Cook, Joselle

Abstract Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

8051 Background: Patients with multiple myeloma (MM) that do not respond to initial therapy have worse outcomes compared to primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not been studied. Methods: From 2007-2019, we reviewed MM patients treated with triplet/quadruplet therapy in our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. Primary refractory disease was defined as either progressive disease or stable disease at 4-6 cycles. The Kaplan-Meier estimates were used for survival probabilities. PFS and OS were calculated from MM diagnosis to progression, escalation/change of treatment, or death, respectively. For the primary refractory group, the second PFS and second OS were measured from the start of second-line therapy. The Cox regression model was used for multivariable analysis with the following variables (age, ISS, induction therapy, FISH, and bone marrow plasma cells at diagnosis). Results: We identified 1127 patients, of which 1086 were evaluated for hematologic response after 4-6 cycles. Of these, 93.3% (1013) had evidence of response, while 6.7% (73) had primary refractory disease. With a median OS of 50.7 months, patients with primary refractory disease had an increased risk for shorter survival in univariable and multivariable analysis (HR: 3.6, 95% CI = 2.61 – 4.96, HR = 3.89, 95% CI = 2.68 – 5.65, respectively). In subgroup analysis of primary refractory patients, the median second PFS and second OS from the first relapse were 11.9 months (95% CI: 8.7 – 17.3 months) and 43.4 (95% CI: 31.4– 75.9 months), respectively. Patients that received 2nd line ASCT had increased second PFS (20.9 vs. 8.1 months, respectively, p < 0.01) and second OS (74.7 vs. 31.3 months, respectively, p = 0.02) compared to patients that did not. Patients that took daratumumab as the second line did not have any significant survival differences compared to those who did not, p = NS. Conclusions: We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population. [Table: see text]

8024 Background: Minimal residual disease (MRD) is prognostic for survival in multiple myeloma (MM). MRD is usually assessed in the bone marrow (BM) by flow cytometry or NGS. MRD by FDG PET/CT provides a global representation of the tumor burden, including response assessment of extramedullary disease. We examined MRD status in MM pts using both BM and PET/CT at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CAR-T between 4/2018 and 12/2022. All PET/CT scans were assessed by radiologists. BM MRD was assessed by flow cytometry with a sensitivity of 10-5. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Results: Among the 157 CAR-T pts, including 89 pts who received FDA-approved CAR-T, median age was 63 years, 59% (92/157) were males, 42% (66/157) had high risk cytogenetics with median of 5 prior lines of therapy, 36% (57/157) had plasmacytoma. Incidence of CRS was 83%, 5% grade ≥ 3 CRS. Incidence of ICANS was 19%, 4% grade ≥ 3 ICANS. CR/sCR rate was 37%. One hundred and thirty-seven pts (87%) had evaluable BM at month (mo) 1, 85% (117/137) were BM MRDneg at mo 1. Baseline demographics were comparable between the two groups except age, % BM plasma cells and use of bridging therapy. Among the MRDneg pts, CR/sCR rate was 44% (51/117) and 95% (111/117) had sFLC below normal. At median follow-up of 13.8 months, median PFS among pts with BM MRDneg at 1 mo was 12 mo (95% CI: 11, 30) vs 3 mo (95%CI: 2, 7) for BM MRDpos (p<0.001). Median OS among pts with BM MRDneg at 1 mo was 34 mo (95% CI: 24, NR) vs 22 mo (95%CI: 7, NA) for BM MRDpos (p<0.01). At month 1, 112 pts had both BM and PET/CT assessments available, 64/112(57%) were both BM MRDneg/PET MRDneg, 38/112 (34%) were MRDneg for either BM or PET and 10/112 (9%) were positive for both BM and PET (MRDpos/PET MRDpos). Baseline demographics except age were comparable between the 2 groups (Table). Rate of conversion from MRDpos to MRDneg was low. Rate of sustained BM and PET MRDneg at mo 12 was 44% (8/18). The median PFS and OS for BM MRDneg/PET MRDneg was significantly longer as compared to others (Table). Conclusions: Achieving FLC below normal, BM MRDneg and PET MRDneg at 1 month, regardless of IMWG response at that time, is prognostic for both PFS and OS in MM pts receiving CAR-T. Failure to achieve any of these confers poor prognosis. [Table: see text]

7530 Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach currently under study for relapsed refractory (R/R) hematologic malignancies. The engineered Vesicular Stomatitis Virus VSV-IFNβ-NIS used in this study encodes interferon beta (IFNβ) and sodium iodine symporter (NIS). Virally-encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. Herein, we report the updated results of the phase 1 clinical trial NCT03017820 of a one-time administration of systemic VSV-IFNβ-NIS among patients (pts) with R/R multiple myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leukemia (AML) with particular focus on the TCL cohort treated at the highest dose level (DL4) without Ruxolitinib. Methods: VSV-IFNβ-NIS was administered as a single IV dose following a classical 3+3 phase I trial, starting at 5e9 TCID50 DL1 through 1.7e11 TCID50 DL4. A dose expansion cohort of 8 additional R/R TCL pts was added at DL4 in view of an initial signal of activity. The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNβ-NIS. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: To date, a total of 43 pts received VSV-IFNβ-NIS: MM (N=21), TCL (N=21) and AML (N=1). In the TCL cohort: at DL4 Group A (no Ruxolitinib), 12 pts were registered, but only 11 pts were treated (mycosis fungoides (MF) N=3; ALK- ALCL N=1; PTCL-NOS N=2; AITL N=4; Nodal PTCL, TFH N=2; ages 33-79). These pts received a median of 3 lines of therapy (range: 1-5). No dose limiting toxicities were observed. Grades 3 and higher AEs were hematologic with transient lymphopenia (63.6%), neutropenia (36.4%) being the most common. The non-hematologic AEs observed included unique toxicities such as CRS grades 1-2 (81.8%); the transient transaminitis grade 1-2 (36.4%) and grade 3 (27.3%) along with thrombocytopenia grade 1-2 (63.6%) and grade 3 (18.2%) were a reflection IFNβ toxicity. All the AEs observed were short lived. Responses were seen in pts with PTCL. At DL4, in pts with systemic PTCL (N=9), there were 5 responses including 3 complete responses (CR) with two long-lasting at 24 months, an ongoing 15 month CR, and a 5 month CR, and 2 partial responses (PR) lasting 5 months in one pts and 6 months in the other. Conclusions: These updated results of single agent VSV-IFNβ-NIS which include pts with PTCL treated at the highest dose level and a dose expansion cohort demonstrates not only the safety of VSV-IFNβ-NIS but also a strong efficacy signal in pts with PTCL with impressive durable responses. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma pts) to obtain additional data on tolerability and efficacy and biomarkers of response in these pts. Clinical trial information: NCT03017820 .

AbstractBackgroundDual‐energy CT with virtual noncalcium (VNCa) images allows the evaluation of focal intramedullary bone marrow involvement in patients with multiple myeloma. However, current commercial VNCa techniques suffer from excessive image noise and artifacts due to material decomposition used in synthesizing VNCa images.ObjectivesIn this work, we aim to improve VNCa image quality for the assessment of focal multiple myeloma, using an Artificial intelligence based Generalizable Algorithm for mulTi‐Energy CT (AGATE) method.Materials and methodsAGATE method used a custom dual‐task convolutional neural network (CNN) that concurrently carries out material classification and quantification. The material classification task provided an auxiliary regularization to the material quantification task. CNN parameters were optimized using custom loss functions that involved cross‐entropy, physics‐informed constraints, structural redundancy in spectral and material images, and texture information in spectral images. For training data, CT phantoms (diameters 30 to 45 cm) with tissue‐mimicking inserts were scanned on a third generation dual‐source CT system. Scans were performed at routine dose and half of the routine dose. Small image patches (i.e., 40 × 40 pixels) of tissue‐mimicking inserts with known basis material densities were extracted for training samples. Numerically simulated insert materials with various shapes increased diversity of training samples. Generalizability of AGATE was evaluated using CT images from phantoms and patients. In phantoms, material decomposition accuracy was estimated using mean‐absolute‐percent‐error (MAPE), using physical inserts that were not used during the training. Noise power spectrum (NPS) and modulation transfer function (MTF) were compared across phantom sizes and radiation dose levels. Five patients with multiple myeloma underwent dual‐energy CT, with VNCa images generated using a commercial method and AGATE. Two fellowship‐trained musculoskeletal radiologists reviewed the VNCa images (commercial and AGATE) side‐by‐side using a dual‐monitor display, blinded to VNCa type, rating the image quality for focal multiple myeloma lesion visualization using a 5‐level Likert comparison scale (−2 = worse visualization and diagnostic confidence, −1 = worse visualization but equivalent diagnostic confidence, 0 = equivalent visualization and diagnostic confidence, 1 = improved visualization but equivalent diagnostic confidence, 2 = improved visualization and diagnostic confidence). A post hoc assignment of comparison ratings was performed to rank AGATE images in comparison to commercial ones.ResultsAGATE demonstrated consistent material quantification accuracy across phantom sizes and radiation dose levels, with MAPE ranging from 0.7% to 4.4% across all testing materials. Compared to commercial VNCa images, the AGATE‐synthesized VNCa images yielded considerably lower image noise (50–77% noise reduction) without compromising noise texture or spatial resolution across different phantom sizes and two radiation doses. AGATE VNCa images had markedly reduced area under NPS curves and maintained NPS peak frequency (0.7 lp/cm to 1.0 lp/cm), with similar MTF curves (50% MTF at 3.0 lp/cm). In patients, AGATE demonstrated reduced image noise and artifacts with improved delineation of focal multiple myeloma lesions (all readers comparison scores indicating improved overall diagnostic image quality [scores 1 or 2]).ConclusionsAGATE demonstrated reduced noise and artifacts in VNCa images and ability to improve visualization of bone marrow lesions for assessing multiple myeloma.

e20001 Background: High dose melphalan followed by autologous stem cell transplant (HDM-ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) despite advances in treatments. Achievement of complete response (CR) is associated with improved overall survival (OS) and progression-free survival (PFS); Minimal Residual Disease (MRD) negativity (-) using next generation flow cytometry with a sensitivity of 10-5 is strongly associated with improved PFS and OS. We investigated the rates of conversion to MRD(-), especially MRD(-) CR following HDM-ASCT in patients with NDMM. Methods: We retrospectively reviewed patients with NDMM who underwent early HDM-ASCT at Mayo Clinic Rochester from May 2018 to July 2019. Response assessment was conducted after induction and within 100 days post-ASCT based on 2016 IMWG criteria, except for using Mass-Fix instead of immunofixation. MRD was assessed in bone marrow using the established Euro Flow protocol with sensitivity of 10-5. The FISH assay was used to risk-stratify patients as high-risk (HR) and standard risk (SR) cytogenetics as per the mSMART guidelines. Primary outcome measure was the conversion to MRD(-) CR after ASCT. Secondary outcomes include the overall conversion to MRD(-) irrespective of IMWG response, the impact of HR cytogenetics and pre-ASCT IMWG response on conversion to MRD(-) CR. Results: Two-hundred and ten patients were included; 126 (60%) were male and median age 62 years (range 32–77 years). There were 78 (44%) patients with HR cytogenetics. Pre-ASCT, 23 patients (11%) achieved MRD(-) CR, and 66 (31%) patients achieved MRD(-) CR post ASCT. Of 187 patients not in MRD(-) CR pre-ASCT, 45 (24%) converted to MRD(-) CR. Table provides a breakdown of the conversion rate of pre-ASCT IMWG response category to MRD(-) CR post ASCT and patients with MRD(+) CR had the highest rate (78%) of conversion. The presence of HR cytogenetics did not impact rates of MRD(-) CR achievement post ASCT irrespective of pre-ASCT IMWG response (p = 1.0). Overall, irrespective of IMWG response, 43 (20%) patients were MRD(-) pre-ASCT (19 in VGPR, 24 in CR or better) and 102 (49%) patients were MRD(-) post-ASCT (36 in VGPR, 66 in CR or better). Among 85 patients in VGPR post-ASCT, 36 were MRD(-) of which 8 (22%) progressed, while 49 were MRD(+) of which 24 (49%) progressed (p = 0.014). Conclusions: Upfront HDM-ASCT in patients with NDMM leads to deeper responses with 24% converting to MRD(-) CR and more than doubling of the total rate of MRD(-) irrespective of IMWG response. [Table: see text]

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).