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Langerhans cell histiocytosis (LCH) is a histiocytic neoplasm that can involve the lungs as single system (LCH-SSL) or multisystem disease (LCH-MSL). The role of full-body radiographic staging to determine whether patients have LCH-SSL or LCH-MSL is unclear. Long-term outcomes of LCH-SSL versus LCH-MSL and multisystem without lung involvement (LCH-MSNL) are unknown. A retrospective study of adult LCH patients seen at our center from January 2000 to 2020 was performed. In Part 1, we addressed utility of whole-body staging imaging among those presenting with isolated pulmonary signs or symptoms. Staging was defined as fluorodeoxyglucose positron emission tomography-computed tomography (CT) or whole-body CT obtained within 3 months of diagnosis. In Part 2, we examined the frequency of developing extra-pulmonary disease over time and mortality in patients with LCH-SSL. In Part 3, we compared the overall survival of LCH-SSL, LCH-MSL, and LCH-MSNL. Part 1: 240 patients with LCH were identified. A total of 112 (47%) had pulmonary signs or symptoms at presentation. Thirty-four (30%) underwent radiographic staging and only one showed evidence of extra-pulmonary disease. Part 2: 108 (45%) were LCH-SSL. Median follow-up duration of 4.5 years (95% confidence interval [CI]: 2.9-6.0). None developed extra-pulmonary disease. Part 3: 5-year survival: 94% (95% CI: 84%-98%) for LCH-SSL, 78% (95% CI: 59%-90%) for LCH-MSL, and 75% (95% CI: 53%-89%) for LCH-MSNL. LCH patients presenting with isolated pulmonary signs or symptoms rarely have extra-pulmonary involvement at the time of diagnosis and generally do not develop extra-pulmonary progression. LCH-SSL has the best overall survival, while LCH-MSL and LCH-MSNL have similar clinical outcomes.

Patients with asymptomatic/smouldering Waldenstrom macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β2 -microglobulin (β2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.

This is a retrospective study of patients with multiple myeloma (MM) who were >75 years old. We identified 394 patients and for non-trial patients (n = 350), immunomodulatory drug (IMiD)+dex (32%) was the most commonly used regimen followed by alkylator with steroids or other therapy (21%), alkylator + proteasome inhibitor (PI)+steroid (18%), and IMiD + PI + dex (13%). Overall, achieving ≥ very good partial response was more in patients receiving a triplet compared to other therapies (46% vs. 21%, p 75 years old.

Multiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut-off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1-15) and 14% of patients had received ≥10 prior lines of therapy. Fifty-three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9-10.3) months and median OS was 28.4 (95% CI 14.6-not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily-treated patients with relapsed/refractory MM, particularly the t(11;14) patient-population.

Comparative data guiding initial therapy for Waldenstrom macroglobulinemia (WM), an infrequently encountered non-Hodgkin lymphoma, are sparse. We evaluated three commonly used frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naive patients with WM, seen at Mayo Clinic between 11/01/2000 and 10/31/2019. The median follow-up was 4.5 (95%CI: 4-5) years. The R-Benda (n=83) cohort demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n=92, ORR: 78%) or BDR (n=45, ORR: 84%) cohorts, p=0.003. Similarly, longer progression-free survival (PFS) was evident with R-Benda use [median 5.2 versus 4.3 (DRC) and 1.8 years (BDR), p=0.0003].The time-to-next therapy (TTNT) favored R-Benda [median, not-reached, versus 4.4 (DRC) and 2.6 years (BDR), p=0.0002). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p=0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naive patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status. This article is protected by copyright. All rights reserved.

Objective To evaluate the clinical outcomes of patients with primary plasma cell leukemia (pPCL) defined by 5% or greater clonal circulating plasma cells on peripheral blood smear and treated with novel agent induction therapies. Patients and Methods A cohort of 68 patients with pPCL diagnosed at the Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to December 31, 2019, and treated with novel agent induction therapies was evaluated. Results The median follow-up was 46 (95% CI, 41 to 90) months. The median bone marrow plasma cell content was 85% (range, 10% to 100%) and median clonal circulaitng plasma cell percentage on the peripheral blood smear was 26% (range, 5% to 93%). There was a preponderance of t(11;14) primary cytogenetic abnormality in this cohort. The median time to next therapy (TTNT) and overall survival (OS) for all patients with pPCL patients in this cohort was 13 (95% CI, 9 to 17) and 23 (95% CI, 19 to 38) months, respectively. However, when stratified by cytogenetic risk, the median TTNT and OS were 16 and 51 months for standard risk vs 9 and 19 months for high risk (P=.01 for OS). Conclusion Primary plasma cell leukemia remains an aggressive disease with poor prognosis despite novel agent–based therapies. Some patients have better than expected survival and this phenomenon may be influenced by the absence of high-risk cytogenetics. Newer treatment regimens are needed to improve the prognosis of this devastating disease.

Induction therapy for multiple myeloma with bortezomib (V), lenalidomide (R), 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 patient 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 42%, 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=0.002), this group achieved shorter time to best response (p=0.01). Weekly every 21 day treatment saw higher VGPR or better rates (p=0.02). 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. This article is protected by copyright. All rights reserved.

Background: The level of scientific evidence in National Comprehensive Cancer Network (NCCN) guidelines for malignant hematological conditions haven't been recently investigated. We describe the distribution of categories of evidence and consensus (EC) among the 10 most common hematologic malignancies with regard to recommendations for staging, initial and salvage therapy, and surveillance. Methods: We reviewed the level of evidence for the 10 most common hematological malignancies by incidence in the United States as of 2020. The NCCN definitions for EC are: category 1, high level of evidence, such as randomized controlled trials, with uniform consensus; category 2A, lower level of evidence with uniform consensus; category 2B, lower level of evidence without a uniform consensus but with no major disagreement; and category 3, any level of evidence but with major disagreement. We compared our results with previously published results from 2011. Results: Of 1353 recommendations, 5%, 91%, 4%, and 1% fell into EC categories 1, 2A, 2B, and 3, respectively, while in 2011 the comparable percentages were 3%, 93%, 4%, and 0%, respectively. Recommendations with category 1 EC were found in all guidelines, except for Burkitt lymphoma. Of all therapeutic recommendations, 6.3% were category 1 EC, with the majority of these (56.4%) pertaining to initial therapy. Guidelines with highest proportions of therapeutic recommendations with category 1 EC were multiple myeloma (12.4%), chronic lymphocytic leukemia/small lymphocytic lymphoma (6.9%), and acute myeloid leukemia (5.6%). Conclusions: Recommendations in the 2020 NCCN guidelines are largely developed from lower levels of evidence but with uniform expert opinion, underscoring the urgent need and available opportunities to expand the current evidence base in malignant hematological disorders.

INTRODUCTION: Little is known on continued response following completion of therapy in light chain (AL) amyloidosis. METHODS: We studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first-line therapy. RESULTS: By 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). CONCLUSIONS: This 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.

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm. To date, there is a lack of U.S. Food and Drug Administration–approved treatments in adult LCH to establish optimal first-line therapy. We conducted a retrospective, single-center case series evaluating the use of BRAF inhibitors in adult patients with BRAFV600E- LCH proven by biopsy. Our case series is the first to report the use of BRAF inhibitors as first-line therapy in adults with LCH. We also report the efficacy with single-agent dabrafenib in adult LCH. All but one of our patients had favorable response to targeted therapy.

The current treatment paradigm of AL amyloidosis lacks effective fibril-directed therapies. Doxycycline has been shown to have anti-fibril properties in preclinical models. In 2012, we reported that posttransplant prophylaxis with doxycycline was associated with improved survival compared to penicillin in patients with haematologic response. We provide here updated results after long-term follow up. We included 553 patients who underwent transplant between July 24th, 1996, and June 24th, 2014. Doxycycline 100 mg daily was used for prophylaxis in patients with penicillin allergy; since 2013, doxycycline was used as the standard for prophylaxis. Prophylaxis was typically continued for a year after transplant. The median follow-up from transplant was 12.7 years. Doxycycline was used for prophylaxis in 33% of patients; the rest received penicillin. The median time to next treatment was 6.0 (95%CI; 4.4–8.8) years and 6.0 (95%CI; 4.9–7.1) years in the doxycycline and penicillin groups, respectively (p = .89). The median overall survival was 12.0 (95%CI: 11.0–19.6) years and 11.0 (95%CI: 9.6–12.7) years in the 2 groups, respectively (p = .17). There was a minimal trend towards improved survival with doxycycline among patients with ≥ very good partial response and among patients with organ response that was not statistically significant. After long-term follow-up, there is no clear evidence to support benefit of doxycycline in the post-transplant setting.

A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities in multiple myeloma (MM). It is unclear whether +1q is independently associated with decreased overall survival (OS). The objective of this study was to evaluate the impact of +1q on clinical characteristics, treatment response, and survival outcomes. We included 1376 Mayo Clinic patients diagnosed with MM from 2005 to 2018 who underwent fluorescence in situ hybridization testing at diagnosis with a panel including the +1q probe. A gain in 1q was found in 391 patients (28%) and was associated with anemia, hypercalcemia, high tumor burden, International Staging System (ISS) stage 3, high-risk (HR) translocations, and chromosome 13 abnormalities. There was no difference in overall response or deeper responses to proteasome inhibitor (PI)–, immunomodulatory drug (iMiD)–, or PI plus IMiD–based induction. Time to next treatment was shorter in patients with +1q compared with those without +1q (19.9 vs 27.7 months; P < .001). On univariate analysis, +1q was associated with increased risk of death (risk ratio [RR], 1.9; P < .001), and decreased OS was seen in all treatment groups. +1q was independently associated with decreased OS on multivariate analysis when other HR cytogenetic abnormalities, ISS stage 3, and age ≥70 years were included (RR, 1.5; P < .001). Gain of >1 copy of 1q was not associated with worse OS compared with gain of 1 copy (4.9 vs 4.3 years; P = .21). +1q was associated with high tumor burden, advanced disease stage, and HR translocations. It is independently associated with decreased OS, even in the setting of novel therapy and transplant.

We evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10-5 ; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD-negative rate after one-line of therapy was 71% (20/28). And, MRD negative rates were higher with stem-cell transplant as first-line therapy (86%, 18/21) vs chemotherapy alone as first-line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD-negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow-up of 14 months, the estimated 1-year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk-adapted trials may help optimize treatment in AL amyloidosis.

Rarity of light-chain amyloidosis (AL) makes randomized studies challenging. We pooled three phase II studies of immunomodulatory drugs (IMiDs) to update survival, toxicity, and assess new response/progression criteria. Studies included were lenalidomide-dexamethasone (Len-Dex) (n = 37; years: 2004–2006), cyclophosphamide-Len-Dex (n = 35; years: 2007–2008), and pomalidomide-Dex (n = 29; years: 2008–2010) trial. Primary endpoint was hematologic response. Overall survival (OS) was calculated from registration to death and progression-free survival (PFS) was calculated from registration to progression or death. Hematologic, cardiac, and renal response/progression was assessed using the modern criteria. Analysis included 101 patients, with a median age of 65 years, 61% male, 37 newly diagnosed (ND), and 64 relapsed/refractory (RR). Median follow-up was 101 months (range 17–150) and 78% of patients died. OS and PFS for pooled cohort were 31 and 15 months, respectively. Forty-eight patients achieved a hematologic response; for ND, 10 patients (28%) achieved ≥VGPR (very good partial response) and 8 (14%) among the RR. Only cardiac stage was prognostic for OS. Common grade ≥3 toxicities were hematologic, fatigue, and rash, and were similar among studies. Hematologic and renal responses occurred more frequently and rapidly using modern response criteria; cardiac response was less frequent but occurred quickly. IMiDs can result in long progression-free intervals/survival with tolerable toxicities. The new response/progression criteria were rapid and allows for tailoring therapy.

Histological transformation in Waldenstrom macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high-grade lymphoma, with median time-to-transformation of 4.5 (range 0-21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non-transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1-23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time-to-transformation (HR 7.9 [95%CI: 2.3-27; P = .001]), with a 5-year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8-6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time-to-transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.

We explored the association between bone marrow plasma cells (BMPCs) and disease presentation and outcome among 1574 AL patients. Three BMPC groups were formulated

BACKGROUND Prior studies in oncology have shown that a higher annual facility patient volume is associated with reduced mortality. Because classic Hodgkin lymphoma is uncommon but highly curable, this study used the National Cancer Database (2003-2014) to analyze whether such a relationship exists for this disease. METHODS The facilities were classified by quartiles, and random intercepts were used to account for clustering of patients within facilities. A Cox regression model was used to determine the volume-outcome relationship. RESULTS There were 47,633 patients with classic Hodgkin lymphoma treated at 1310 facilities. The first quartile (Q1), which included 58.4% of the facilities, treated 3 or fewer patients per year, whereas the fourth quartile (Q4), which included 5.9% of the facilities, treated more than 9 patients per year. Compared with the patients treated at Q4 facilities, those treated at lower quartile facilities had a higher risk of death (hazard ratio for the third quartile [HR], 1.19; 95% confidence interval [CI], 1.1-1.29; HR for the second quartile, 1.28; 95% CI, 1.19-1.38; HR for Q1, 1.29; 95% CI, 1.2-1.39) after adjustments for all other factors (P

Thromboses are prevalent in POEMS syndrome, but few risk factors for POEMS-associated thrombosis have been identified. The objective of this study is to identify novel risk factors for POEMS-associated thrombosis. In this retrospective cohort of 230 POEMS patients, 27% developed thrombosis. Arterial events were slightly more common than venous. Stroke accounted for 26% of all thromboses and 53% of arterial events. There were differences in baseline features between the thrombosis group and the no thrombosis group, and these were driven by patients with arterial thrombosis. Risk factors for arterial thrombosis included thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload and splenomegaly. Hyperprolactinemia appeared to be a risk factor for venous thrombosis. The risk of thrombosis was most striking among men with elevated hemoglobin (32% versus 5%, p < 0.001) and hematocrit (42% versus 5%, p < 0.001) compared to men without. Most thromboses occurred prior to POEMS directed therapy, and most that occurred during therapy happened within 3 months of diagnosis. Twenty-one percent of patients with thrombosis had recurrence. In recognition of high overall rates of thrombosis in this population, all patients with POEMS syndrome should receive prophylactic antiplatelet therapy, and clinicians should consider anticoagulation in patients with risk factors for POEMS-associated thrombosis. This article is protected by copyright. All rights reserved.

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamon Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counselling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms. This article is protected by copyright. All rights reserved.

Immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, offers several advantages over immunofixation for the detection and isotyping of serum monoclonal protein, including superior sensitivity and specificity, the ability to differentiate therapeutic monoclonal antibodies, and the rapid identification of light chain (LC) N-glycosylation. We identified 6315 patients with MASS-FIX performed at our institution since 2018. Of these, 4118 patients (65%) with a wide array of plasma cell disorders (PCD), including rare monoclonal gammopathies of clinical significance, had a positive MASS-FIX. Two-hundred twenty-one (5%) of the MASS-FIX positive patients had evidence of LC N-glycosylation, which was more commonly identified in IgM heavy chain isotype, kappa LC isotype, and in diagnoses of immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other PCD. This cross-sectional study describes the largest cohort of patients to undergo MASS-FIX in routine clinical practice. Our findings demonstrate the widespread utility of this assay, and confirm that LC N-glycosylation should prompt suspicion for AL amyloidosis and CAD in the appropriate clinical context.

Introduction Methemoglobin (MetHb) and sulfhemoglobin (SHb) measurements are useful in the evaluation of cyanosis. When one or both values are elevated, additional analysis is important to establish the etiology of the disorder. Methemoglobinemia occurs from acquired or hereditary causes with diverse treatment considerations, while true sulfhemoglobinemia is only acquired and treatment is restricted to toxin removal. Some toxic exposures can result in a dual increase in MetHb and SHb. Hereditary conditions, such as M-Hemoglobin variants (M-Hbs), can result in increased MetHb and/or SHb values but are clinically compensated and do not require treatment if they are cyanotic but otherwise clinically well. Methods Herein, we report 53 hemoglobin variant cases that have associated MetHb and SHb levels measured by an adapted Evelyn-Malloy laboratory assay method. Results Our data indicate M-Hbs cause variable patterns of MetHb and SHb elevation in a fairly reproducible pattern for the particular variant. In particular, α globin chain M-Hbs can mimic acquired sulfhemoglobinemia due to an isolated increased SHb value. Conclusion If the patient appears clinically well other than cyanosis, M-Hbs should be considered early in the evaluation process to differentiate from acquired conditions to avoid unnecessary testing and treatment regimens and prompt genetic counseling.

Ibrutinib-related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2-4] and 5·7 (95% CI: 4-12) months, respectively. The median follow-up was 19 (95% CI: 14-21) months; 18-month progression-free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3-16·7) months, and the median duration-of-response was 32 (range: 23-32) months. Twenty-five patients (31%) had discontinued therapy at last follow-up (68% due to treatment-related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial-fibrillation (11%) were common non-haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Objective To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy. Patients and Methods We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×109/L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts. Results A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT. Conclusion Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present.

Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long-term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis (n = 186) were the subject of this study. Ten-year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10-year survivors compared to those who did not survive to 10 years. All-time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first-line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty-seven percent of the 10-year survivors did not require a second-line therapy. The median treatment-free survival (TFS) among the 10-year survivors was 10·5 years (interquartile range 7·4-12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long-term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.

The prognostic significance of novel agent-induced thrombocytopenia in newly diagnosed multiple myeloma (MM) is unknown. We identified 665 newly diagnosed patients receiving proteasome inhibitors and/or immunomodulators with pretreatment platelet counts ≥100,000/µL. Median progression-free survival (PFS) was 1.88 years (95% CI 1.48-2.38) for patients who developed treatment-related thrombocytopenia (100,000/µL) within sixty days of initiation of first-line therapy, compared to 2.64 years (95% CI 2.39-2.78) in patients who did not (

We retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and transthoracic echocardiogram (TTE) in diagnosing cardiac involvement in patients with biopsy-proven systemic immunoglobulin light chain amyloidosis seen at the Mayo Clinic between 1 January 2006 and 30 December 2015. We analyzed 2 cohorts: patients undergoing endomyocardial biopsy for suspicion of cardiac involvement (cohort 1) and patients who had serum NT-proBNP and comprehensive echocardiographic evaluation at diagnosis (cohort 2). Of 179 patients undergoing endomyocardial biopsy (cohort 1), 173 (97%) had evidence of amyloid deposition, with 159 having NT-proBNP performed at the time of the procedure. The NT-proBNP was elevated (>300 pg/mL) in all 159 patients (sensitivity, 100%; median NT-proBNP, 4917 pg/mL; range, 355-69 541). The left ventricular ejection fraction, interventricular septal thickness, and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%), respectively. Among cohort 2 (n = 342), 259 (76%) had an elevated NT-proBNP, of whom 237 (92%) had an abnormality detected on TTE. Of 83 patients with normal NT-proBNP

We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), or solitary plasmacytoma (SPC). There is a lack of data regarding impact of these pre-existing monoclonal gammopathies (MGs) on MM outcomes. Patients with prior diagnosis of MGUS, SMM, or PC from 1973 to 2015 (cases) were identified from our institution's database and compared to those without a known MG (controls). The primary outcome of interest was overall survival (OS). Multivariate analysis was performed to ascertain factors impacting all-cause mortality. We identified 774 patients with a prior diagnosis of MGUS, SMM or SPC (cases) and a control population (1:2) matched for the year of diagnosis (n = 1548). After a median follow-up of 81 months, the cases showed a longer median OS than the controls (71 months vs. 56 months). The improved OS was limited to those with a known prior diagnosis of SMM (80 months) and SPC (95 months), compared to MGUS (60 months). Multivariable analysis revealed that MM patients with known prior MG had less overall mortality than those without, and this was limited to prior SMM/SPC group (HR 0.68, 95% CI: 0.50-0.93), as compared to the MGUS group (HR 0.83, 95% CI: 0.66-1.05).

It is well known that staging of patients with AL amyloidosis at diagnosis predicts for survival, but there is a paucity of literature delineating the prognostic value of these systems at relapse. We evaluated the prognostic value of AL staging among 413 patients initiated with second-line therapy between 2000 and 2015. Both the Revised Mayo 2012 and the European revision of Mayo 2004 staging systems were used. The median time from initial treatment to second-line therapy was 11.7 months. The first-line therapy was autologous stem cell transplant (ASCT) in 179 (43%) patients and non-ASCT therapies in 234 patients. Median survival from the institution of second-line therapy was 61 months. Both the Mayo 2004 and 2012 staging systems were of prognostic benefit at second-line therapy with respective risk ratios of 2.78 (95% CI: 2.15, 3.58) and 3.03 (95% CI: 2.33, 3.93) for patients with > stage 2 disease. On multivariate analysis, the predictive value of staging at second-line therapy was independent of stage at diagnosis and prior ASCT as first-line therapy. This study indicates that the Mayo staging systems work well at second-line therapy. Consequently, it is suitable for the stratification of patients in trials for relapsed, refractory AL amyloidosis.

The plasma cell proliferative index (PCPI) provides an insight into plasma cell biology in plasma cell disorders. It recognizes cells that are actively synthesizing DNA and gives an indication of the proliferative rate of the malignant plasma cells.The PCPI has been shown to be a prognostic tool in patients with multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic impact of PCPI in 306 patients with smoldering multiple myeloma (SMM). The median age was 66 (56-73) years and 61% (n=186) were males. The median follow-up for the entire cohort was 10.2 years (95% confidence interval: 9.0-10.9). One-hundred sixty-nine (55%) patients were alive at the time of study analysis while 118 (39%) had progressive disease. The median time to progression was 5.9 years (95% confidence interval: 4.8-8.2). Symptomatic events at the time of progression included anemia in 41% (n=48), bone complications in 37% (n=44), renal complications in 9% (n=11), hypercalcemia in 2% (n=2) and development of amyloidosis in 2% (n=2). Seventeen patients (14%) were categorized as having progression due to rapid progressive elevation in the serum free light chains (sFLC) and/or progressive increase in the size of their M-spike. The median time between the diagnosis and PCPI date was 0 months (interquartile range 0-1). An elevated PCPI was defined as a level >0.5%. Seventy-nine (26%) patients had an elevated PCPI. Patients with an elevated PCPI were significantly older (median age: 69 years for elevated PCPI vs 64 years for low PCPI (p= 0.008) and predictably had more proliferative disease with a higher rate of patients with bone marrow plasma cells >20% (48% for elevated PCPI vs 34% for low PCPI, p=0.03). An elevated PCPI predicted a shorter time to progression (TTP); median 3.0 years versus 7.1 years for those with a low PCPI (p= 0.0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI; 49% versus 20% (p PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow up and consideration of early intervention trials. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; spectrum: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Consultancy; janssen: Consultancy; Physicians Education Resource: Consultancy; Teva: Consultancy; celgene: Consultancy; annexon: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; Medscape: Consultancy; Apellis: Consultancy; Ionis: Honoraria. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. Materials and Methods We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. Results Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. Conclusion Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. Implications for Practice The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.

The current definition of plasma cell leukemia (PCL)— ≥ 20% circulating plasma cells (CPCs) on peripheral smear and plasma cell count ≥ 2 × 109/L—may be too stringent. We reviewed outcomes of 176 multiple myeloma (MM) patients diagnosed between 1971 and 2016, and who had CPCs detectable at diagnosis, to determine whether a lower threshold could be used to diagnose PCL. Median overall survival (mOS) was 1.1 years (95% CI 0.8–1.4) and was similar between patients with n = 54, mOS = 1.4 years [0.7–2.0]), 5–19% (n = 63, mOS = 1.1 years [0.7–1.4]), and ≥ 20% CPCs (n = 59, mOS = 1.1 years [0.7–1.5], p = 0.349). As survival was similar between those with 5–19% and ≥ 20% CPCs, we stratified patients by p = 0.154). Outcomes of those with ≥ 5% CPCs were much poorer when compared with a cohort of MM patients diagnosed between 1971 and 2016, who did not have CPCs at diagnosis (n = 9724, mOS = 4.4 yrs [4.3–4.5], p n = 62, mOS = 1.4 years [0.8–2.5]) compared with patients with standard risk (n = 1326, mOS = 7.5 years [7.0–8.7]) and high-risk MM (n = 381, mOS = 4.3 years [3.5–4.9], p

Achieving a complete response (CR) is associated with improved overall survival (OS) in multiple myeloma (MM), but data on duration of CR (DurCR) are limited. We evaluated 351 patients (2004–2016), achieving CR with first-line therapy. Patients with sustained DurCR ≥ 24 months (n = 177) had better OS; 150 vs. 81 months, p

Symptomatic hyperviscosity is a well-established phenomenon in Waldenstrom macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity-related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre-empt hyperviscosity-related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate-analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time-to-initial therapy was 6.9 years and only 15% developed hyperviscosity-related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity-related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM-directed therapy.

Introduction: The utility of amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after starting treatment has not been explored. Given the high early mortality in this disease, restaging remote from the diagnosis may have clinical value. We designed this study to evaluate whether the currently used staging systems are prognostic when applied at 3 and 6 months from starting first-line treatment, and whether stage migration impacts survival. Methods: This is a retrospective study including patients with systemic light chain amyloidosis diagnosed between January, 1st 2006 and June, 30th 2019 and were seen in Mayo Clinic, Rochester, MN within 90 days of diagnosis; the analysis included 535 and 301 patients who had restaging data available for at least one of the staging systems at 3 and 6 months, respectively. Patients were grouped into 4 stages using the 2015 European modification of the Mayo 2004 staging system based on values of cardiac biomarkers (cardiac troponin T and NTproBNP), and using the Mayo 2012 staging system based on cardiac biomarkers and the difference in serum free light chain concentration (dFLC). Overall survival (OS) was calculated from the time of re-staging until death or last follow up. Results: Using the modified Mayo 2004 staging system at 3 months from starting first-line treatment, median OS was 11.8 [95%CI: 11.4-not reached (NR)], 10.8 (95%CI: 9.4-NR), 4.6 (95%CI: 2.8-6.7), and 1.1 (95%CI: 0.7-2.6) years in patients with stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012 staging at 3 months, OS was 11.8 (95%CI: 10.9-NR), 9.0 (95%CI: 6.2-NR), 5.2 (95%CI: 3.3-6.1), and 0.8 (95%CI: 0.7-1.1) years in patients with stage I, II, III, and IV, respectively (Figure 1a &b). Using the modified Mayo 2004 staging system at 6 months from starting first-line treatment, median OS was NR (95%CI: NR-NR), 9.8 (95%CI: 6.2-NR), 5.4 (95%CI: 3.2-9.0) and 0.9 (95%CI: 0.6-3.7) years in patients with stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012 staging at 6 months, OS was NR (95%CI: 8.4-NR), NR (95%CI: 7.9-NR), 4.6 (95%CI: 3.0-6.5), and 0.9 (95%CI: 0.2-1.8) years in patients with stage I, II, III, and IV, respectively (Figure 1c &d). On multivariate analysis, advanced (stage > 2) modified Mayo 2004 stage (HR: 1.6, P=0.004) and advanced (stage > 2) Mayo 2012 stage (HR: 2.4, P For both systems, worsening stage at 3 months or at 6 months was associated with a worse survival than retaining the original stage. In contrast, improving stage as compared to remaining in same stage was not associated with better survival at 3 or 6 months (Table 1). When the analysis was restricted to patients who had an advanced stage at diagnosis, improving stage at 3 months was associated with longer survival compared to retaining the original stage, with both modified Mayo 2004 (10.8 vs. 3.3 years, P Conclusion: The modified Mayo 2004 and the Mayo 2012 staging systems have independent prognostic value when used for restaging after 3 and 6 months from initiation of first-line treatment. Migration to a higher stage from diagnosis predicts decreased survival, compared to retaining the same stage. Stage improvement is associated with a better OS in patients with advanced stage at diagnosis. Disclosures Dispenzieri: Alnylam, Intellia, Janssen, Takeda, Pfizer, Prothena, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy. Dingli:Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Janssen: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Gertz:Alnylam: Consultancy; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Amyloidosis Foundation: Research Funding; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: 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; International Waldenstrom Foundation: Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Cellectar: Other; 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; Kite Pharma: Consultancy, Research Funding; MedImmune: Research Funding; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, 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; Karyopharm: Consultancy; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Sanofi: Research Funding.

Context This is the first in human Phase 1 dose escalation trial of oncolytic Vesicular Stomatitis Virus (VSV) incorporating interferon beta and sodium iodine symporter transgenes (VSV-IFNβ-NIS) to be administered intravenously in patients with relapsed and refractory hematologic malignancies. Objective The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. The secondary objectives were to determine safety and efficacy of VSV-IFNβ-NIS. Correlative objectives included monitoring viremia and virus shedding. Design This was a 3+3 phase 1 clinical trial from April 2017 to August 2020 including adult patients (pts) with relapsed refractory multiple myeloma (MM), T-cell lymphoma (TCL), or acute myeloid leukemia (AML). Results Fifteen patients received VSV-IFNβ-NIS: MM (7), TCL (7), and AML (1); median age was 64 years, 60% male, and median prior lines of systemic cancer therapies was 5 (range, 2 to 11). Three patients were treated at each dose level (DL) 1 through 3 (respectively 0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL 4 (1.7x1011 TCID50). There were no dose-limiting toxicities. Hematologic AEs, particularly lymphopenia (73%) were the predominant grade 3 and 4 AEs. Non-hematologic AE of interest were grade 1 (6.7%) and 2 (46.6%) cytokine release syndrome, of which only 1 patient required transient norepinephrine support. Objective responses were seen in patients with TCL. There was a 3-month partial response (PR) in a patient treated at DL 2 after 11 prior systemic therapies. However, compelling responses were seen at DL 4 with a deepening 6-month PR in a patient with PTCL and ongoing CR, even 14 months after VSV in another patient with cutaneous relapse of PTCL; both patients received 5 prior lines of therapy. Viremia rapidly declined after infusion, and there was no significant viral shedding. Neutralizing anti-VSV antibodies developed by day 29. IFNβ appeared to indicate intratumoral amplification with TCL patients mounting the highest levels. Conclusions A single intravenous dose of VSV-IFNβ-NIS up to 1.7x1011 is safe in heavily pre-treated patients with hematologic malignancies and appears to be most effective as a single agent at DL 4, especially in patients with TCL. Future trials of combination strategies with immune-modulatory drugs are currently being planned. Grant Acknowledgements Mayo Clinic Multiple Myeloma Specialized Program of Research Excellence (SPORE), Grohne gifts, Phillips gift, and Liu gift.

Three 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.

Key Points Question Is anemia in patients with critical illness associated with persistent anemia following discharge? Findings In this cohort study of 6901 adults hospitalized for critical illness, 41% had prevalent anemia preceding hospitalization and 74% of those without prehospitalization anemia developed incident anemia, for an overall anemia prevalence of 80% at hospital discharge. Rates of complete recovery from hospital discharge anemia at 12 months posthospitalization for those alive with available hemoglobin assessments were 58% for mild anemia, 39% for moderate anemia, and 24% for severe anemia. Meaning The findings of this study suggest that anemia is common and often persistent in the first year after critical illness., Importance Anemia is common and has been associated with poor outcomes in the critically ill population, yet the timing and extent of hemoglobin recovery remains incompletely described, which may have important implications for clinical outcomes following discharge from intensive care. Objectives To describe longitudinal changes in anemia status during and after critical illness and assess the associations between hemoglobin concentrations and postdischarge mortality. Design, Setting, and Participants A population-based cohort study was conducted from January 1, 2010, to December 31, 2016, in Olmsted County, Minnesota; data analysis was performed from June 1 to December 30, 2019. Participants included 6901 adults (age ≥18 years) admitted to intensive care. Main Outcomes and Measures Hemoglobin concentrations in the 12 months before hospitalization, during hospitalization, and in the 12 months after discharge, categorized by anemia severity (mild, hemoglobin ≥10.0 to, This cohort study examines the presence of anemia in critically ill patients and outcomes after discharge.

Autologous stem cell transplantation (ASCT) is an important treatment modality in multiple myeloma (MM). However, relapse following ASCT is considered almost inevitable. This study aimed to characterize exceptional responders to ASCT, defined as progression-free survival (PFS) >8 years in the absence of maintenance therapy. We retrospectively analyzed patients treated at Mayo Clinic between August 1, 1998 and January 3, 2006, and included those with symptomatic MM, treated with an ASCT within 12 months of diagnosis. We found that 46 (9%) of the 509 patients who underwent ASCT during the study period were exceptional responders. The median duration of follow-up from diagnosis was 16.2 (interquartile range 14.3–17.7) years. The best response to therapy was a complete response (CR) or better in 34 (74%) of patients, and less than a CR in 12 (26%) of patients. The median PFS was 13.8 (95% confidence interval 10.5–18.5) years, and at the time of the last hematology assessment, 24 of 46 (52%) patients remained in remission. In conclusion, we showed that a small subset of patients with MM attains durable disease control without maintenance therapy post ASCT. Pre-emptive identification of these patients may help prevent undue toxicities and costs of subsequent therapy.

Waldenstrom Macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic involvement of the bone marrow and serum IgM monoclonal protein of any size [1]. The clinic...

Response assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.

Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response. This study was designed to evaluate these associations. This is a retrospective study including 2027 Mayo Clinic patients diagnosed with MM between February 2004 and February 2018 who had cytogenetic testing by FISH at diagnosis. Translocations t(4;14), t(14;16), t(6;14), and t(14;20) were associated with anemia, beta2microglobulin >5.5 µg/ml and ≥50% bone marrow plasma cells; t(4;14) was associated with higher serum monoclonal protein and plasma cell proliferation. Overall response rate to proteasome inhibitor (PI)-based treatment was higher for IgH translocations compared to trisomies (83% vs. 71%, P = 0.002), but was higher for trisomies with immunomodulatory drug (IMiD)-based treatment (87% vs. 75%, P P P = 0.003) treatments. Outcomes were superior with PI + IMiD combinations in all groups. Our results show that t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high-risk disease characteristics, and IgH translocations and trisomies may be associated with better responses to PIs and IMiDs, respectively.

Transplant-associated thrombotic microangiopathy (TA-TMA) has a wide range of presentations after hematopoietic stem-cell transplantation (HSCT). We retrospectively studied the risk factors and outcomes of patients with early (≤day 100) and late (>day 100) TA-TMA. Among the 1451 HSCT recipients, early TA-TMA occurred in 45 (3.1%) patients at a median of 27 (3-91) days, and late TA-TMA in 39 (2.7%) patients at a median of 303 (122-2595) days. Patients with early TA-TMA were more likely to have high blood calcineurin-inhibitor levels (P < .001) and acute graph-vs-host disease (GVHD, P < .001), while late TMA patients were more likely to have chronic GVHD (P < .001). The estimated median overall survival after onset of TMA for the entire cohort was 6 months. The estimated median overall survival was not reached in patients with an improvement of TMA vs 2 months in patients with no improvement (P < .001). In the early TMA group, older age (for every 10 years, HR 1.40; 95% CI 1.00-1.94; P = .049) and bacterial infection (HR 2.42; 95% CI 0.98-6.00; P = .056) were positively associated with mortality. Switching to MMF treatment (HR 0.40; 95% CI 0.16-0.99; P = .047) and improvement of TMA (HR 0.08; 95% CI 0.03-0.25; P < .001) were negatively associated with mortality in the multivariate analysis. In the late TMA group, the improvement of TMA was the only independent predictor associated with a lower risk of death (HR 0.05; 95% CI 0.02-0.19; P < .001). Mortality rates in both early and late TMA remain unacceptably high. Future studies are needed for early diagnosis, trigger identifications, and use of targeted treatments.

We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) patients seen at Mayo Clinic to determine whether a bone marrow biopsy (BM) is necessary in all patients diagnosed with a monoclonal protein. A total of 2254 MM, 397 SMM, and 5836 MGUS patients were included in the study. A total of 29 (1.3%) MM patients “without CRAB/FLC” were identified where BM or advanced imaging was critical for diagnosis, 8 (0.3% MM cohort) of whom were diagnosed with MM solely on BM findings (plasma cells > 60%). Without BM or advanced imaging none of these patients would be classified low-risk MGUS. A total of 314 (79%) MGUS-like SMM patients were identified where classification of SMM was based on BM findings. Without BM 97 would be classified as low/low-intermediate-risk MGUS and 151 intermediate or high-risk MGUS; 66 had missing information precluding classification. Only three (

Purpose This study aimed to characterize the white blood cell differential of tobacco smoking-induced leukocytosis and describe the longitudinal impact of smoking cessation on this peripheral blood abnormality. Methods Medical records of patients undergoing evaluation by hematologists for persistent leukocytosis were reviewed. Patients in whom leukocytosis was determined to be secondary to tobacco use after exclusion of other causes were identified. Demographic and laboratory data were collected at time of diagnosis. Patients were longitudinally followed and information regarding smoking cessation and follow-up white blood cell values were recorded. Results Forty patients were determined to have smoking-induced leukocytosis. The median age was 49.5 years (range: 28-75 years), 24 patients were female, and the mean body mass index (BMI) was 31.5 kg/m2. The mean white blood cell count was 13.3 × 109/L (range: 9.8-20.9 × 109/L); 39 patients had absolute neutrophilia (98%), 21 had lymphocytosis (53%), 20 had monocytosis (50%), and 19 had basophilia (48%). During follow-up, 11 patients either quit (n = 9) or reduced (n = 2) tobacco use. Reduction in tobacco smoking led to a significant decrease in mean white blood cell count (13.2 × 109/L vs 11.1 × 109/L, P = 0.02). The median time to decrease in white blood cell count following reduction in tobacco use was 8 weeks (range: 2-49 weeks). Conclusions Tobacco-induced leukocytosis was characterized by a mild elevation in total white blood cell count and was most commonly associated with neutrophilia, lymphocytosis, monocytosis, and basophilia. Cessation of smoking led to improvement in leukocytosis. Tobacco history should be elicited from all patients presenting with leukocytosis to limit unnecessary diagnostic testing, and counseling regarding smoking cessation should be offered.

In the current era, the impact of bone marrow plasma-cell percentage (BMPC%) at diagnosis of multiple myeloma (MM) is not well described. We evaluated the prognostic impact of BMPC% ≥ 60% versus < 60% in 1426 newly diagnosed MM patients. Median progression-free and overall survival were shorter for patients with BMPC% ≥ 60%, even in a multivariate analysis that included known prognostic factors for MM. BACKGROUND: Previous reports have suggested that a higher bone marrow plasma-cell percentage (BMPC%) is associated with worse outcomes. However, it is unknown whether BMPC% is an independent predictor because genetic information was not available at that time. Currently the impact of BMPC% at diagnosis of multiple myeloma (MM) is not well described. PATIENTS AND METHODS: We evaluated the prognostic impact of BMPC% ≥ 60% versus < 60% in 1426 newly diagnosed MM patients. All patients had an estimation of their BMPC% at diagnosis, and the highest percentage was used. Progression-free survival (PFS) and overall survival (OS) analyses were performed by the Kaplan-Meier method. Univariate and multivariate analyses for PFS and OS using the Cox proportional hazards model were performed for age, Revised International Staging System (R-ISS) score, creatinine level, and BMPC%. RESULTS: BMPC% ≥ 60% was found in 562 patients (39%), and the median PFS was shorter for these patients compared to BMPC% < 60% (22.6 vs. 32.1 months; P < .0001). Also, for OS, the median was shorter for the higher BMPC% group (53.4 vs. 75.4 months; P < .0001). On the multivariate analysis for PFS, age ≥ 65 years (hazard ratio [HR], 1.46; P < .0001), R-ISS (1-2 vs. 3) (HR, 0.49; P < .0001), and BMPC% ≥ 60% (HR, 1.23; P = .015) were predictive. On the multivariate analysis for OS, age ≥ 65 years (HR, 2.23; P < .001), R-ISS (1-2 vs. 3) (HR, 0.41; P < .0001), and BMPC% ≥ 60% (HR, 1.24; P = .02) were also predictive. CONCLUSION: BMPC% ≥ 60% at diagnosis is predictive for PFS and OS, even in a multivariate analysis that included known prognostic factors for MM.

Objective To assess the prevalence of coagulation abnormalities in patients with systemic light chain (AL) amyloidosis and their association with disease-related characteristics, disease progression, and survival. Patients and Methods This is a retrospective study of patients with AL amyloidosis seen at Mayo Clinic, Rochester, Minnesota, from January 1, 2006, to December 31, 2015. We studied the association between abnormal coagulation parameters and baseline characteristics and their association with survival outcomes. Results The study included 411 patients. Abnormalities at diagnosis included prolonged clotting times and coagulation factor deficiencies; prolonged prothrombin time (PT) and factor X (FX) deficiency were found in 19% (73 of 390) and 43% (177 of 411) of patients, respectively. The FX deficiency was associated with higher Mayo stage, involvement of more than 1 organ, liver and cardiac involvement, and greater than 10% bone marrow plasma cells. On univariate analysis, the risk for disease progression or death was higher in patients with abnormal values for PT and factor V, factor VII (FVII), FX, and factor XII compared with those with normal values. Prolonged PT and FVII and FX deficiencies were independent predictors of death after adjusting for Mayo stage and more than 1 organ involvement. Only 106 patients had repeat testing after treatment; no clear relationship was found between treatment response and changes in coagulation parameters. Conclusion Coagulation abnormalities occur in a significant proportion of patients with AL amyloidosis and are associated with advanced disease and inferior outcomes. Larger studies are needed to establish whether a relationship exists between treatment response and improvement in individual parameters.