation agents within the classes often have slightly different toxicity profiles than did their predecessors. These factors must be addressed, and their risks mitigated by the multidisciplinary team. This review presents a summary of the evolution of drug development for MM. For each targeted agent, the efficacy data from pivotal trials and highlights of the risks that were demonstrated in trials, as well as during post-marketing surveillance, are presented. Specific risks associated with agents within the classes, that are not shared with all new class members, are described. A table presenting these potential risks, with recommended nursing actions to mitigate toxicity, is provided as a quick reference that nurses may use during the planning, and provision, of patient care.

Daratumumab, a human IgG1 kappa monoclonal antibody targeting CD38 has transformed the treatment paradigm of multiple myeloma (MM). With the identification of CD38 as a crucial receptor involved in immune system function, it became an ideal target for monoclonal antibody (mAb) drug development in MM. Daratumumab's unique multifaceted mechanism of action has led to great success in the treatment of relapsed refractory multiple myeloma (RRMM) as well as newly diagnosed multiple myeloma (NDMM) patients. Along with its efficacy comes a low toxicity profile, improved further with the introduction of subcutaneous daratumumab. With such success within MM, daratumumab is now being explored in other disease states. This article will review daratumumab's drug development, practical use, and future potential indications.

This cohort study assesses the concordance of 3 models to stratify risk for progression to multiple myeloma in an independent cohort of patients with smoldering multiple myeloma.

Background. Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy. Methods. This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect. Results. At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade >= 3 and five grade 1-2 treatment-related adverse events. Conclusion. Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.

Importance High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment sensitive. Objective To evaluate the use of carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance therapy as early intervention in high-risk smoldering myeloma and to determine the rates of minimal residual disease (MRD)-negative complete response (CR). Design, Setting, and Participants In this single-arm, single-center, phase 2 nonrandomized controlled trial, responses were evaluated at every cycle during KRd treatment and every 3 cycles subsequently. Bone marrow biopsies and imaging were performed by cycle 8 and then annually. The study enrolled patients from May 29, 2012, to July 23, 2020, at the National Institutes of Health Clinical Center, a highly specialized tertiary cancer center. Patient key eligibility criteria included a diagnosis of high-risk smoldering myeloma based on the Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria. Interventions Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m2 (first 2 doses, 20 mg/m2), dexamethasone (20 mg, cycles 1-4; 10 mg, cycles 5-8 twice weekly), and lenalidomide 25 mg (days 1-21) followed by twenty-four 28-day cycles of maintenance lenalidomide 10 mg (days 1-21). Stem cell harvest and storage were optional. Main Outcomes and Measures The primary outcome was the MRD-negative CR rate. Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma. Results A total of 54 patients (median age, 59 years [range, 40-79 years]; 30 men [55.6%]; and 2 Asian [3.7%], 15 Black [27.8%], 1 Hispanic [1.9%], and 36 White [66.7%] patients) were enrolled, with a median potential follow-up time of 31.9 months (range, 6.7-102.9 months). The MRD-negative CR rate was 70.4% (95% CI, 56.4%-82.0%), with a median sustained duration of 5.5 years (95% CI, 3.7 years to not estimable). The 8-year probability of being free from progression to multiple myeloma was 91.2% (95% CI, 67.4%-97.9%), and no deaths occurred. Nonhematologic grade 3 adverse events occurred in 21 patients (38.9%) and included thromboembolism, rash, and lung infection, with no grade 4 events. Conclusions and Relevance Results of this phase 2 nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease. Randomized clinical trials are needed to confirm this favorable benefit-to-risk profile. Trial Registration ClinicalTrials.gov Identifier: NCT01572480.

Summary Skeletal survey (SS) continues to be used in the community to detect bone disease in patients with multiple myeloma (MM). While the false‐negative rate is high, the specificity of SS is less well characterised. Here, we compare the diagnostic accuracy of SS compared to 18 F‐FDG‐PET/CT (positron emission tomography/computed tomography) in 79 patients referred to our tertiary centre with a diagnosis of smouldering MM. SS had a specificity of 83·1% (95% confidence interval: 72·0–90·5%). This study reinforces the importance of using more specific imaging techniques to avoid inaccurate diagnosis that could lead to the risks associated with unnecessary therapy in patients with smouldering MM.

Background: Multiple myeloma (MM) is the 2nd most common hematologic malignancy and remains incurable despite significant treatment advances over the last decade. Patients with relapsed/refractory multiple myeloma (RRMM), who have exhausted available therapies, have limited treatment options and a median survival as brief as 6 months (Richardson PG et al., Oncology 2010). Immune checkpoint inhibitors (CPI) have dramatically changed treatment paradigms in multiple cancers, with growing evidence that radiation therapy (XRT) may synergize with these agents via the abscopal effect. MM cells express high levels of PD-L1. Preclinical models have demonstrated rejection of murine myeloma when PD-L1 blockade was combined with XRT (Kearl TJ et al., Journal of Immunology 2013), as well as longer survival in myeloma-bearing mice compared to controls (Jing W et al., Journal for ImmunoTherapy of Cancer 2015). Early phase single arm clinical trials with combinations of immunomodulatory drugs (IMiDs) and CPI showed response rates between 33 and 76% (Pianko MJ et al., Stem Cell Investigation 2017)(San Miguel J et al., Blood 2015)(Badros A et al., Blood 2017). However, subsequent phase 3 studies revealed a potential safety signal of this combination (FDA 2017). Nonetheless, a subset of patients appear to attain durable responses (Badros A et al., Blood Advances 2019). CPI combined with other therapies such as XRT, that help to prime the immune system, hold great promise in the treatment of patients with RRMM. Herein, we describe our phase II study of avelumab, an anti-PD-L1 IgG1 antibody with potential antibody-dependent cellular cytotoxic properties, in combination with XRT in patients with RRMM. Methods: Trial Design: The primary endpoint of this trial is to assess the systemic response rate with the combination of avelumab and XRT in the treatment of extramedullary plasmacytomas or active lytic lesions in patients with RRMM using the 2016 IMWG response criteria. Secondary endpoints include determination of complete response rate, progression-free survival, and overall survival. Patients will undergo bone marrow biopsies and imaging (PET/CT and DW-MRI) at baseline, during disease response evaluations, and at the end of treatment. Treatment: Treatment consists of a 4-week lead-in with avelumab at a flat dose of 800mg IV every 2 weeks followed by concurrent XRT of 5Gy for 5 consecutive days directed toward the plasmacytoma/lytic lesion (Figure 1). Monotherapy avelumab, 800mg IV every 2 weeks, will continue indefinitely until disease progression or unacceptable toxicity. Analysis: This is a single arm trial with a Simon minimax two-stage phase II trial design that will enroll up to 27 patients. The first stage will enroll 13 evaluable patients, and if 0 of the 13 have a clinical response, then no further patients will be accrued due to futility. If 1 or more of the first 13 patients have a response, then accrual will continue until a total of 27 evaluable patients have been treated in the second stage. This will provide a two-sided alpha of 5% and a Power of 80% to rule out an ORR of 5% in favor of a response rate of 20%. Response fractions and time to event endpoints will be reported along with 90 and 95% two-sided confidence intervals with nominal p values. Eligibility: Patients must have previously treated relapsed MM or RRMM refractory to, ineligible for, or intolerant of, available myeloma therapies and have ≥ 1 extramedullary plasmacytoma and/or lytic lesion. Lesions must be amenable to, and clinically indicated for, treatment with localized XRT. Eligible patients must have documented evidence of progressive disease on, or after, their most recent regimen as defined by the IMWG criteria. They must have achieved at least a minimal response to one or more prior regimens. Exclusionary criteria include patients with: clinically unstable lesions where a delay in XRT may be detrimental; active autoimmune diseases or history of serious autoimmune-related disorders; uncontrolled intercurrent illnesses; concurrent use of immunosuppressant medications; and recent or current anti-cancer treatment prior to the first dose of avelumab. Current Enrollment: This study is actively enrolling patients to the first stage. At the time of this submission, 4 patients have been enrolled and have received at least one dose of trial therapy. Clinical trial registry number: NCT03910439. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: avelumab not approved in myeloma

Background: HR-SMM is a plasma cell disorder with a 5-year risk of progression to symptomatic multiple myeloma (MM) of ~75% without therapy. Early treatment with novel therapies, may decrease the risk of progression and prolong survival as evidenced by studies (Quiredex and ECOG E3A06) comparing lenalidomide ± dexamethasone to observation. Randomized studies in MM have demonstrated that triplet are superior to doublet regimens and whole exome sequencing in HR-SMM suggests a more treatment-sensitive biology. Together, these support our initial pilot study (Korde et al, JAMA Onc 2015) in using effective therapy with KRd-R as early intervention. Given the favorable initial results of our pilot in terms of minimal residual disease (MRD) negativity rates, we designed a single-arm, phase 2 study with the primary objective of determining the rate of MRD negative complete remissions. Herein, we show that rates of MRD negativity are high and they are sustained with the use of KRd-R. Methods: Patients with HR-SMM (Mayo Clinic or PETHEMA models) received eight 28-day cycles of carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after 4 cycles of KRd and then resumed treatment without an intent for early high-dose melphalan with stem cell support (HDM-ASCT). After 8 cycles of KRd, patients transitioned to receive maintenance therapy with lenalidomide 10 mg PO days 1-21 for 24 additional cycles. Prophylactic antiviral and anticoagulation was mandated for all. MM laboratory evaluations were performed at the start of every cycle during KRd and every 3 cycles during -R and every 3 months during indefinite follow up. Bone marrow biopsies and PET/CTs were performed by the end of cycle 8 induction and then annually indefinitely. The primary objective was to determine the rate of MRD negative remissions by validated multi-color flow cytometry (≤10-5 sensitivity). Key secondary objectives included progression free survival (PFS) to symptomatic myeloma and biochemical progression per IMWG, duration of MRD negativity, overall response rate (ORR), and duration of response. Results: As of 7/15/2020, 52 patients meeting eligibility criteria were enrolled and their demographics and disease characteristics are shown in Table 1. With a median potential follow up of 27.3 months, the primary objective of MRD negative CR rate was 70.2% and the MRD negative ≥VGPR rate was 80.9%, Table 2. The median duration of MRD negativity was 5.5 years with 2 and 5 -year rates of 78% and 55%, respectively. The median time to progression to MM and time to biochemical progression was not reached with 90-month rates of 90% and 78%, respectively - 2 patients progressed to symptomatic MM and 4 patients biochemically. The ORR was 100% and 78% achieved a best response of stringent CR. No deaths occurred. All grade and Grade 3-4 treatment-related adverse events occurred in 90% and 33% of patients, respectively. Grade 3-4 toxicities occurring in >1 patient included neutropenia (19%), lymphopenia (13%), thromboembolism (12%), anemia (8%), rash (8%), leukopenia (6%), lung infection (6%), ALT increase (4%), diarrhea (4%), hyperglycemia (4%), hypophosphatemia (4%), and thrombocytopenia (4%). Other Grade 3-4 adverse events of interest occurring in ≤1 patient included atrial fibrillation, creatinine increase, dyspnea, febrile neutropenia, heart failure, hypertension, and neoplasm. Treatment discontinuation occurred in 4 patients; 3 due to toxicity and 1 due to patient withdrawal. Conclusions: Treatment of HR-SMM with KRd-R to prevent symptomatic MM resulted in an MRD negative CR rate of 70% with a median duration of 5.5 years. At the 5-year landmark, only 10% of patients developed MM which is favorable compared to historical rates with no treatment of ~75%. Alternative approaches using monotherapy lenalidomide (Lonial et al, JCO 2019) resulted in no CRs and a 5-year progression rate of 22% with a treatment discontinuation rate of 51% compared to 7% in our study. More aggressive approaches include GEM-CESAR (Mateos et al, ASH 2019) incorporating HDM-ASCT with KRd-R. Importantly, the rate of MRD negativity reported in GEM-CESAR was 56% compared to 70% in this study. Overall, the benefit compared to risk with KRd in SMM is very favorable. Future randomized trials will be needed to lock in this conclusion. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Manasanch:Quest Diagnostics: Research Funding; Sanofi: Research Funding; JW Pharma: Research Funding; Merck: Research Funding; Takeda: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Research Funding. Bhutani:BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute; Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Landgren:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Seattle Genetics: Research Funding. OffLabel Disclosure: carfilzomib, lenalidomide, and dexamethasone are not approved for smoldering myeloma.

8532 Background: Per NCCN Guidelines for smoldering multiple myeloma (SMM), whole body radiography, i.e. skeletal survey (SS), should be used to rule out osteolytic bone lesions. If negative, more sensitive imaging techniques such as whole body 18F-FDG-PET/CT(PET/CT), MRI, or low dose CT should be used to differentiate between SMM and multiple myeloma (MM). The false-negative rate of SS is high (30-70%). The frequency of false-positive SS in SMM is less well known but important because of its common use in community practice. We examine the specificity of SS in patients with a presumed diagnosis of SMM and question if SS is still warranted prior to modern imaging techniques to confirm a diagnosis of SMM. Methods: Records of patients sequentially referred from the community and evaluated for a presumed diagnosis of SMM at the National Institutes of Health Myeloma Program between April 2010 to January 2020 were reviewed. Patients with a SS and PET/CT performed within 30 days were included. Positive findings on PET/CT were defined per the 2014 IMWG criteria as one or more sites of osteolytic bone destruction seen on CT. The sensitivity and specificity of SS were calculated using PET/CT as the reference test. Results: Charts from 144 patients with presumed SMM were reviewed. A total of 76 SMM patients had both a SS and PET/CT performed within 30 days of each other. Sixty-four patients (84.2%) showed concordant results. Twelve (15.8%) patients had discordant imaging results. SS was falsely negative in 3 (4.7% (95% CI: 1.2%-14.2%)) patients and falsely positive in 9 (69.2% (95% CI: 38.9%-89.6%)) patients. SS had a sensitivity of 57.1% (95% CI: 20.2%-88.2%) and a specificity of 86.9% (95% CI: 76.2-93.5). Conclusions: In patients presumed to have SMM, disease burden is low thus highly sensitive imaging modalities are needed to rule out bone disease. This study confirms the low sensitivity of SS in the SMM population. It more importantly points out the low specificity of SS in SMM. The IMWG no longer recommends conventional SS prior to whole body CT (or PET/CT) as first imaging choice in SMM. While the argument may be made that SS should still be used upfront due to low cost and widespread availability, this study shows the risk of overestimating disease. Over 10% of patients in this series had false positive disease on SS and thus at risk of receiving unnecessary treatment. Not only concerning for patient toxicity but more so financial toxicity. If SS is used, it is important to review positive findings directly with a radiologist and consider follow-up confirmatory imaging.

Introduction A direct association exists between minimal residual disease (MRD) negativity and prolonged survival in multiple myeloma (MM) (Landgren et al, BMT 2016). 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography (PET/CT) is a recommended monitoring technique for patients with MM as persistence of FDG uptake after induction therapy, prior to maintenance, is an independent risk factor for progression. Therefore PET/CT and MRD detection in the bone marrow are complementary prognostic tools prior to initiation of maintenance therapy. In patients with smoldering multiple myeloma (SMM), the presence of a focal FDG-avid lesion without underlying osteolytic lesion on PET/CT is associated with rapid progression to MM. However, little is known about the prognostic value of PET/CT for SMM patients receiving treatment. Herein, we show that treatment of high risk (HR)-SMM with carfilzomib, lenalidomide, and dexamethasone with lenalidomide maintenance (KRd-R) leads to sustained remissions detected on PET/CT imaging. Methods Trial design including key results for KRd-R in HR-SMM (NCT01572480) has been submitted to the meeting separately (abstract ID: 136148). As part of the study design, all eligible patients had bone marrow biopsies with multicolor flow cytometry (MRD sensitivity, 10-5) and whole-body PET/CT performed at baseline and at key time points, including achievement of complete response (CR) or completion of KRd induction (8 cycles), after 1 and 2 years of -R maintenance, and annually thereafter. PET/CTs were evaluated by nuclear medicine radiologists blinded to flow cytometry and considered positive if at least one focal hypermetabolic (above background reference) lesion and/or heterogenous bone marrow involvement were present, as defined by the IMWG (Hillengass et al. Lancet Oncol 2019). Results As of data cutoff, 46 patients had completed at least 8 cycles of therapy and had 2 sequential PET/CTs performed. By the end of induction therapy, no patient developed progressive disease and the overall response rate was 100%. Approximately 72% of patients with baseline negative PET/CTs remained negative, 11% of patients had resolution of previous focal/heterogenous FDG avidity, 15% of patients had decrease or stable focal/ heterogenous lesions, and 2% developed new focal lesions. Table 1 shows the results at subsequent time points of one and two years of maintenance therapy. Throughout this time period, one patient developed a lytic lesion after 1 year of maintenance therapy. However, 3 patients had either resolution or decrease in focal/heterogenous lesions. Specifically, after 8 cycles of combination therapy, 33 patients (70.2%, 95% CI 55.9 - 81.4%) had a response of MRD negative CR based on bone marrow flow cytometry and 26 patients (55.3%; 95% CI 41.2-68.6%) had a negative PET/CT in addition to MRD negative CR (Table 2). Conclusions It is important to evaluate the tools used in MM response assessment specifically in the SMM population as more studies report results of treatment in this population. MRD information can be used as a biomarker to evaluate the efficacy of different treatment strategies. This study demonstrates an exceptionally high rate of concordance between MRD negativity by flow cytometry and negative PET/CT after 8 cycles of KRd. However, 15% of patients were MRD negative yet had positive findings on PET/CT. While these lesions were not biopsy proven, some resolved during maintenance therapy. Further follow-up is needed to determine whether early MRD negativity in bone marrow with negative PET/CT correlates to longer overall survival and decreased progression to MM compared to those patients with a positive PET/CT. The use of PET/CT imaging may increase our understanding in assessing depth response to treatment in HR-SMM patients and be an important outcome predictor. Disclosures Korde: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other.