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Introduction: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin amyloid (ATTR). We used the iStopMM study revised reference ranges for serum free light-chain (sFLC) corrected for eGFR to identify ATTR patients with light-chain MGUS (LC-MGUS). Characteristics and frequencies of the ATTR cohort with underlying MGUS was compared to a cohort of MGUS patients without ATTR., Patients and Methods: A retrospective analysis of ATTR and MGUS patients evaluated at our center between January 2014 to December 2021. A total of 149, predominantly male (87.5%) ATTR patients with a median age of 82 were included. This cohort was compared to 228 MGUS patients., Results: Of the 149 ATTR patients, 27 (18.1%) had coexisting MGUS. Among ATTR patients with MGUS, 12/27 (44%) had LC-MGUS based on sFLC abnormalities assessed using the iStopMM reference ranges. Of the MGUS only cohort, 44/228 (19.3%) met criteria for LC-MGUS. Utilizing the iStopMM reference ranges, 6 ATTR patients did not meet criteria for abnormal sFLCs, uncovering a 20% false-positive rate., Conclusion: We noted higher rates of MGUS, particularly LC-MGUS, among ATTR patients when compared to our MGUS only cohort. The high prevalence remained after utilizing the iStopMM sFLC corrected for eGFR reference ranges. Additionally, 6 ATTR patients with renal-dysfunction would have met MGUS criteria if not evaluated using the iStopMM revised measures. These findings emphasize careful interpretation of sFLC abnormalities and encourage providers to keep ATTR on the differential when work-up uncovers sFLC aberrations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Higher cumulative dose of bortezomib, a key component of Multiple Myeloma (MM) treatment regimens, has been shown to improve outcomes in MM patients, but must be balanced with toxicities including peripheral neuropathy. In this study, we studied the effect of cumulative bortezomib dose on survival, depth of response, and discontinuation rate in transplant ineligible MM patients., Patients and Methods: Data from 70 patients treated with Cyclophsophamide, Bortezomib, and Dexamethasone (CyBorD) in a single Canadian center were grouped according to above vs below median cumulative bortezomib dose and analyzed for progression-free survival (PFS), overall survival (OS), depth of response, and discontinuation rate., Results: There was a trend for lower discontinuation rate (45.7% vs. 68.6%, P = .052) and significantly lower rate of neuropathy-related discontinuation (5.7% vs. 22.9%, P = .035) in patients who received higher than 43.1 mg/m² of bortezomib. The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P = .225) and significantly higher rate of very good partial response or better (77.1% vs. 51.4%, P = .024). There was significantly longer PFS (24.3 vs. 9.1 months, P = .012) and a trend for longer OS (22.4 vs. 61.3 months, P = .061) in the higher-dose group. In landmark analysis after 180 days, PFS (23.5 vs. 24.3 months, P = .941) and OS were similar in both groups., Conclusion: Higher cumulative bortezomib dose showed a lower rate of discontinuation, longer survival, and deeper response. Determining risk of treatment intolerance remains important for treatment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Considerable progress has been made in therapeutic options for multiple myeloma (MM). Understanding the current landscape of MM treatment options and associated outcomes in the real world is important in providing key insights into clinical and knowledge gaps which could be targeted for further optimization., Methods: The Canadian Myeloma Research Group Database (CMRG-DB) is a prospectively maintained disease-specific database with >7000 patients. The objective of this study was to describe the trends in the treatment landscape and outcomes including early mortality, time to next treatment, and overall survival (OS) in each line of treatment stratified by autologous stem cell transplant (ASCT) receipt among newly-diagnosed MM patients in Canada between 2007 and 2018., Results: A total of 5154 patients were identified among which 3030 patients (58.8%) received an upfront ASCT and 2124 (41.2%) did not. At diagnosis, the median age was 64 years and 58.6% were males. Bortezomib and lenalidomide were most frequently used (>50%) in first and second-line treatment respectively among both the ASCT and non-ASCT cohort. The median OS was 122.0 months (95% Cl 115.0-135.0 months) and 54.3 months (95% CI 50.8-58.8 months) for the ASCT and non-ASCT cohort respectively with an incremental decrease in OS in each subsequent line of treatment., Conclusion: We present the largest study to date in the Canadian landscape showing the characteristics, therapy usage, and outcomes among MM patients. This information will be critical in benchmarking current outcomes and provide key insight into areas of unmet needs and gaps for improvement of MM patients nationally., (Copyright © 2022. Published by Elsevier Inc.)

Background: CyBorD (cyclophosphamide, bortezomib, and dexamethasone) is an effective regimen for the treatment of patients with newly diagnosed immunoglobulin light chain (AL) amyloidosis. CyBorD can induce rapid hematologic responses (HRs). However, it remains inadequate to enhance outcomes in high-risk groups. In addition, minimal information is available on the impact of minimal residual disease (MRD) in overall survival., Patients and Methods: All consecutive patients with newly diagnosed AL amyloidosis treated with CyBorD from January 2012 to August 2018 were evaluated. HR and organ response was assessed as per standard guidelines. Further, MRD was evaluated by multiparameter flow cytometry in patients with confirmed complete response (CR)., Results: After a median of 4 cycles, HR was seen in 31 (91.2%) cases, including CR in 9 (26.5%), very good partial response in 9 (26.5%), and partial response in 13 patients (38.2%). Organ response at 6 months was documented in 11 (32.4%) cases. With respect to cardiac response, a > 30% decrease of NT-proBNP was observed in 4 (19%) of 21 evaluable cases (NTproBNP > 650 ng/L) at a median of 6 months. The median progression-free survival was 26.7 months. Patients who achieved CR exhibited a better overall survival compared with those without CR (P = .001). No difference on overall or progression-free survival among cases achieving CR irrespective of their MRD status was observed (P > .05)., Conclusions: In summary, CyBorD showed a ≥ very good partial response rate of 53% with 26.5% achieving CR, which is similar to that seen in previous studies. In addition, MRD negativity assessed by multiparameter flow cytometry in patients with CR resulted in no difference on survival outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD., Methods: We retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin-conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation., Results: Reactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000-500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4-20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD occurred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable., Discussion: In conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000-500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse., (Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Multiple myeloma is a heterogeneous disease with diverse clinical courses and patient outcomes. Although the introduction of novel agents has improved the overall survival (OS) of multiple myeloma patients, reports have highlighted that a subset of patients persists who experience early relapse (ER) and whose prognosis is significantly poorer than that of patients with a longer therapy response., Methods: The purpose of the present study was to understand the effect of ER on OS and identify other predictors of OS. We analyzed the outcomes of 257 patients who had undergone novel agent-based induction and single autologous stem cell therapy at our center from 2010 to 2016., Results: ER occurred in 35 patients (13.6%), and the group had a greater percentage of high-risk cytogenetics (48.5% vs. 23.3%; P = .0001), a lower percentage of a very good partial response or better (51.4% vs. 80.5%; P = .001), and a shorter median OS (17.8 months vs. not realized; P = .0001) compared with the non-ER group. Multivariate analysis showed that the presence of ER, high-risk cytogenetics, and lactate dehydrogenase > 350 UI/L are independent prognosticators for OS (P < .05)., Conclusions: Our results have demonstrated that ER is an important clinical indicator of patients at high risk. As applications of novel agents evolve, further studies are required to tailor therapy for this patient group., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: A variety of validated prognostic markers for multiple myeloma has been described to help inform clinical practice. Recently, a robust system has been introduced for clinical use and is being adopted by the International Myeloma Working Group Revised International Staging System (RISS). The RISS was developed using data from patients enrolled in clinical trials. Consequently, its utility is less clear in unselected patients with myeloma., Materials and Methods: All consecutive patients newly diagnosed with multiple myeloma treated and followed up at Tom Baker Cancer Center from January 2004 to October 2015 were included in the present study. A total of 381 consecutive patients were identified and retrospectively classified as having RISS I, II, and III., Results: RISS I exhibited a median overall survival and progression-free survival of not reached and 38.9 months compared with 77.9 and 26.9 months and 29.9 and 15.3 months for RISS II and III, respectively. These results correlated well with those seen in the International Staging System (ISS). Multivariate analysis showed that age > 65 years, ISS stage III, abnormal lactate dehydrogenase and high-risk chromosomal abnormalities by fluorescence in situ hybridization [t(4:14), deletion 17p, and t(14;16)] are independent prognostic factors for overall survival and progression-free survival, and β 2 -microglobulin ≥ 5.5 mg/L, C-reactive protein > 20 mg/L, and creatinine > 200 μmol/L are not., Conclusion: We have confirmed the role of RISS in unselected nonclinical trial patients and suggest that increased serum lactate dehydrogenase and high-risk cytogenetics are very robust prognosticators when combined with the ISS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The proteasome is an exciting target for the development of novel anticancer therapies. Recent evidence has suggested that bortezomib, a dipeptide boronate proteasome inhibitor, exhibits unprecedented single-agent activity in amyloid light chain (AL) amyloidosis., Patients and Methods: We performed a retrospective review of the use of bortezomib-containing regimens to assess the rapidity and quality of response at our institution., Results: A total of 52 patients with documented newly diagnosed and relapsed AL amyloidosis treated with bortezomib-containing regimens were identified from our institutional database. After a median of 4 cycles (range, 1-22 cycles), a hematologic response was seen in 49 patients (94.2%), including a complete response in 15 (28.8%), a very good partial response in 25 (48.1%), and a partial response in 9 (17.3%). At 6 weeks, 37 patients had already achieved a partial response. An organ response at 6 months was documented in 31 patients (59.6%). With respect to the cardiac response, a > 30% decrease in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) was observed in 17 of 35 evaluable patients (48.6%; NT-proBNP > 650 ng/L) at a median of 6 months. Overall survival was shorter for the patients with NT-proBNP > 5000 ng/L and for those who achieved less than a very good partial response., Conclusion: Bortezomib is a safe and well-tolerated therapy for patients with AL amyloidosis with a rapid hematologic response and cardiac response, as assessed by the NT-proBNP level., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: More than 400 preclinical studies report ≥ 1 compound as cytotoxic to multiple myeloma (MM) cells; however, few of these agents became relevant in the clinic. Thus, the utility of such assays in predicting future clinical value is debatable., Patients and Methods: We examined the application of early-phase trial experiences to predict future clinical adoption. We identified 129 drugs explored as single agents in 228 trials involving 7421 patients between 1961 and 2013., Results: All drugs in common use in MM (melphalan, dexamethasone, prednisone, cyclophosphamide, bendamustine, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, and doxorubicin) demonstrated a best reported response rate of ≥ 22%. Older agents, including teniposide, fotemustine, paclitaxel, and interferon, also appear active by this criterion; however, if mean response rates from all reported trials for an agent are considered, then only drugs with a mean response rate of 15% partial response are in clinical use., Conclusion: Our analysis suggests that thresholds of 20% for best or 15% for mean response are highly predictive of future clinical success. Below these thresholds, no drug has yet reached regulatory approval or widespread use in the clinic. Thus, this benchmark provides 1 element of the framework for guiding choice of drugs for late-stage clinical testing., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Using laser microdissection and mass spectrometry (MS)-based proteomics, we subtyped amyloid deposits from 130 cases of hepatic amyloidosis. Although we confirmed that immunoglobulin light chain amyloidosis was the most frequent cause of hepatic amyloidosis, leukocyte cell-derived chemotaxin 2 (LECT2) amyloidosis (ALect2) accounted for 25% of cases. This novel finding was associated with Hispanic ancestry, incidental discovery of amyloid in liver specimens sampled for other unrelated conditions, and a characteristic pattern of hepatic amyloid deposition. Although ALect2 patients had a common LECT2 polymorphism, pathogenic mutations were not discovered, suggesting that constitutive or compensatory LECT2 overexpression led to ALect2 deposition. These findings indicate that ALect2 is a common cause of hepatic amyloidosis in the population of the United States, and subtyping hepatic amyloid deposits by an accurate analytic method such as MS is required for optimal clinical management of hepatic amyloidosis patients and to avoid incorrect and unnecessarily toxic therapies.

Background: Multiple myeloma (MM) is a plasma cell disorder characterized by the presence of specific genetic and cytogenetic aberrations that define unique subgroups with different outcomes. On the basis of the ploidy status, MM can be subdivided into hyperdiploid MM (H-MM) and non-hyperdiploid MM (NH-MM). NH-MM is an entity that encompasses hypodiploid, pseudodiploid, and near tetraploid MM and is associated with a higher number of immunoglobulin heavy-chain (IgH) translocations., Materials and Methods: We have systematically analyzed the structure of the karyotypic evolution in NH-MM and identified several genetic features of their complex karyotypic patterns., Results: On the basis of statistical models used in complex karyotypes, we were able to identify the temporal order in which the genetic aberrations occur in NH-MM. In this analysis, whole chromosome losses and IgH translocations were commonly seen, and -13/13q- and t14q32 were defined as early genetic events in the karyotypic evolution of NH-MM. Furthermore, chromosome 1 and 17 abnormalities were associated with a late karyotypic phase of evolution consistent with the recognized pattern of acquired events deemed to be associated with these type of genetic aberrations., Conclusion: Accumulation of genetic aberrations in NH-MM above a threshold results in malignant transformation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: A major conclusion drawn from the accumulated cytogenetic data on solid tumors and some hematologic malignancies is that tumors progress by the acquisition of chromosomal changes, as reflected by more aggressive tumors containing a larger number of chromosomal abnormalities. An additional observation is that some chromosomal changes appear early in the disease progression, and some others appear late., Material and Methods: On the basis of this information, a model for karyotypic evolution in chronic lymphocytic leukemia (CLL) is presented. The Mitelman Database of Chromosomes in Cancer was searched, and 1749 abnormal karyotypes were assessed. The main clones were analyzed, and chromosomal gains and losses were used to design a model of genetic acquisition based on the calculation of a variable called time to occurrence (TO)., Results: Our comprehensive study of genetic abnormalities in a large number of CLL karyotypes revealed that most CLL has 2 chromosomal aberrations at diagnosis. Moreover, the temporal analysis suggests that trisomy 12 is an early event in the biological evolution of CLL., Conclusion: These results highlight the possibility of targeted therapies affecting the genes located on this chromosome (cyclin D, cyclin D2, cyclin-dependent kinase 2, and cyclin-dependent kinase 4)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is highly effective in multiple myeloma. We treated patients with light chain amyloidosis (AL) before stem cell transplantation (ASCT), instead of ASCT in ineligible patients or as salvage. Treatment was a combination of bortezomib (1.5 mg/m2 weekly), cyclophosphamide (300 mg/m2 orally weekly), and dexamethasone (40 mg weekly). Seventeen patients received 2 to 6 cycles of CyBorD. Ten (58%) had symptomatic cardiac involvement, and 14 (82%) had 2 or more organs involved. Response occurred in 16 (94%), with 71% achieving complete hematologic response and 24% a partial response. Time to response was 2 months. Three patients originally not eligible for ASCT became eligible. CyBorD produces rapid and complete hematologic responses in the majority of patients with AL regardless of previous treatment or ASCT candidacy. It is well tolerated with few side effects. CyBorD warrants continued investigation as treatment for AL.