11505 Background: Kaposi sarcoma (KS), caused by Kaposi sarcoma herpesvirus (KSHV), is a multicentric angioproliferative tumor seen in people with and without HIV. Abemaciclib (abema) is an oral cyclin-dependent kinase (CDK) inhibitor that targets CDK4 (cyclin D1) and CDK6 (cyclin D3), and is FDA-approved for breast cancer. In vitro studies of KSHV-infected cells have shown that CDK4/6 inhibitors enhance host immune cell surface expression and T-cell activation induced by these cells. Here, we investigate the safety and activity of abema in participants (pts) with KS. Methods: In this open label, non-randomized, two-stage Phase I/II study of pts with KS, there were two primary objectives. Phase I evaluated the safety and tolerability of abema in pts with KS using a 3+3 dose de-escalation design to identify a maximum tolerated dose (MTD). The first group of pts were treated at dose level 1 (DL) of 200mg twice daily for days 1-28 of a 28-day cycle. Intra-participant dose reductions were permissible for abema-related toxicities. Phase II assessed the overall response rate of abemaciclib of all participants and stratified by prior systemic KS therapy (Arm 1 target: 15 pts with previously treated KS and Arm 2 target: 10 participants with untreated KS). Eligibility criteria included adherence to antiretroviral therapy in people with HIV (PWH) for > 8 weeks prior to enrollment and no concomitant strong CYP3A4 inhibitors. KS response was evaluated using the modified AIDS Clinical Trials Group criteria. Results: Thirty-four pts (33 men) with a median age of 43 years were enrolled. Twenty-five (74%) were PWH and 27 pts had stage T1 KS (6 pts had either gastrointestinal and/or lung involvement). Among PWH, the baseline median HIV viral load was <20 copies/ml and the median CD4 T-cell count was 308 cells/µL (interquartile range: 176-468 cells/µl). In Phase I, 6 pts (4 PWH) were enrolled at 200mg BID with no dose-limiting toxicities. In Phase II, 17 pts (14 PWH) were enrolled to Arm 1, and 11 pts (7 PWH) enrolled to Arm 2. Overall, 3 pts (2 in Arm 1 and 1 in Arm 2) did not proceed after one cycle due to grade 2 anxiety in 2 pts and tremor in 1 pt that were unrelated to study therapy. These pts were replaced as KS response was not evaluable. The most common grade 1/2 adverse events were diarrhea (92%) and creatinine elevation (64%). Neutropenia of all grades was noted in 63% and 13 pts had dose reductions for recurrent grade 3 or grade 4 neutropenia. Among 31 evaluable pts receiving >2 cycles, 24 pts had a partial response (PR) (77% [95% confidence interval (CI): 59-90%]), 4 pts had stable disease and 2 pt had progressive disease. Sixteen of 21 pts who prior KS therapy had a PR (76% [95% CI: 53-92%]) and 8 of 10 pts in Arm 2 with previously untreated KS had a PR (80% [95% CI: 44-98%]). Conclusions: Abema is a novel therapeutic option in KS, with notable activity among pts with previously untreated KS. Adverse events were managed with dose reduction and supportive measures. Clinical trial information: NCT04941274 .

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.

OBJECTIVE:There are four conditions caused by Kaposi sarcoma herpesvirus (KSHV): Kaposi sarcoma, KSHV-associated multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV inflammatory cytokine syndrome (KICS). These KSHV-associated disorders (KADs) often occur in people with HIV and can lead to multiorgan dysfunction requiring admission to the ICU. However, little is known about patient outcomes in this setting.METHODS:A retrospective study of patients with KADs admitted to the ICU between 2010 and 2021 was conducted, examining KAD admission diagnoses, HIV characteristics, selected cytokine profiles, and ICU interventions. Primary outcomes were 60-day and median overall survival from ICU admission to death from any cause.RESULTS:Forty-seven patients (all but one with HIV coinfection) were included. At ICU admission, 44 patients (94%) were on antiretroviral therapy with a median CD4 + count of 88 cells/μl and HIV viral load of 23 copies/ml. The most common presentation was respiratory failure alone (19%) or with hypotension (17%). Twenty-two (47%) patients had presumed KICS (with or without Kaposi sarcoma) at admission and an additional KAD was diagnosed in 36% of these patients. IL-6 levels did not vary across KAD subtype. Twenty (43%) patients received KAD-directed therapy in the ICU. Sixty-day survival was 70% and median overall survival was 9 months.CONCLUSION:The majority of patients with HIV and KADs admitted to the ICU had well controlled HIV. Additional KAD were diagnosed during ICU admission in a proportion of patients who presented with presumed KICS. Critical illness did not preclude a subset of patients from receiving KAD-directed therapy in the ICU.

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.

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.