Go, Ronald S.

AbstractThree sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5–5.3, p = .001] and 2.5 [CI: 1.4–4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17–0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post‐treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post‐treatment. These differences are important when choosing endpoints for clinical trials.

AbstractInduction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment‐emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first‐line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty‐five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21‐day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22–56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.

AbstractIntroductionLittle is known on continued response following completion of therapy in light chain (AL) amyloidosis.MethodsWe studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first‐line therapy.ResultsBy end of therapy (EOT), 46% of patients achieved a CR and 54% a VGPR. With no further therapy, 17.5% of patients were upstaged from VGPR to CR (delayed CR), with a median of 9 months. Compared with CR and VGPR at EOT, patients with a delayed CR were characterized by higher proportion of t(11;14) and lower rate of trisomies. Autologous stem cell transplant was more frequent in the delayed CR group. Patients with a delayed CR were characterized by minimal residual disease negativity and organ response rates similar to patients with CR at EOT and higher than patients achieving VGPR at EOT. Patients with a delayed CR had a longer PFS/OS compared to patients with CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; 10‐year OS 87% vs 71% vs 56%, P < .001).ConclusionsThis study characterizes delayed CR in AL amyloidosis, highlights its prognostic impact which is at least similar to those who achieved CR at EOT, and underlines another aspect of response monitoring.

SummaryMeasurable residual disease (MRD) assessment by marrow‐based next‐generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false‐negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MASS‐FIX). Of all 61 complete responders who were NGF‐negative for MRD, around day‐100 post ASCT, 59% were MASS‐FIX‐positive. At median follow‐up of 26 months, 69% of MASS‐FIX(+)/NGF(−) patients were alive and progression‐free versus 96% of MASS‐FIX(‐)/NGF(−) patients, P = 0·02. MASS‐FIX, a simple peripheral blood‐based assay complements marrow‐based NGF to accurately prognosticate patients with myeloma.

Rosai-Dorfman disease (RDD) is a rare histiocytosis with heterogenous clinical features. In this study, we characterized the histologic and phenotypic features in 33 RDD patients to better define the pathologic diagnosis. Cases included 24 patients with extracutaneous disease (“R” group), and 9 patients with lesions limited to the skin or subcutaneous tissue (“C” group). We identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD, expressed in 97% of RDD cases. In contrast, OCT2 expression was seen in 0% of Erdheim-Chester disease cases and 6.7% of Langerhans cell histiocytosis cases. Other markers useful in the diagnosis of RDD included S100 (100%), CD163 (88%), and cyclin D1 (97%). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30%), p16 (64%), and phosphorylated extracellular signal-regulated kinase (45%); RDD was uniformly negative for ZBTB46, CD1a, and langerin. Within the “R group” of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease ( P <0.05). Identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers our understanding of this complex disease and allows for more uniform classification.

INTRODUCTION: Autoantibody effects of monoclonal proteins have been described in multiple organ systems. We previously found a 5-fold higher prevalence than expected of monoclonal gammopathy (MG) in adults with TMA (21% versus 4.2%; Ravindran A et al, Kidney Int 2017). Here we investigated the prevalence of MG in patients undergoing evaluation for TMA with an ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) activity assay performed as part of routine clinical care to evaluate for a signal of possible autoantibody pathophysiology in patients with immune thrombotic thrombocytopenic purpura (iTTP). METHODS: WAfter IRB approval, waste plasma samples from patients who had ADAMTS13 activity and inhibitor assay (Lifecodes, ATS-13, Immucor) were archived. Eligible patients included those with the following: i) ADAMTS13 activity level &lt; 30% (n=26), ii) ADAMTS13 activity level &gt;30% but with prior documentation of a value &lt; 30% (n=4). A control cohort (n=49) of patients with ADAMTS13 activity level &gt;30% (and no prior samples with a level &lt; 30% recorded) was also included. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry detection (MALDI-TOF) was used for MG assessment. Mass spectrometry findings of only an IgG kappa MG appearing consistent with rituximab were reviewed and considered negative for MG if the patients had received rituximab prior to sample collection. Medical records were retrospectively reviewed and the following patients were excluded: i) &lt;18 years of age (n=4), ii) iTTP in remission (n=4) at the time of sample collection, and iii) absence of microangiopathy (n=11). RESULTS: Sixty patients met eligibility criteria with the following final diagnoses: iTTP (n=14), transplant-associated TMA (n=12), infection (n=11), malignancy (n=6), complement-mediated TMA (n=5), drug-induced TMA (DITMA; n=5), shock liver (n=2), pancreatitis (n=1), cryoglobulinemia (n=1), and multifactorial (n=3). The median age was 56.5 years (yr) (standard deviation 14.4, range18-81) and 58% of patients were female. The median age was similar among patients with (57 yr) and those without MG (56 yr). Median ADAMTS-13 activity of the whole study population was 52% (0-100%); 6/14 patients with an inhibitor screen performed on the same sample had a positive result; median titer was 1.2 Bethesda units (range &lt;0.4 - 2.8). Treatments of the acute presentation included corticosteroids (n=32), plasma exchange (n=21), rituximab (n=9), and eculizumab (n=4). None of these patients received a multiple myeloma-type treatment regimen as part of their acute management. A MG was identified in 25 patients: monoclonal in 14 patients, biclonal in 10 patients, and triclonal in 1 pt. Among the 14 patients with a single monoclonal protein, the distribution of heavy and light chains was as follows: IgG (9; 64%), IgM (3; 21%), IgA (2; 14%), lambda (8; 57%), kappa (6; 43%). Receipt of immune-modifying treatment at the time of sample draw was identified in 24 patients (9/25 with a monoclonal protein, 15/35 without a monoclonal protein; not statistically significant by 2-tail Fisher's exact test [p=0.79]), including cancer-directed therapy (n=9), graft-versus-host disease prophylaxis (n=8), solid organ transplant anti-rejection therapy (n=5), and autoimmune disease treatment (n=2). Overall, the proportion of patients with monoclonal gammopathy was similar between iTTP and other diagnoses, detailed in Table 1. Among the 14 pt with iTTP, 4 had a monoclonal protein (IgG kappa [n=2], IgA lambda [n=2]). Additionally, 1 pt with iTTP had biclonal proteins (IgG kappa and IgA kappa), which was consistent with a known prior history of monoclonal gammopathy of undetermined significance. A monoclonal protein was present in 2 of the 6 pt with a detectable inhibitor titer (0.6 and &lt;0.4 Bethesda units). CONCLUSIONS: Patients undergoing evaluation for iTTP with ADAMTS-13 activity testing had a high prevalence of monoclonal proteins across variable underlying diagnoses. In this heterogeneous cohort there was no significant association between iTTP and the presence of MG to support an autoantibody pathophysiologic role. Disclosures Murray: The Binding Site: Patents & Royalties: Patent Use of Mass Spec to identify monoclonal proteins licensed to The Binding Site. Pruthi:HEMA Biologics: Honoraria; Instrumentation Laboratory: Honoraria; Merck: Honoraria; CSL Behring: Honoraria; Genentech Inc.: Honoraria; Bayer Healthcare: Honoraria.

Introduction: In general, the use of an immunomodulator (IMiD), proteasome inhibitors (PI) and dexamethasone (dex) for the treatment of MM is associated with better outcomes. The management of elderly patients with multiple myeloma (MM) is challenging due to difficulty in managing their co-morbidities and inability to tolerate treatment side effects. We evaluated therapies and outcomes of elderly patients with newly diagnosed MM. Methods: This is a retrospective study of patients with MM who were &gt;75 years old treated at the Mayo Clinic, Rochester from January 2004 to January 2018. We included patients who were treated on clinical trials as well as off-trials. Patients were classified as receiving treatment with IMiD+PI+dex, alkylator+PI+steroid, IMiD+dex, PI+dex, alkylator+IMid+steroid, and other (alkylator with steroid or steroid only). Treatment response was documented as well as the progression-free (PFS), defined as the time from therapy initiation to disease relapse or death from any cause and overall survival (OS), defined as the time from start of treatment to death from any cause. A multivariate analysis for factors affecting OS was done including the following variables: being on a triplet combination (alkylator+PI+steroid, IMid+PI+dex, or alkylator +IMiD+steroid), revised international staging system (R-ISS)(stage 3 vs. 1-2), bone marrow plasma cell percentage (BMPC%)(&gt;60% vs. ≤60%), and receiving treatment during or after 2010 vs. before 2010. Analysis was done for patients treated off-trials, as well as, including trial patients. Results: We identified 394 patients with MM who were &gt;75 years old and 246 (62%) were male. For non-trial patients (n=350), IMiD+dex (32%) was the most commonly used regimen followed by alkylator with steroid or steroid only (20%), alkylator+PI+steroid (18%), and IMid+PI+dex (13%). The remaining patients were treated with PI+dex (12%) and alkylator +IMiD+steroid (5%). Forty-four patients (11%) were treated in clinical trials with alkylator+IMid+steroid (47%), IMiD+dex (25%), IMiD+PI+dex (14%), and alkylator+PI+steroid (14%). The median follow up was 45.9 months with an interquartile range of 28.2 to 75.6 months. Overall, achieving very good partial response or complete response was more likely in patients who were treated with an IMid+PI+dex (58%) or alkylator+PI+steroid (47%), compared to in other therapies (5-30%)(P&lt;0.0001). The PFS and OS for non-trial patients are displayed in Figure 1 (A,B) and for all, including trial patients in (C,D). Overall, the median OS was significantly longer in patients who were treated with a triplet in non-trial as well as all patients. In a multivariate for OS including non-trial patients, predictors for better OS included receiving a triplet (HR: 0.63, P=0.02) and not having an R-ISS stage 3 (HR: 0.39, P=0.001). This was also found when including trial patients (using a triplet, HR: 0.65, P=0.01 and not having an R-ISS stage 3, HR: 0.35, P=0.0002). Conclusion: In MM patients &gt;75 years old, being able to receive triplet therapy is associated with better survival. This study provides better understanding of the natural history of MM outside of trials in the elderly age group. Disclosures Dispenzieri: Celgene: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Intellia: Research Funding; Takeda: Research Funding; Janssen: Research Funding. Dingli:Bristol Myers Squibb: Research Funding; Alexion: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Sanofi-Genzyme: Consultancy; Apellis: Consultancy; Janssen: Consultancy; Karyopharm Therapeutics: Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Celgene: Honoraria. Gertz:Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Prothena: Other: personal fee; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee; Springer Publishing: Patents & Royalties; Proclara: Other; DAVA oncology: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Teva: Speakers Bureau; Sanofi: Other; Research to Practice: Other; Celgene: Other; Abbvie: Other; Aurora Bio: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Amgen: Other: personal fee; Appellis: Other: personal fee; Annexon: Other: personal fee. Kumar:Carsgen: Other, Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Cellectar: Other; Genecentrix: Consultancy.

Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach for relapsed refractory hematologic malignancies. The Indiana strain of Vesicular Stomatitis Virus (VSV) has been engineered to encode interferon beta (IFNβ) and sodium iodine symporter (NIS) to produce VSV-IFNβ-NIS. The virally encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. The NIS is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. Here we present results of Arm A (patients with low tumor burden) of the Phase I clinical trial (NCT03017820) of intravenous administration of VSV-IFNβ-NIS for patients (pts) with relapsed refractory hematological malignancies: MM, AML, and TCL. Methods: This was a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (50% tissue culture infectious dose) level 1 through 1.7x10^11 TCID50 dose level 4 given as a single IV dose. The primary objective was determining the maximum tolerated dose of VSV-IFNβ-NIS alone; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding and changes in the immune profile of peripheral blood leukocytes. Adverse events (AEs) are reported based on CTCAE v4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014; 124(2):188-195) criteria. Results: From April 2017, 12 pts have received IV VSV-IFNβ-NIS in Arm A: MM (7), TCL(4) and AML(1); 3 pts were treated at each dose level (DL) 1 to 4. At DL1, there were five grade 3 hematologic AEs (leukopenia [1], neutropenia [1], lymphopenia [3]) and no grade 3+ non-hematologic AEs. At DL2, three grade 3 hematologic AEs (anemia [2], lymphopenia [1]), four grade 4 hematologic AEs (neutropenia [1], leukopenia [1], lymphopenia [1] and thrombocytopenia [1]). There was 1 event of grade 2 CRS at DL2, two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). At DL3, there was one grade 4 hematologic AE (neutropenia [1]), three grade 3 hematologic AEs (lymphopenia [2], leukopenia [1]), and one grade 3 non-hematologic AE (vasovagal reaction [1]). One grade 2 and grade 1 CRS by Lee criteria were observed. At DL4, there were three grade 3 hematologic AEs (lymphopenia [1], neutropenia [1], thrombocytopenia [1]), and three grade 3 non-hematologic AEs (AST increase [1], skin infection [1], soft tissue infection [1])and two grade 2 CRS. There were no dose limiting toxicities. There was one partial response (DL2) and one complete response (DL4); 3 pts had stable disease, 7 pts progressed. The MM pts receiving VSV-IFNβ-NIS at DL4 had stable disease. Six of the 7 MM pts demonstrated transient reduction in serum level of involved free light chain (LC) after VSV-IFNβ-NIS infusion, with median 20.4% reduction of the involved LC within 48 hrs. Viremia was detectable in all pts at the end of infusion, to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hrs post infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. The IFN levels were detectable within 30 minutes of infusion and peaked between 4 and 48 hrs. The pts with a diagnosis of TCL mounted higher hIFNβ levels within 48 hrs. Remarkably, the TCL pt with CR (DL4) mounted a peak hIFNβ response of 18213.3pg/ml at 48 hrs post infusion, approximately 15-fold higher than any other pt enrolled in the study; and highest neutralizing antibody titer (1:40960). Conclusion: VSV-IFNβ-NIS can be safely administered by intravenous infusion in pts with hematological malignancies, up to a dose level of 1.7 x 1011 TCID50, without dose limiting toxicities and no CRS higher than grade 2. In this small phase 1 study, pts with T-cell lymphoma demonstrated the strongest signal of response, with one confirmed partial response at DL2 and one complete response at DL4. IFNβ is an early biomarker of tumor susceptibility; the magnitude of IFNβ elevation appears to correlate with treatment response. There were no confirmed responses in pts with MM, but the 20.4% transient reduction in LC suggests that combination strategies with VSV-IFNβ-NIS may result in deeper and sustained responses in MM. Future trials investigating combination strategies with immune modulatory drugs are being planned. Disclosures Peng: Imanis: Other: Equity Ownership. Witzig:Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Incyte: Consultancy; Acerta: Research Funding; MorphSys: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Dispenzieri:Intellia: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Gertz:Celgene: Consultancy; Annexon: Consultancy; Sanofi: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; NCI SPORE MM: Research Funding; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; Ionis/Akcea: Consultancy; Spectrum: Consultancy, Research Funding; Prothena: Consultancy; DAVA oncology: Speakers Bureau; i3Health: Consultancy; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; International Waldenstrom Foundation: Research Funding. Dingli:Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Kumar:Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Sanofi: Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Karyopharm: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Genecentrix: Consultancy; Tenebio: Other, Research Funding. Russell:Imanis: Other: Equity Ownership. OffLabel Disclosure: This describes of administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and human interferon, in Patients with Relapsed or Refractory Hematologic malignacies