ALBERT

Beschreibung: Background While kidney disease (KD) is a well described complication of multiple myeloma (MM), occurring in up to 40% of patients, the incidence, pathological manifestations, and clinical correlations associated with KD in patients with Waldenström's Macroglobulinemia (WM) or IgM MGUS remain to be clarified. Methods Out of 1,738 patients with consensus criteria defined WM (N=1,655) or IgM MGUS (N=83) diagnosis who were evaluated in the WM clinic at our institution from 2001-2015, we selected those individuals with at least one of the following abnormalities: serum creatinine ≥1.3; estimated GFR (eGFR)

Beschreibung: Introduction: Approximately 40% of patients with Waldenström macroglobulinemia (WM) have an activating somatic mutation in CXCR4, including both nonsense and frameshift variants. There are limited data on the impact of CXCR4 mutations on the outcomes to therapy in WM patients. Mounting evidence suggests that CXCR4 mutations adversely affect depth of response and progression-free survival (PFS) to ibrutinib in patients with WM. Methods: We performed a pooled analysis evaluating the impact of CXCR4 mutations and CXCR4 mutation subtypes on response, PFS and survival after frontline treatment initiation (SAFTI) on 76 WM patients who received proteasome inhibitor-based primary therapy. All patients were participants on three prospective clinical trials evaluating the combinations of bortezomib, dexamethasone and rituximab (BDR; ClinicalTrials.Gov ID NCT00250926), carfilzomib, dexamethasone and rituximab (CaRD; ClinicalTrials.Gov ID NCT01470196), and ixazomib, dexamethasone and rituximab (IDR; ClinicalTrials.Gov ID NCT02400437) in previously untreated patients with WM, and were treated at the Bing Center for WM. All patients met criteria for a clinicopathological diagnosis of WM and for treatment initiation, according to the guidelines established by the 2nd International Workshop for WM (IWWM). CXCR4 mutations were divided in nonsense and frameshift mutations, as previously described. Response to therapy was assessed using response criteria by the 3rdIWWM. We fitted univariate and multivariate logistic regression and proportional-hazard Cox regression models for major response and PFS and SAFTI, respectively. P-values

Beschreibung: Background: Proteasome-inhibitor (PI) based therapy is highly effective and widely utilized in the treatment of Waldenstrom's Macroglobulinemia (WM), though published data on the long-term impact of PI-based therapy, including treatment-related peripheral neuropathy and secondary malignancies remains limited. Methods: We performed a prospective, multicenter study of bortezomib, dexamethasone and rituximab (BDR) in symptomatic, previously untreated WM patients. Treatment consisted of bortezomib 1.3 mg/m2 administered intravenously along with dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m2 on day 11 as part of a 21-day cycle for 4 consecutive cycles as induction therapy. Maintenance therapy followed 12 weeks after induction therapy, and consisted of one cycle of BDR therapy every 12 weeks for a total of 4 cycles. Dose reduction or drug omission was permitted for toxicity. Herpes zoster prophylaxis and H2-blocker were required. Results: Twenty-three patients received a median of seven cycles of treatment. The median baseline characteristics were as follows: age 66 years; bone marrow involvement 55%; serum IgM 4,830 mg/dL; serum IgA 45 mg/dL; serum IgG 418 mg/dL; hemoglobin 10.1 g/dL; and B2M 3.3 mg/L. Extramedullary disease was present in 4 (17%) patients. Following treatment, median serum IgM levels declined to 557 mg/dL (p2 toxicities were as follows: peripheral neuropathy (N=16); neutropenia (N=13); infections without neutropenia (N=13); thrombocytopenia (N=10) and steroid related hyperglycemia (N=6). Discontinuance of bortezomib occurred in 14 (60%) patients for peripheral neuropathy; dexamethasone for steroid intolerance in 3 (13%) patients; and rituximab for antibody-related neutropenia in one patient (4%). For the 16 patients experiencing bortezomib related peripheral neuropathy, neuropathic complaints resolved (N=8); decreased to Grade 1 (N=5); remained unchanged (N=2); or were unevaluable (N=1) with prolonged follow-up. Conclusions: BDR is a highly effective regimen producing high overall and major response rates, as well as long progression-free and overall survival intervals in previously untreated, symptomatic patients with WM. No unexpected toxicities were encountered. Secondary malignancies did not appear associated with protocol therapy. Reversible neurotoxicity constituted the most common adverse event associated with BDR using a twice-weekly schedule of administration of bortezomib, and resulted in high rates of proteasome-inhibitor discontinuance. Efforts to identify more neuropathy sparing approaches, including alternative schedules and routes of bortezomib administration, as well as novel neuropathy sparing proteasome-inhibitors are warranted given these encouraging long-term efficacy findings in WM. Disclosures No relevant conflicts of interest to declare.

Beschreibung: Background: Waldenström's macroglobulinemia (WM) is an incurable B-cell lymphoplasmacytic lymphoma. B-cell maturation antigen (BCMA) serves as one of the receptors for B-cell activating factor (BAFF) or a proliferation-inducing ligand (APRIL), which are members of the tumor necrosis factor (TNF) family that can induce activation of NF-κB and promote survival of B cells, including neoplastic B cells. We previously showed that serum BCMA levels are elevated in multiple myeloma (MM) patients, and correlated with disease status and overall survival (OS). In this study, we sought to determine whether BCMA levels are elevated in the serum of WM patients, track with conventional WM tumor markers, and correlate with disease status and OS. Methods: Data was obtained on a total of 67 WM patients who received treatment in one of two clinics that specialize in the treatment of WM. Serum BCMA levels were determined with a polyclonal anti-BCMA antibody using an ELISA (R&D Systems, Minneapolis, MN). Mann-Whitney analysis was used to measure differences in serum BCMA levels between WM patients and healthy subjects as well as the clinical status of WM patients. Using Kaplan-Meier analysis, OS (median follow up 5.1 years) in WM patients was measured from the time of the first assessment of serum BCMA levels in each patient. In addition, serum BCMA levels were compared to serum M-protein and IgM levels in 12 patients, serially, during their individual courses of treatment. Results: We compared serum BCMA levels for all 67 patients, including 27 untreated WM patients to healthy subjects (n = 76). Serum BCMA levels were markedly elevated in all WM patients (median 79.53 ng/mL), including those who were untreated (median 82.72 ng/mL) versus healthy subjects (median 6.32 ng/mL, p 〈 0.0001 for both comparisons). Serum BCMA values were compared to both serum M-protein and IgM levels in 12 WM patients during their disease course. Serum BCMA levels consistently correlated with changes in both of these established WM serum markers during their course of disease. Serum BCMA levels of WM patients also correlated with patient disease status at the time of sample collection. Specifically, serum from patients achieving 〉 partial response (PR, n = 12) showed significantly lower levels of BCMA than samples from patients with either stable disease (SD, n = 8, p = 0.030) or progressive disease (PD, n = 21, p = 0.0004). OS (median 12.5 years) was determined among patients in the highest serum BCMA quartile (n=16; quartile range 128.91-812.48 ng/mL) and compared to levels in the lower three quartiles (n = 48; range 20.13-128.85 ng/mL). Notably, OS was shorter among patients in the top quartile compared to those in the other three quartiles (p = 0.02). Conclusions: This is the first study to demonstrate that serum BCMA levels are elevated in Waldenström's macroglobulinemia patients. Importantly, serum BCMA levels correlated with both serum IgM and M-protein levels, as well as tracked with these established WM biomarkers for individual patients during their course of disease. Additionally, patients with levels of BCMA in the highest quartile exhibited shorter OS. Thus, serum BCMA represents a new serum biomarker to predict outcome and monitor patients with Waldenström's macroglobulinemia. Disclosures No relevant conflicts of interest to declare.

Beschreibung: Background: Waldenstrom macroglobulinemia (WM) is an indolent malignancy characterized by extended survival, and affects predominantly older individuals, who are at risk for secondary malignancies (SM). The objectives of our study were to characterize incidence and outcomes of SM after WM diagnosis using the Surveillance, Epidemiology and End Results (SEER) database. Methods: Using the SEER-13 data from 1992-2011, we calculated standardized incidence ratios (SIR) with 95% confidence intervals (CI) for rates of solid and hematologic SM in WM patients compared with matched general population, excluding synchronous tumors. We compared SIR in groups defined by attained age, calendar year, sex and race. SIRs from SM with less than 10 cases are not reported. Also, overall survival (OS) after a malignancy diagnosis was compared between patients with or without antecedent WM in Cox proportional-hazard regression models adjusting for attained age, sex, race and tumor stage using SEER-18 data from 2000-2011. The outcome of interest for survival was hazard ratio (HR) with 95% CI. Results: Among the 4,676 WM patients in the SEER-13 database, 681 SM were recorded (Table). The overall SIR was 1.49 (95% CI 1.38-1.61) and the median time to SM was 3.7 years (95% CI 3.2-4.2 years). The cumulative incidence of SM was 9.5% (95% CI 8.6-10.5%) at 5 years, and 16.1% (95% CI 14.8-17.3%) at 10 years. The cumulative incidence at 10 years was 12.2% (95% CI 11.1-13.3%) for solid tumors and 4.2% (95% CI 3.5-4.9%) for hematologic SM. The excess risk of solid tumors peaked between 5-10 years from WM diagnosis (SIR 1.1, 1.4 and 1.1 for latency of 0-5, 5-10 and more than 10 years, respectively), while for hematologic malignancies it grew continuously with time (SIR 3.8, 4.4 and 6.7, respectively). The risk of solid tumors was significantly increased for cancers of the lung, urinary tract, thyroid gland and melanoma, but not for breast, prostate or colorectal cancer. Among lymphomas, diffuse large B-cell (DLBCL) was the most frequent subtype. Patients younger than 65 had a significantly higher SIR for any SM (SIR 2.2, 95% CI 1.9-2.6) than those 65 years or older (SIR 1.4, 95% CI 1.3-1.5). The SIR for SM was similar in the 1990s (SIR 1.3, 95% CI 1.1-1.6) and 2000s (SIR 1.5, 95% CI 1.4-1.7). The SIR for solid tumors was the same (SIR 1.2) among men and women, but for hematologic malignancies the excess risk was significantly higher in women (SIR 5.8, 95% CI 4.6-7.2) than men (SIR 3.4, 95% CI 2.8-4.2). There was no difference for white and non-white patients, either for aggregate SM or for the solid/hematologic categories. Compared with age- and sex-matched population and adjusting for race and stage, OS was worse with antecedent WM for colon cancer (HR, 2.0, 95% CI 1.4-2.7), melanoma (HR, 2.6, 95% CI 1.8-4.0) and DLBCL (HR, 1.9, 95% CI 1.2-3.0). It was not significantly different for acute leukemia (HR 0.9, 95% CI 0.5-1.4), prostate (HR 1.2, 95% CI 0.9-1.6), breast (HR 1.1, 95% CI 0.7-1.9), bladder (HR 1.2, 95% CI 0.8-1.7), thyroid (HR 0.9, 95% CI 0.1-6.0) or lung cancer (HR 1.2, 95% CI 1.0-1.4). Conclusions: Patients with WM have a 49% higher risk of a SM than the general population. Further research is needed to elucidate the increased incidence of leukemia and DLBCL possibly resulting from therapy and transformation, respectively, and melanoma, lung, bladder and thyroid cancers, possibly associated with defective immune surveillance. Comparatively poor survival in WM patients with colon cancer underscores the need for guideline-adherent screening and therapy. Table Incidencea SIR 95% CI Excess casesa All malignancies 681 1.5 1.4-1.6 95 Solid tumors 484 1.2 1.1-1.3 35 Lung 101 1.5 1.2-1.8 14 Prostate 95 1.0 0.8-1.3 1 Urinary tract 62 1.4 1.1-1.8 8 Colorectal 48 0.9 0.7-1.2 -2 Other gastrointestinal 43 1.0 0.7-1.4 0 Breast 43 1.0 0.8-1.4 1 Melanoma 35 1.9 1.3-2.7 7 Other gynecologic 21 1.3 0.8-2.0 2 Head and neck 13 0.9 0.5-1.6 0 Thyroid 10 2.7 1.3-4.9 3 Hematologic malignancies 174 4.2 3.6-4.9 56 All lymphomas 120 4.4 3.6-5.2 39 Diffuse large B-cell 31 4.3 2.9-6.1 10 Extranodal marginal zone 16 14.8 8.5-24.1 6 Other indolent B-cell 19 3.7 2.2-5.8 6 Myeloma 31 4.7 3.2-6.6 10 Acute leukemia 15 3.2 1.8-5.3 4 a per 10,000 person-years Disclosures No relevant conflicts of interest to declare.

Beschreibung: Introduction: The Bruton tyrosine kinase inhibitor ibrutinib is the only FDA approved therapy for the treatment of symptomatic Waldenstrom macroglobulinemia (WM), and has been associated with high response rates and durable progression-free survival (PFS). Factors associated with depth of response and PFS duration are not well established. We performed a retrospective study aimed at identifying predictive and prognostic factors in WM patients treated with ibrutinib. Methods: We included consecutive patients with a diagnosis of WM treated with ibrutinib monotherapy evaluated at the Dana-Farber Cancer Institute since January 2012 through March 2019. Patients with Bing-Neel syndrome (WM involving the central nervous system) were excluded. Baseline clinical and laboratory characteristics were gathered. MYD88 and CXCR4 mutations were assessed using polymerase chain reaction assays and Sanger sequencing. Responses at 6 months were assessed using criteria from IWWM3. PFS was defined as the time from ibrutinib initiation until last follow-up, death or progression. Univariate and multivariate logistic regression models were fitted for partial response (PR) and very good partial response (VGPR) at 6 months, and Cox proportional-hazard regression models were fitted for PFS. Results: A total of 252 patients were included in our analysis. Selected baseline characteristics include: age ≥65 years (60%), hemoglobin

Beschreibung: Introduction: Ibrutinib is an oral Bruton Tyrosine Kinase inhibitor, approved for the treatment of symptomatic Waldenstrom Macroglobulinemia (WM). MYD88 and CXCR4 mutations affect progression-free survival (PFS) in patients with WM. In some cases, ibrutinib dose reductions are needed for the management of toxicity. However, it remains unclear if ibrutinib dose reductions adversely affect PFS in WM patients. Methods: We evaluated 217 consecutive patients with the clinicopathological diagnosis of WM who were symptomatic and received treatment with ibrutinib. We analyzed relevant clinical features and their association with the risk of dose reduction, using logistic regression models, as well as PFS using Cox proportional-hazard regression models. Time to events was estimated using the Kaplan-Meier method. p

Beschreibung: Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

Beschreibung: Introduction: Rituximab-containing regimens are commonly used for primary therapy in patients with symptomatic Waldenstrom macroglobulinemia (WM), and response is defined by decrease in serum IgM levels. In previous studies, we and others observed that in certain WM patients completing rituximab-based primary therapy, serum IgM levels continued to decline following completion of therapy, deepening the response to therapy. To further clarify the frequency and clinical characteristics, we evaluated a large population of treatment naïve patients treated at our WM center with rituximab-containing regimens. Methods: Patients with a clinicopathological diagnosis of WM requiring therapy based on criteria from the 2ndInternational Workshop for WM (IWWM) who received a rituximab-containing regimen as primary therapy in the WM center at our institution from 2005 to 2016 were included. Responses were defined per criteria from the 6thIWWM. Findings were stratified based on patients having received, or not, maintenance therapy after induction therapy. We gathered pertinent clinical data, including responses at the end of induction, at the end of maintenance, and at the lowest serum IgM level after completion of induction and/or maintenance. Response deepening was defined as 25% decrease in serum IgM at any point after completion of therapy. Results: 179 patients met eligibility criteria for this study. Induction therapy consisted of bortezomib, dexamethasone and rituximab (BDR) (N=86; 48%); bendamustine and rituximab (Benda-R) (N=57; 32%); cyclophosphamide, dexamethasone and rituximab (CDR) (N=36; 20%). 117 (65%) patients received maintenance therapy. There were no differences in baseline characteristics for age, gender, serum IgM, hemoglobin level, bone marrow involvement, hemoglobin, platelet count, beta-2-microglobulin level, MYD88 and CXCR4 mutation status, time to therapy, regimen, and receipt of maintenance therapy vs. observation status. At baseline, median serum IgM levels for patients who received maintenance was 4,445 mg/dl (range 289-8,100 mg/dl) and for those who were observed was 4,400 mg/dl (range 155-10,020 mg/dl) (p=0.37). Following induction therapy, median serum IgM levels declined to 969 mg/dl (range 33-5,940 mg/dl) and 1,366 mg/dl (114-7,108 mg/dl) for patients who subsequently received maintenance or were observed (p

Beschreibung: Hematopoietic cell kinase (HCK) is a member of the SRC family tyrosine kinases (SFKs) that is down-regulated in later stages of B-cell ontogeny. In MYD88 mutated B-cell lymphomas, HCK is aberrantly over-expressed and is activated and triggers multiple growth and survival pathways including BTK, PI3Kδ/AKT and ERK1/2 which are essential to tumor cell survival. Ibrutinib, a pleiotropic inhibitor of BTK, that produces remarkable responses in MYD88 mutated WM, ABC-DLBCL, and Primary CNS Lymphoma was found also potently inhibits HCK. Mutations that abolish ibrutinib-HCK binding greatly diminish anti-tumor activity in MYD88 mutated lymphoma cells, highlighting the importance of HCK as an essential target in MYD88 driven diseases. To clarify the transcriptional regulation of HCK in MYD88 mutated malignancies, we performed promoter binding TF profiling, PROMO weighted transcription factor (TF) consensus binding analysis, and chromatin immuno-precipitation (ChIP) studies. We identified PAX5, and mutated MYD88 downstream signaling mediators, STAT3, AP-1 and NF-kB as important drivers of HCK transcription. Knockdown of PAX5, a crucial regulatory factor required for B-cell commitment and identity, abrogated HCK transcription in MYD88 mutated lymphoma cells. Deletion of STAT3, AP-1 or NF-kB binding sites greatly reduced corresponding TFs binding and HCK promoter activity, indicating the importance of MYD88 directed signaling in the regulation of HCK transcription. Among AP-1 complex components, JunB but not c-Jun showed greatest relevance to TLR/MYD88 signaling and regulation of HCK transcription. Since STAT3 and NF-kB are known downstream mediators of mutated MYD88 signaling, we focused on the function of JunB. JunB phosphorylation increased following MYD88 pathway activation through TLR4 (with LPS-EB) or TLR9 (with ODN-2006), as well as lentiviral mediated expression of mutated MYD88 (L265P) but not wild type MYD88 (MYD88-WT) at Thr102 and Thr104 in either MYD88 mutated BCWM.1 cells or MYD88-WT Ramos cells. Conversely, c-Jun phosphorylation was not impacted by either intervention. Knockdown of MYD88 in BCWM.1 WM cells also reduced the phosphorylation of JunB, while c-Jun phosphorylation showed modest increase. Moreover, knockdown of JunB reduced HCK protein levels in MYD88 mutated WM and ABC-DLBCL cells. These data demonstrate that JunB is an important mediator of mutated MYD88 signaling among AP1 complex members and is directly involved in the regulation of HCK expression in MYD88 mutated B-cell lymphoma. The findings provide new insights into the transcriptional regulation of HCK by MYD88 driven TFs, and opportunities for further advancing targeted therapeutics in MYD88 driven B-cell malignancies. Disclosures Hunter: Janssen: Consultancy. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.