Higher Plasma Cell Burden Predicts for Early Death In Patients with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1893-1893 ◽  
Author(s):  
Cheng E. Chee ◽  
S. Vincent Rajkumar ◽  
Morie Abraham A Gertz ◽  
Martha Lacy ◽  
Steven Zeldenrust ◽  
...  
Keyword(s):  
Research Funding ◽  
Plasma Cells ◽  
Troponin T ◽  
Early Death ◽  
Organ Damage ◽  
Early Mortality ◽  
Al Amyloidosis ◽  
End Organ Damage ◽  
M Spike ◽  
Beta 2 Microglobulin

Abstract Abstract 1893 Background: Recent data has shown that the level of immunoglobulin free light chain (FLC) is a prognostic factor for patients with AL amyloidosis. Approximately 25% of patients with AL amyloidosis have coexistent multiple myeloma (MM) with myeloma-related end-organ damage and patients may also present with 310% plasma cells (PC) in the bone marrow (BM) in the absence of any MM features. The goal of this study was to determine the effect of increased BM plasmacytosis in the absence of MM end-organ damage on early mortality. Methods: We performed a retrospective study of 263 consecutive patients with AL amyloidosis seen at Mayo Clinic within 30 days of diagnosis from July 2002 – April 2009, to compare the effect of PC burden among those who died within 90 days of diagnosis (n=88) and those who survived more than 90 days after diagnosis (n=175). Only those patients with documented BM PC were included in this study. MM end-organ damage was defined according to the CRAB criteria. Results: In those who died <90 days after diagnosis and patients who lived beyond 90 days, the proportion of patients with 310% BM PC were 57% and 55%, respectively. Overall survival (OS) was significantly shorter in the early mortality group when there was 310% BM PC present at diagnosis (25 vs. 54 days, p=0.006), but this was not observed in the group who survived beyond 90 days (Figure 1). In patients with 310% BM PC, troponin-T, ejection fraction (EF), and hemoglobin (Hgb) were significantly worse in the early mortality cohort but patients who survived beyond 90 days had significant increase in intraventricular septal (IVS) thickness and beta-2 microglobulin (Table 1). As expected, patients with 310% BM PC in both cohorts had significantly higher serum M-spike and involved FLC (Table). The same cohort of patients were analyzed substituting MM-related end-organ damage for 310% BM PC and similar results were observed with the exception of uric acid and calcium being significantly higher in the early mortality cohort with MM (results not shown). Conclusion: This study demonstrated that an excess of early—but not late—deaths occur in AL amyloidosis patients with 310% BM PC at diagnosis. In our cohort, this finding can be attributed to higher troponin-T levels, indicating more severe cardiac involvement as observed by worse cardiac function. These findings warrant additional investigation. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

scholarly journals Follow-up Care of Monoclonal Gammopathy of Undetermined Significance: A Guide for Primary Care Physicians

2021 ◽  
Vol 8 (5) ◽  
Author(s):  
Hammad Z ◽  
◽  
Hernandez E ◽  
Tate S ◽  
◽  
...  
Keyword(s):  
Plasma Cell ◽  
Primary Care Physicians ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Organ Damage ◽  
M Protein ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
End Organ Damage ◽  
Undetermined Significance

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a condition in which M protein, an abnormal monoclonal immunoglobulin, is present in the blood at a nonmalignant level. Specifically, it is defined by: blood serum M protein concentration <3 g/dL (<30 g/L), <10% plasma cells in the bone marrow, and no evidence of end organ damage [1,2]. Evidence of end organ damage includes hypercalcemia, renal insufficiency, anemia, and bone lesions. These are indicative of MGUS progression and which can be attributed to the monoclonal plasma cell proliferative process [3]. MGUS occurs in 3% of the general population older than 50 years. Incidence increases with age and varies with sex with higher rates observered in males than females [1,4]. MGUS is the most common plasma cell disorder, with 60% of patients that present to the Mayo Clinic with a monoclonal gammopathy being diagnosed with MGUS [3]. While it is typically an asymptomatic condition, it is premalignant disorder to other monoclonal gammopathies. Multiple Myeloma (MM) is almost always preceded by MGUS and the majority of patients will have detectable levels of M protein for at least 5 years prior to MM diagnosis [5,6]. MGUS also precedes immunoglobulin light chain (AL) amyloidosis and Waldenstrom Macroglobulinemia (WM) and tends to progress to disorders at a fixed but unrelenting rate of 1% per year [4].

Unraveling Early Mortality In Patients with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4990-4990
Author(s):  
Cheng E. Chee ◽  
Vincent Rajkumar ◽  
Morie Gertz ◽  
Martha Lacy ◽  
Steven Zeldenrust ◽  
...  
Keyword(s):  
Organ Failure ◽  
Plasma Cell ◽  
Research Funding ◽  
Troponin T ◽  
Early Mortality ◽  
Cell Labeling ◽  
Al Amyloidosis ◽  
Renal Nerve ◽  
Treatment Information ◽  
Number Of Patients

Abstract Abstract 4990 Background: Although there have been improvements in 5-year overall survival (OS) rates among patients with AL amyloidosis over the past decades, OS is still poor, and death rates within the first 3–6 months after diagnosis have not changed significantly. This retrospective study was performed to identify risk factors for and causes of death during the first 90 days following diagnosis of AL amyloidosis. Method: From July 2002 to April 2009, 301 patients with a diagnosis of AL amyloidosis who were seen at Mayo Clinic within 30 days of diagnosis were identified from the dysproteinemia database. The 100 who died within 90 days were the focus of our study. The other 201 who were alive beyond 90 days were used as a comparator group. Outside physician offices were contacted to obtain further information pertaining to treatment and cause of death for our study group. Results: Of the 100 patients with early death, median age at diagnosis was 63.7 years (range: 34.7–89.4). 25 patients were diagnosed with concurrent multiple myeloma (MM) based on MM-specific end-organ damage. Overall, the number of patients with 2, 3 and 4 organs (cardiac, renal, nerve or liver) involved with amyloidosis was 37, 15 and 4, respectively. Using the cardiac biomarker staging system, 78% of 46 evaluable patients were stage III at diagnosis followed by 22% stage II and no stage I. Table 1 describes the characteristics of the studied population. Amyloid-related deaths were identified in 61 patients with the most common cause being cardiac arrest or sudden death (33%) followed by end-organ failure (24%). Treatment was started in 50% of patients; 34% received no treatment; and no treatment information was available for the remainder. OS was 54.5 days in patients who received treatment as compared to 7.5 days in those who received no treatment (p<0.0001); outcomes were similar in the group in whom no treatment information was available and those patients who were known to have received treatment. Melphalan with dexamethasone was the most common treatment (21%) and was associated with improved OS compared to other treatments including novel agents (57 vs. 26 days, p=0.003). Outcomes were no different if the patients had received novel therapies, but numbers were small. When compared to patients who lived for more than 90 days from their diagnosis, patients with early mortality had higher median intraventricular septum (IVS) (15 vs. 13 mm, p<0.0001), lower ejection fraction (EF) (50 vs. 64%, p<0.0001), and higher troponin-T (0.125 vs. 0.01 ng/ml, p<0.0001) and NT-proBNP (9020 vs. 1292 pg/ml, p<0.0001). We also found that patients who died within 90 days of their diagnosis had significantly higher plasma cell labeling index (PCLI), uric acid, beta-2 microglobulin, involved free light chain (FLC) and creatinine. Conclusion: This study highlights the characteristics of patients who died within 90 days of diagnosis of AL amyloidosis. The majority of patients died from arrhythmia and organ failure. This implies that other interventions aside from treatment of the underlying plasma cell (PC) disorder will likely be required to change the early outcomes of this disease. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Trend towards Improved Day 100 and 2-Year Survival After SCT for AL Amyloidosis: Outcomes Before and After 2006

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3554-3554
Author(s):  
Morie Abraham Gertz ◽  
Martha Lacy ◽  
Angela Dispenzieri ◽  
Shaji Kumar ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Research Funding ◽  
Troponin T ◽  
Safety Margin ◽  
Early Mortality ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Time Period ◽  
Before And After ◽  
Short Term Mortality

Abstract Abstract 3554 Introduction: The role of SCT in the management of Ig light chain (AL) amyloidosis remains undefined. Patients: We report 422 patients (Table 1) who received SCT for AL amyloidosis to compare outcomes of patients treated before January 2006 with those of patients treated from January 2006 until December 1, 2009. Results: Day 100 all-cause mortality decreased over this time period from 12% to 7% (P=.09) figure 1. Survival at 2 years increased from 78% to 82%. Figure 2 The major determinants of early mortality (before day 100) were the presence of cardiac involvement with amyloid and increased levels of cardiac biomarkers, lower serum albumin, higher serum creatinine, and a higher number of organs involved. (Table 2) On multivariate survival analysis, higher levels of serum troponin T and N-terminal pro–brain natriuretic peptide were the only predictors of early mortality after SCT. Conclusion: Improved supportive care and refined patient selection has improved the safety margin for patients undergoing SCT; short-term mortality showed a more than 40% decrease after 2005. Recognition of this decrease in mortality is important for physicians caring for these patients as they weigh the pros and cons of SCT vs novel agent-based treatment in management of amyloidosis. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Multiple Myeloma: Most Common End-Organ Damage and Management

2007 ◽  
Vol 5 (2) ◽  
pp. 170-178 ◽  
Author(s):  
Mohamad A. Hussein
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Percutaneous Vertebroplasty ◽  
Surgical Techniques ◽  
Organ Damage ◽  
Early Mortality ◽  
Adjunctive Treatment ◽  
Plasma Cell Dyscrasia ◽  
End Organ Damage ◽  
Minimally Invasive Surgical

End-organ damage is the factor that differentiates plasma cell dyscrasia requiring therapy (active multiple myeloma [MM]) from disease that does not require therapy (monoclonal gammopathy of undetermined significance and smoldering [asymptomatic] MM). Progressive skeletal destruction is the hallmark of MM and responsible for principle morbidity in the disease. The spine is the most afflicted skeletal organ, and vertebral fractures have significantly contributed to its poor prognosis. Early mortality in MM is usually attributed to the combined effects of active disease and comorbid factors. Infection and renal failure are the main direct causes of early mortality. Using bisphosphonates to manage skeletal events mainly by preventing or slowing the destructive process has become an important adjunctive treatment in MM. Advances in minimally invasive surgical techniques, such as percutaneous vertebroplasty and kyphoplasty, offer these patients less-invasive options for treating vertebral collapse and restoring function. The aggressive management of other complications of the disease through more effective and less toxic therapy that targets the primary disease, in addition to supportive care, is resulting in patients experiencing less morbidity and probably lower mortality. This article reviews recent advances in the understanding of bone disease in MM, the role of bisphosphonates in preventing skeletal events, and available data on percutaneous vertebroplasty and kyphoplasty, and discusses the management of infection and renal failure, which seem to be responsible for high initial mortality and thereby compromise the current advances in therapy.

Serum Free Light Chain Ratio in Distinguishing Smoldering Multiple Myeloma From Active Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3948-3948
Author(s):  
Jeremy T Larsen ◽  
Shaji Kumar ◽  
S. Vincent Rajkumar
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Predictive Value ◽  
Plasma Cells ◽  
Organ Damage ◽  
End Organ Damage ◽  
Cut Point ◽  
Smoldering Multiple Myeloma ◽  
Bone Marrow Plasma

Abstract Abstract 3948 Background: Smoldering multiple myeloma (SMM) is an asymptomatic precursor disease of multiple myeloma, and is defined by excess bone marrow plasma cells and monoclonal protein without evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions [CRAB]). The identification of SMM patients with more aggressive underlying disease remains a challenge. We hypothesize that SMM is a clinical entity comprised of both premalignant, high-risk MGUS and early multiple myeloma in transition to malignant disease, which may be differentiated with the use of the serum FLC (FLC) ratio. Methods: This was a retrospective analysis of 586 patients with newly diagnosed SMM from 1970–2010 with available stored serum samples around the time of diagnosis to be utilized for quantification of FLC ratios. SMM was defined by the International Myeloma Working Group 2003 definition; serum M-protein ≥ 3 g/dL and/or ≥ 10% bone marrow plasma cells with no evidence of CRAB features. The immunoglobulin FLC assay (Binding Site, U.K.) was used for testing. The FLC ratio was calculated as κ/λ (reference range 0.26–1.65). The involved/uninvolved FLC ratio was recorded to simplify the reporting of data. Receiver Operating Characteristics (ROC) curves were created to assess the ability of the FLC ratio to discriminate patients who progressed to symptomatic multiple myeloma (MM) in the first 2 years or at any point during follow-up versus patients without evidence of progression. Patients with less than 24 months follow-up without progression were censored. The optimal diagnostic cut-point for FLC involved/uninvolved ratio to identify patients with progressive disease from the ROC curve was >88.6 (equivalent to <0.011 or >88.6). For ease of clinical application, the optimal value for involved/uninvolved FLC ratio was rounded to >100. Time to progression (TTP) from date of the initial FLC to active MM was calculated using Kaplan-Meier analysis and compared to patients with a high (>100) and low (<100) involved/uninvolved FLC ratio at time of SMM diagnosis. TTP within 24 months of the initial FLC was also calculated. Results: During the study period, 54% of patients progressed to active MM. On ROC analysis, a cut-point of >100 corresponded to a sensitivity of 25% (95% CI, 20.5–30.4) and specificity of 99.3% (97.3–99.9), with positive likelihood (+LR) ratio of 33.9 (38.1–41.0), negative likelihood ratio (−LR) of 0.75 (0.2–3.0), positive predictive value (PPV) of 97.6 (91.5–99.7) and negative predictive value of 53.0 (48.5–57.4). Using the ROC to assess progression to MM within 24 months (Figure 1), sensitivity was 29.6% (23.5–36.4), specificity 94.5% (91.7–96.5), +LR 5.36 (4.3–6.6), -LR 0.75 (0.5–1.1), PPV 85.8 (77.7–91.8), and NPV 54.3 (49.8–58.9). Median TTP to active MM in the FLC >100 group was 15 months (9–17) versus 52 months (44–60) in the FLC <100 group (p <.0001) [Figure 2]. In the FLC ratio >100 group, progression at 1 year was 47%, 76% at 2 years, and 90% at 3 years. Only 25% of the FLC <100 patients had progressed at 2 years. The most common progression event was bone disease (42%), followed by anemia (26%), renal impairment (23%), and hypercalcemia (5%). Conclusion: Elevation of the FLC ratio >100 (or <0.01) is highly specific for the future development of active MM, with 76% of these patients developing end-organ damage requiring therapy within 2 years. Risk of transformation to MM in the FLC <100 group was similar to previously reported rates of 10% per year for the first 5 years. Development of an FLC ratio >100 is associated with increasing disease burden and in this study behaved in a malignant fashion rather than a precursor state. The FLC is a simple and useful predictor of progression to MM in SMM, and patients with FLC ratios of <0.01 or >100 within the first 2 years of SMM diagnosis should be monitored especially closely. Future studies are needed to determine optimum cutoffs for FLC ratio to where a change in definition of MM could be considered. Disclosures: No relevant conflicts of interest to declare.

The Majority of Patients with Relapsing Light Chain (AL) Amyloidosis Are Not Eligible for Enrollment Onto Clinical Trials: Using Screen Failures to Define Major Unmet Medical Needs

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1786-1786 ◽  
Author(s):  
Heather Landau ◽  
Raymond L. Comenzo ◽  
Tasneem Balasinorwala ◽  
Melissa Warner ◽  
Ola Landgren ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Organ Damage ◽  
M Protein ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Medical Needs ◽  
Measurable Disease

Abstract Background: Hematologic response criteria in AL amyloidosis are based on reduction of FLCs and correlate with organ improvement and survival in the front-line setting (Palladini 2012). Hematologic progression is defined from complete response (CR) as any detectable monoclonal (m) protein or abnormal FLC ratio (light chain must double); and from partial response (PR) as a 50% increase in serum or urine m-protein to > 0.5g/dl or 200mg/d respectively; or a 50% increase in FLC to > 10mg/dL based on consensus criteria (Gertz 2005); while cardiac and renal progression criteria have recently been validated (Palladini 2012 & 2014). Trials enrolling relapsed pts define measurable disease by a difference in FLC (dFLC) >5mg/dl such that accurate responses (VGPR, PR) can be assessed. However, many pts with hematologic and/or organ progression fail to meet dFLC > 5mg/dL set by inclusion criteria (if progression from CR) or the high bar of FLC > 10mg/dL set by the progression criteria and are ineligible for clinical trials. Composite criteria for progression of disease involving both hematologic measures and biomarkers of organ damage do not exist. The goal of the current study was to characterize pts with AL and evidence of progressive disease who were ineligible for clinical trials in order to determine the magnitude of this problem and define potential AL study populations whose medical needs are not being met. Methods: Previously treated AL pts screened for clinical trials from 5/2013 to 5/2015 at Memorial Sloan Kettering Cancer Center and Tufts Medical Center were reviewed retrospectively. Trials included 1) phase I/II trial of carfilzomib (NCT01789242), 2) phase I trial of ixazomib (NCT01318902) and 3) phase III trial of ixazomib/dexamethasone versus physician's choice (NCT01659658). Inclusion for all 3 required relapsed AL with dFLC >5mg/dl and evidence of organ damage. Pts with progressive hematologic and/or organ disease (by consensus or validated criteria) who were screened for these trials were included in this analysis. Results: Among 36 pts screened, 33% (N=12) enrolled. Yet, 67% (N=24) with hematologic (N=14), cardiac (N =6) and/or renal (N=11) progression were ineligible. Median age was 61 years (range, 41-78); prior lines of therapy were 1 in 38%, 2 in 38% and >2 in 25%. Median BNP, TROP, serum ALB, eGFR and 24hr urine total protein were: 283pg/mL (36-2197), 0ng/mL (0-0.09), 3.4g/dL (1.3-4.8), 66ml/min (7-128) and 1800 mg/24hrs (trace-12,875), respectively. Median involved FLC was 6.48mg/dl (0.93-52.6) and dFLC 4.69mg/dl (0.01-52). 58% (14/24) were ineligible due to dFLC <5mg/dl, which was the most common reason for screen failure despite meeting hematologic and/or organ criteria for progression. Others were excluded for multiple myeloma (N=2), cardiac stage III (N=4), prior malignancy (N=1), number of prior therapies (N=1) and low creatinine clearance (N=2). 92% (22/24) have received therapy: 19 off study, 2 on alternate trials and 1 eventually qualified with dFLC >5mg/dl; 2 are being monitored for FLC progression with unclear clinical implications. One-third of patients ineligible for these trials have died. Conclusions: The finding that only 1/3 of pts with AL amyloidosis and hematologic or organ progression requiring therapy are eligible for clinical trials demonstrates the limitations of the current definitions of progression and "measurable disease" criteria for enrolling relapsed pts on trials. The necessary decision to treat pts with organ progression in advance of their meeting a criterion for FLC progression (to >10mg/dl) indicates that this arbitrarily defined value needs to be revised. Moreover, time to next therapy rather than progression free survival (as currently defined) is a more relevant clinical trial end point. More sensitive, validated hematologic progression and composite criteria defining progression of hematologic and organ disease are critically needed to identify patients whose level of hematologic disease progression and risk of organ damage is at variance with current criteria as defined by FLCs. This will enable novel therapies that have the potential to reduce the risks of end-stage organ failure and death to be tested in this population. Disclosures Landau: Spectrum Pharmaceuticals: Honoraria; Prothena: Consultancy, Honoraria; Onyx: Honoraria, Research Funding; Janssen: Consultancy; Janssen: Consultancy; Takeda: Research Funding. Comenzo:Prothena: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Takeda Millennium: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees. Landgren:BMJ Publishing: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Medscape: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy. Giralt:CELGENE: Consultancy, Honoraria, Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding.

Evaluation of the Concordance of Two Free Light Chains Assays to Identify High Risk Smoldering Myeloma Patients.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2070-2070 ◽  
Author(s):  
Caroline Moreau ◽  
Emmanuel Rouger ◽  
Basile Henriot ◽  
Martine Escoffre ◽  
Martine Sebillot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Binding Site ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Organ Damage ◽  
Free Light Chain ◽  
Poor Correlation ◽  
Specificity And Sensitivity

Abstract Background Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM). According to 2003 classification, the IMWG (International Myeloma Working Group) recommended only to treat patients with end organ damage - often referred as CRAB criteria (hypercalcemia, renal failure, anemia and radiological bone lesions). The standard of care for SMM was to postpone treatment until progression to symptomatic disease occurred. The average annual risk of progression of SMM to MM was 10%/year. In 2014 IMWG proposed a revised classification including 3 new criteria that enable early diagnosis of MM before organ damage. The new criteria of MM needs the presence of more than 10% clonal bone marrow plasma cells combined with either the presence of end organ damage (CRAB criteria) or one of following new biomarkers of malignancy: bone marrow plasma cells ≥60%, serum free light chains (FLC) ratio ≥100 and ≥2 focal lesions on MRI. The FLC criteria were established with Freelite™ assay (The Binding Site Company) and have not been validated with other available assays. Freelite™ assay which used polyclonal antibodies was available since 2001. More recently N Latex assay (Siemens Healthyneers) using monoclonal antibodies has been commercialized in Europe. It is now well know that there is a good correlation between the 2 assays even though results in absolute values are not numerically identical. In this context, the aim of this study was to evaluate the concordance between the two assays to identify high risk SMM, when considering the biomarker of malignancy FLC ratio ≥100. Methods This is a retrospective study including 185 patients with SMM according to 2003 IMWG criteria. FLC concentration and ratio were evaluated in frozen sera with both assays in a BN Prospec and evolution status was collected. Results The average age was 62.5 (± 10.2) years old. Results revealed poor correlation between the 2 assays with a Slope Passing-Bablok value of 0.63 (0.57-0.67) for the FLC κ and of 0.44 (0.35-0.62) for the κ/ λ ratio ≥ 100, and concordance in determining the level of FLC λ with a Slope Passing-Bablok 1.16 (0.99-1.40). A Freelite™ratio ≥ 100 was found in 27 patients (14.3%), and a N Latex ratio ≥ 100 was found in 10 patients (5.3%). All but one patients with an N Latex ratio ≥ 100 had also a Freelite™ ratio ≥ 100. Mean of follow up was 2.4 years. A progression toward MM was observed in 77 (40.7%) patients. Among the 27 patients with Freelite™ ratio ≥ 100, 14 patients (55.5%) have evolved toward MM (figure 1A). Specificity and sensitivity for a Freelite™ ratio ≥ 100 were respectively 88.7% (95% CI 81.8 to 94.0%) and 20.3% (95% CI 11.8 to 31.2%). With the N Latex Assay, only 10 patients had a FLC ratio ≥ 100, in which 7 patients have evolved towards MM. Specificity and sensitivity for a N-Latex ratio ≥ 100 were respectively be 67.0% (95% CI 57.4 to 75.6%) and 53.2% (95% CI 41.5 to 64.7%). Given the poor predictive performance of a N-Latex ratio ≥ 100 we determined that a N-Latex ratio ≥ 70 have adequate specificity of 95.5% (95% CI 89.9 to 98.5%) and a sensitivity of 13.0% (95% CI 6.4 to 22.6%) (figure 1B). 15 patients (8.1%) patients had a N-Latex ratio ≥ 70. Among these, 10 patients (66.6%) have evolved toward MM. Conclusion Our study shows poor correlation between the two FLC assays in SMM patients. A Freelite™ ratio ≥ 100 had a lesser specificity than previously described (specificity 95% in Larsen study [1]). The 100 cut-off value was not performant enough for N-Latex assay. A new ratio is thus needed and was found to be 70 to have sufficient specificity and sensitivity. This result need to be validated in an independent cohort. However, with a Freelite™ ratio ≥ 100 or an N Latex ratio ≥ 70, a significant number of patients would have been overtreated. Physicians should be aware of the limits of both assays. 1.Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;27:941-6. Figure 1 probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Figure 1. probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Disclosures Moreau: The Binding Site: Other: supply of free light chain assays ; SIEMENS: Other: supply of free light chain assays , Research Funding. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding.

Definition of a high-risk population among patients with AL amyloidosis not undergoing autologous stem cell transplantation using bone marrow plasmacytosis and the presence of CRAB.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8516-8516
Author(s):  
Taxiarchis Kourelis ◽  
Morie Gertz ◽  
Martha Lacy ◽  
Francis Buadi ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Autologous Stem Cell Transplant ◽  
Bone Lesions ◽  
High Risk Population ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Beta 2 Microglobulin

8516 Background: There is consensus that light chain amyloidosis (AL) patients with CRAB criteria (abnormal calcium or renal function, anemia or lytic bone lesions) also have multiple myeloma (MM). These patients are typically excluded from AL trials; however, AL patients with >= 10% bone marrow plasma cells (BMPC) in the absence of CRAB are included in trials along with AL with < 10% BMPC. We postulated that the currently used dichotomy may be incorrect and examined the spectrum of AL with and without MM. Methods: We identified 1,272 patients with AL seen within 90 days of diagnosis, between January 1, 2000, and December 31, 2010. We defined the population of patients with coexisting MM based on the existence of CRAB (AL-CRAB-MM). Patients without CRAB were divided into two groups, AL-only (<10% BMPC) and AL-PC-MM (>=10% BMPC). Results: Among the 1,272 patients, 117 (9%) had AL-CRAB-MM, 476 (37%) had AL-PC-MM, and 679 (53%) had AL only. Their respective median overall survivals (OS) were 16.2, 15.8, and 28.4 months (p<0.0001). Autologous stem cell transplant (ASCT) was performed in 203 (30%), 138 (29%) and 23 (20%) patients respectively. Since the outcomes of AL-CRAB-MM and AL-PC-MM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, AL-CRAB-MM and AL-PC-MM retained negative prognostic value independent of age, cardiac stage, prior autologous stem cell transplant (ASCT), beta 2 microglobulin, and dFLC. We next considered whether patients received ASCT as part of their treatment. For those patients who never received ASCT, the 5-year OS were 19%, 14%, and 31%, p<0.001, for AL-CRAB-MM, AL-PC-MM, and AL only respectively. In contrast, for those patients who received ASCT, the respective 5-year OS were 46%, 56%, and 73%, p<0.001. Conclusions: AL patients with >=10% BMPCs have a poor prognosis similar to patients with AL-CRAB-MM and should therefore be considered as AL with MM.

scholarly journals Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy

2016 ◽  
Vol 135 (3) ◽  
pp. 172-190 ◽  
Author(s):  
Eli Muchtar ◽  
Francis K. Buadi ◽  
Angela Dispenzieri ◽  
Morie A. Gertz
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Treatment Options ◽  
Organ Damage ◽  
Major Effect ◽  
Response To Treatment ◽  
Al Amyloidosis ◽  
Prognostic Effect ◽  
Amyloid Light Chain ◽  
Immunoglobulin Light Chain Amyloidosis

Immunoglobulin amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, where the culprit amyloidogenic protein is immunoglobulin light chains produced by marrow clonal plasma cells. AL amyloidosis is an infrequent disease, and since presentation is variable and often nonspecific, diagnosis is often delayed. This results in cumulative organ damage and has a negative prognostic effect. AL amyloidosis can also be challenging on the diagnostic level, especially when demonstration of Congo red-positive tissue is not readily obtained. Since as many as 31 known amyloidogenic proteins have been identified to date, determination of the amyloid type is required. While several typing methods are available, mass spectrometry has become the gold standard for amyloid typing. Upon confirming the diagnosis of amyloidosis, a pursuit for organ involvement is essential, with a focus on heart involvement, even in the absence of suggestive symptoms for involvement, as this has both prognostic and treatment implications. Details regarding initial treatment options, including stem cell transplantation, are provided in this review. AL amyloidosis management requires a multidisciplinary approach with careful patient monitoring, as organ impairment has a major effect on morbidity and treatment tolerability until a response to treatment is achieved and recovery emerges.

scholarly journals In Vitro and inVivo Activity of Melflufen in Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3100-3100 ◽  
Author(s):  
Ken Flanagan ◽  
Muntasir M Majumder ◽  
Romika Kumari ◽  
Juho Miettinen ◽  
Ana Slipicevic ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Lines ◽  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Advisory Committees

Background: Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by plasma cell secretion of misfolded light chains that assemble as amyloid fibrils and deposit on vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell directed therapeutics, aimed at preferentially eliminating the clonal population of amyloidogenic cells in bone marrow are expected to reduce production of toxic light chain and alleviate deposition of amyloid thereby restoring healthy organ function. Melphalan flufenamide ethyl ester, melflufen, is a peptidase potentiated alkylating agent with potent toxicity in myeloma cells. Melflufen is highly lipophilic, permitting rapid cellular uptake, and is subsequently enzymatically cleaved by aminopeptidases within cells resulting in augmented intracellular concentrations of toxic molecules, providing a more targeted and localized treatment. Previous data demonstrating multiple myeloma plasma cell sensitivity for melflufen suggests that the drug might be useful to directly eliminate amyloidogenic plasma cells, thereby reducing the amyloid load in patients. Furthermore, the increased intracellular concentrations of melflufen in myeloma cells indicates a potential reduction in systemic toxicity in patients, an important factor in the fragile amyloidosis patient population. To assess potential efficacy in amyloidosis patients and to explore the mechanism of action, we examined effects of melflufen on amyloidogenic plasma cells invitro and invivo. Methods: Cellular toxicity and apoptosis were measured in response to either melflufen or melphalan in multiple malignant human plasma cell lines, including the amyloidosis patient derived light chain secreting ALMC-1 and ALMC-2 cells, as well as primary bone marrow cells from AL amyloidosis patients, using annexin V and live/dead cell staining by multicolor flow cytometry, and measurement of cleaved caspases. Lambda light chain was measured in supernatant by ELISA, and intracellular levels were detected by flow cytometry. To assess efficacy of melflufen in vivo, the light chain secreting human myeloma cell line, JJN3, was transduced with luciferase and adoptively transferred into NSG mice. Cell death in response to melflufen or melphalan was measured by in vivo bioluminescence, and serum light chain was monitored. Results: Melflufen demonstrated increased potency against multiple myeloma cell lines compared to melphalan, inducing malignant plasma cell death at lower doses on established light chain secreting plasma cell lines. While ALMC-1 cells were sensitive to both melphalan and melflufen, the IC50 for melphalan at 960 nM was approximately 3-fold higher than melflufen (334 nM). However, ALMC-2 cells were relatively insensitive to melphalan (12600 nM), but maintained a 100-fold increase in sensitivity to melflufen (121 nM). Furthermore, while 40% of primary CD138+ plasma cells from patients with diagnosed AL amyloidosis responded to melflufen treatment in vitro, only 20% responded to melphalan with consistently superior IC50 values for melflufen (Figure 1). Light chain secreting cell lines and AL amyloidosis patient samples were further analyzed by single cell sequencing. We further examined differential effects on apoptosis and the unfolded protein response in vitro in response to either melflufen or melphalan. This is of particular interest in amyloidosis, where malignant antibody producing plasma cells possess an increased requirement for mechanisms to cope with the amplified load of unfolded protein and associated ER stress. As AL amyloidosis is ultimately a disease mediated by secretion of toxic immunoglobulin, we assessed the effects of melflufen on the production of light chain invitro, measuring a decrease in production of light chain in response to melflufen treatment. Finally, we took advantage of a recently described adoptive transfer mouse model of amyloidosis to assess the efficacy of melflufen and melphalan in eliminating amyloidogenic clones and reducing the levels of toxic serum light chain in vivo. Conclusions: These findings provide evidence that melflufen mediated toxicity, previously described in myeloma cells, extends to amyloidogenic plasma cells and further affects the ability of these cells to produce and secrete toxic light chain. This data supports the rationale for the evaluation of melflufen in patients with AL amyloidosis. Figure 1 Disclosures Flanagan: Oncopeptides AB: Employment. Slipicevic:Oncopeptides AB: Employment. Holstein:Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy. Lehmann:Oncopeptides AB: Employment. Nupponen:Oncopeptides AB: Employment. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.

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