scholarly journals Defective binding of the third component of complement (C3) to Streptococcus pneumoniae in multiple myeloma

Blood ◽  
1984 ◽  
Vol 63 (4) ◽  
pp. 949-957 ◽  
Author(s):  
BD Cheson ◽  
HS Walker ◽  
ME Heath ◽  
RJ Gobel ◽  
J Janatova
Keyword(s):  
Multiple Myeloma ◽  
Streptococcus Pneumoniae ◽  
Elevated Serum ◽  
Normal Serum ◽  
Complement C3 ◽  
Complement Pathway ◽  
Serum Factors ◽  
Increased Risk ◽  
History Of ◽  
Type 3

Abstract Patients with multiple myeloma (MM) are at an increased risk for infections with bacteria that require opsonization with complement. Because Streptococcus pneumoniae is the most frequently encountered pathogen in these patients, we investigated the ability of serum from patients with MM to mediate the binding of C3b, the major opsonin of the complement system, to S. pneumoniae. S. pneumoniae types 3, 14, and 25 were chosen for study, since S. pneumoniae type 3 activates primarily the classical complement pathway (CCP), type 25 primarily the alternative complement pathway (ACP), and type 14 both pathways. S. pneumoniae were treated with normal serum or serum from 17 patients with MM, and the bound C3b was quantified with fluorescein-conjugated anti-C3 in a spectrophotofluorometric assay. Despite normal or elevated serum concentrations of C3, total hemolytic complement, and C-reactive protein in all of the MM sera, factor B in 16/17 such sera, and C4 in 14/17 MM sera studied, all 17 sera demonstrated a defect in C3b binding to type 3 (32.7% +/- 6% of normal). In addition, serum from 15/17 patients bound decreased amounts of C3b to types 14 (39.6% +/- 8%) and 25 (52.2% +/- 8%). Mixing normal serum with MM serum restored MM C3b binding activity to all three S. pneumoniae types, suggesting that the defect was related to a deficiency rather than an inhibitor of C3 activation. Although MM patients are unable to produce specific antibodies to bacterial antigens, the addition of anti-S. pneumoniae antibodies to MM serum did not enhance C3b binding to any of the S. pneumoniae types. However, when S. pneumoniae were opsonized in a mixture of MM serum and C3-depleted normal serum, C3b binding was restored to all three S. pneumoniae types, demonstrating that MM C3 functions normally in the presence of other normal serum factors. In the present studies, the MM C3b binding defect appeared to correlate with the incidence of S. pneumoniae infections. Serum from patients with a history of an S. pneumoniae infection bound significantly less C3 (20.5% +/- 4%) than those study patients without a history of an S. pneumoniae infection (55.8% +/- 8%) (p less than 0.0025). Thus, MM serum has a defect in the activation of C3, and this may contribute to the increased susceptibility of MM patients to S. pneumoniae infections.

scholarly journals Defective binding of the third component of complement (C3) to Streptococcus pneumoniae in multiple myeloma

Blood ◽  
1984 ◽  
Vol 63 (4) ◽  
pp. 949-957
Author(s):  
BD Cheson ◽  
HS Walker ◽  
ME Heath ◽  
RJ Gobel ◽  
J Janatova
Keyword(s):  
Multiple Myeloma ◽  
Streptococcus Pneumoniae ◽  
Elevated Serum ◽  
Normal Serum ◽  
Complement C3 ◽  
Complement Pathway ◽  
Serum Factors ◽  
Increased Risk ◽  
History Of ◽  
Type 3

Patients with multiple myeloma (MM) are at an increased risk for infections with bacteria that require opsonization with complement. Because Streptococcus pneumoniae is the most frequently encountered pathogen in these patients, we investigated the ability of serum from patients with MM to mediate the binding of C3b, the major opsonin of the complement system, to S. pneumoniae. S. pneumoniae types 3, 14, and 25 were chosen for study, since S. pneumoniae type 3 activates primarily the classical complement pathway (CCP), type 25 primarily the alternative complement pathway (ACP), and type 14 both pathways. S. pneumoniae were treated with normal serum or serum from 17 patients with MM, and the bound C3b was quantified with fluorescein-conjugated anti-C3 in a spectrophotofluorometric assay. Despite normal or elevated serum concentrations of C3, total hemolytic complement, and C-reactive protein in all of the MM sera, factor B in 16/17 such sera, and C4 in 14/17 MM sera studied, all 17 sera demonstrated a defect in C3b binding to type 3 (32.7% +/- 6% of normal). In addition, serum from 15/17 patients bound decreased amounts of C3b to types 14 (39.6% +/- 8%) and 25 (52.2% +/- 8%). Mixing normal serum with MM serum restored MM C3b binding activity to all three S. pneumoniae types, suggesting that the defect was related to a deficiency rather than an inhibitor of C3 activation. Although MM patients are unable to produce specific antibodies to bacterial antigens, the addition of anti-S. pneumoniae antibodies to MM serum did not enhance C3b binding to any of the S. pneumoniae types. However, when S. pneumoniae were opsonized in a mixture of MM serum and C3-depleted normal serum, C3b binding was restored to all three S. pneumoniae types, demonstrating that MM C3 functions normally in the presence of other normal serum factors. In the present studies, the MM C3b binding defect appeared to correlate with the incidence of S. pneumoniae infections. Serum from patients with a history of an S. pneumoniae infection bound significantly less C3 (20.5% +/- 4%) than those study patients without a history of an S. pneumoniae infection (55.8% +/- 8%) (p less than 0.0025). Thus, MM serum has a defect in the activation of C3, and this may contribute to the increased susceptibility of MM patients to S. pneumoniae infections.

Insulin treatment fails to abolish the teratogenic potential of serum from diabetic rats

1996 ◽  
Vol 134 (4) ◽  
pp. 459-466 ◽  
Author(s):  
Parri Wentzel ◽  
Ulf J Eriksson
Keyword(s):  
Glucose Concentration ◽  
Insulin Treatment ◽  
Ketone Bodies ◽  
Diabetic Rats ◽  
Normal Serum ◽  
Serum Factors ◽  
Crown Rump Length ◽  
Increased Risk ◽  
Control Serum ◽  
Teratogenic Potential

Wentzel P, Eriksson UJ. Insulin treatment fails to abolish the teratogenic potential of serum from diabetic rats. Eur J Endocrinol 1996;134:459–66. ISSN 0804–4643 Maternal diabetes during pregnancy constitutes an increased risk for congenital malformations in the offspring. Previous studies have identified several serum components with teratogenic activity, e.g. glucose and β-hydroxybutyrate, but have also suggested that the teratogenic influence of the diabetic environment on the developing embryo is multifactorial and may depend upon changed concentrations of several maternal metabolites. In the present investigation we aimed to assess the teratological impact of small, concomitant alterations in a series of metabolites, particularly those not previously identified as teratogens. We thus investigated the influence of a mild diabetic environment by culturing gestational day-9 rat embryos in serum from insulin-treated diabetic rats for 48 h in vitro, and compared the embryonic outcome with that obtained after culture in normal serum and in serum from manifestly diabetic rats without insulin treatment. The glucose concentration was adjusted to 10 or 30 mmol/l in the cultures, and the embryos were evaluated with respect to crown–rump length, protein and DNA content, number of somites and malformation score (comparing major, minor or no malformations). We found that increased glucose levels caused embryonic maldevelopment in both normal and diabetic serum, and that despite normalization of the diabetic state, the serum from the insulin-treated diabetic rats caused more growth retardation than the nondiabetic control serum. The normalized diabetic serum was also more teratogenic than the normal serum at the low glucose concentration, whereas the serum from the manifestly diabetic rats tended to cause more dysmorphogenesis at 30 mmol/l glucose than both the normal and normalized diabetic serum. The results suggest that the teratogenicity of maternal serum in diabetic pregnancy is not mediated exclusively by increased concentrations of glucose and ketone bodies. The efforts to diminish the teratogenic effects of a diabetic environment should therefore include normalization of a multitude of serum factors, including glucose and ketone bodies. Parri Wentzel, Department of Medical Cell Biology, University of Uppsala, Biomedicum, PO Box 571, S-751 23 Uppsala, Sweden

scholarly journals Mice with Impaired Extrathyroidal Thyroxine to 3,5,3′-Triiodothyronine Conversion Maintain Normal Serum 3,5,3′-Triiodothyronine Concentrations

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 954-960 ◽  
Author(s):  
Marcelo A. Christoffolete ◽  
Rafael Arrojo e Drigo ◽  
Fernanda Gazoni ◽  
Susana M. Tente ◽  
Vanessa Goncalves ◽  
...  
Keyword(s):  
Biological Effects ◽  
Elevated Serum ◽  
Normal Growth ◽  
Normal Serum ◽  
C3h Mice ◽  
Serum T3 ◽  
Serum T4 ◽  
Hormone Homeostasis ◽  
Type 3

For T3 to mediate its biological effects, the prohormone T4 must be activated by removal of an outer-ring iodine by the type 1 or 2 deiodinases (D1 and D2) with approximately 60% of the daily T3 production in rodents being produced extrathyroidally through this pathway. To further define the role of these enzymes in thyroid hormone homeostasis, we backcrossed the targeted disruption of the Dio2 gene into C3H/HeJ (C3H) mice with genetically low D1 expression to create the C3H-D2KO mouse. Remarkably, these mice maintain euthyroid serum T3 levels with normal growth and no decrease in expression of hepatic T3-responsive genes. However, serum T4 is increased 1.2-fold relative to the already elevated C3H levels, and serum TSH is increased 1.4-fold. Despite these increases, thyroidal 125I uptake indicates no difference in thyroidal activity between C3H-D2KO and C3H mice. Although C3H-D2KO hepatic and renal D1 activities were well below those observed in wild-type mice (∼0.1-fold for both), they were 8-fold and 2-fold higher, respectively, relative to C3H mice. Thyroidal D1 and cerebral cortical type 3 deiodinase activity were unchanged between C3H-D2KO and C3H mice. In conclusion, C3H-D2KO mice have notably elevated serum T4 levels, and this, in conjunction with residual D1 activity, is likely an important role in the maintenance of euthyroid serum T3 concentrations.

Cardiotoxicity Risk with Bortezomib Versus Lenalidomide for Treatment of Multiple Myeloma: A Propensity-Matched Study of 1,128 Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3046-3046
Author(s):  
John Reneau ◽  
Dennis Asante ◽  
Holly Van Houten ◽  
Francis Buadi ◽  
Amir Lerman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Multiple Myeloma ◽  
Administrative Claims ◽  
Cardiac Events ◽  
Kaplan Meier ◽  
Increased Risk ◽  
Significant Difference ◽  
History Of ◽  
Acute Mi ◽  
Matched Study

Abstract Background: Proteasome inhibitors and immunomodulatory drugs are currently an integral part of the management of multiple myeloma. Pre-clinical and clinical studies suggest that bortezomib, the first approved proteasome inhibitor for the management of multiple myeloma, may be associated with an increased risk of cardiac events such as heart failure (HF), acute myocardial infarction (MI), and arrhythmia. The goal of this study was to evaluate the rate of adverse cardiac events in patients treated with bortezomib compared to lenalidomide. Methods: This retrospective, propensity-matched study using a large, national administrative claims database included multiple myeloma patients who initiated bortezomib and a comparison group (matched on age, sex, year of drug initiation, baseline HF, hyperlipidemia, hypertension, history of MI, arrhythmia and Charlson comorbidity index) who initiated lenalidomide between January 2008 and December 2014. Those who received both bortezomib and lenalidomide were excluded from the analysis. The primary endpoints were time to hospitalization for HF, acute MI and arrhythmia. Rates of hospitalizations were computed per 100 patient years (PY). Cox proportional hazard models were used to obtain hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 1,128 patients (564 bortezomib users and 564 lenalidomide users, mean age of 69, 47% female, and average follow-up time of 438 days) were included in the analysis. The rate of hospitalization for HF, acute MI, and arrhythmia was 5.76/100 PY, 2.57/100 PY, and 3.10/100 PY respectively among bortezomib users and 2.45/100 PY, 1.47/100 PY, and 2.85/100 PY respectively among lenalidomide users. In the propensity score matched models, the risk of hospitalization for acute MI and arrhythmia with bortezomib was similar to lenalidomide (HR 1.60 [95% CI 0.73-3.49] and HR 1.01 [95% CI 0.54-1.90] respectively). The risk of hospitalization for HF with bortezomib use was significantly higher compared to lenalidomide (HR 2.10 [95% CI 1.18-3.74], Figure 1). Further stratification of the patient population by baseline HF status showed that those with baseline HF (n=212) were significantly more likely to be hospitalized for HF following treatment with bortezomib compared to lenalidomide. The rate of hospitalization for HF in the population with baseline HF was 24.12/100 PY among bortezomib users and 8.77/100 PY among lenalidomide users (HR 2.24 [95% CI 1.04-4.83]). Those without baseline HF (n=916) had similar rates of hospitalization for HF when treated with bortezomib and lenalidomide (2.83/100 PY and 1.29/100 PY respectively, HR 2.05 [95% CI 0.86-4.91]). Conclusion: The current study shows that bortezomib use in patients treated for multiple myeloma is associated with an increased risk of hospitalization for heart failure, but not acute MI or arrhythmia. Those with HF prior to initiating therapy with bortezomib had a significantly increased risk of hospitalization for HF when compared to those treated with lenalidomide. There was no significant difference in the rate of hospitalization for HF in those without a baseline diagnosis of HF. Collectively, these data have important implications for the management of patients with multiple myeloma, especially those with a history of HF at the time of therapy initiation. Figure 1. Kaplan Meier plot for HF hospitalizations. Figure 1. Kaplan Meier plot for HF hospitalizations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Systemic Mastocytosis Associated with “Smoldering” Multiple Myeloma

Diagnostics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 88
Author(s):  
Magda Zanelli ◽  
Stefano Ricci ◽  
Maurizio Zizzo ◽  
Francesca Sanguedolce ◽  
Federica De Giorgi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Systemic Mastocytosis ◽  
Elevated Serum ◽  
Cell Lineage ◽  
Right Hemicolectomy ◽  
X Rays ◽  
History Of ◽  
Magnetic Resonance Imaging Mri ◽  
Marrow Cellularity

A 79-year-old woman presented with a long history of peripheral eosinophilia. Previous right hemicolectomy for colonic polyposis was reported. Laboratory tests were notable for mild macrocitic anaemia and eosinophilia. β2 microglobulin and serum tryptase levels were elevated. Serum immunofixation revealed IgA/kappa monoclonal protein. Bence-Jones protein was positive. Bone marrow (BM) biopsy revealed the coexistence of two neoplastic components. Cohesive clusters of bland-looking, spindle-shaped mast cells, representing 20% of marrow cellularity, were close to aggregates of mature plasma cells occupying 40% of marrow cellularity. Molecular analysis on marrow aspirate demonstrated KIT D816V mutation, TET2 mutation, monoallelic deletion of TP53/17p13 and trisomy of ATM/11q23. A bone density study revealed mild osteoporosis. Full skeletal X-rays and magnetic resonance imaging (MRI) of spine and hips showed multiple, small rarefaction areas and an old L1-L2 fracture, both ascribed to osteoporosis. The association of systemic mastocytosis (SM) and multiple myeloma (MM) is very uncommon. The coexistence of SM with MM placed our patient in the SM with associated clonal haematological non-mast-cell lineage disease (SM-AHN) subtype. Midostaurin therapy was started.

scholarly journals Prospective Study of Apixaban for Primary Prevention of Venous Thromboembolism in Patients with Multiple Myeloma Receiving Immunomodulatory Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1233-1233 ◽  
Author(s):  
Robert Frank Cornell ◽  
Samuel Z. Goldhaber ◽  
Brian G Engelhardt ◽  
Javid Moslehi ◽  
Madan Jagasia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Primary Prevention ◽  
Major Bleeding ◽  
Study Drug ◽  
Medical Intervention ◽  
Mechanical Trauma ◽  
Major Hemorrhage ◽  
Increased Risk ◽  
History Of

Abstract Introduction Immunomodulatory/cereblon-binding drugs (IMiDs), including lenalidomide and pomalidomide, have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic foundation at all phases of therapy. While these agents are generally well-tolerated, their increased risk of venous thromboembolism (VTE), in particular deep vein thrombosis and pulmonary embolism, presents a major clinical challenge for the treatment of MM. Apixaban, a direct oral anticoagulant which directly blocks Factor Xa, has been approved for treatment in patients with VTE. Apixaban has not been prospectively evaluated for thromboprophylaxis in MM in the US. In this phase IV single-arm study (NCT02958969), we prospectively evaluate the safety and efficacy of apixaban for primary prevention of VTE in patients with MM receiving IMiD therapy. Methods Fifty patients with MM on IMiD therapy received apixaban 2.5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for 6 months. Patients requiring therapeutic anticoagulation or with history of prior VTE were excluded. Patients stopped aspirin while on apixaban. Primary safety outcomes were rates of major hemorrhage and clinically relevant non-major hemorrhage over 6 months. Major bleeding was defined as overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, requiring transfusion of ≥ 2 units of blood, occurring in a critical site, or contributing to death. Clinically relevant non-major bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, surgical intervention, or interruption of the study drug. The primary efficacy outcome was the rate of symptomatic VTE over 6 months. Results Baseline characteristics are listed (Table). Median age was 63 years (range 51-74) with 50% of patients being male. Patients had received a median of 2 lines of therapy (range 0-8), and the majority (82%) had received prior autologous stem cell transplantation (AutoSCT). Patients received apixaban thromboprophylaxis in combination with lenalidomide (58%) or pomalidomide (42%). The majority (66%) received IMiDs for post-autoSCT consolidation or maintenance therapy. Most (80%) had traditional cardiovascular (CV) risk factors prior to initiation of apixaban, including hypertension (50%), obesity (46%), history of smoking (34%) and hyperlipidemia (32%). At planned interim analysis at 3 months (range 23-149 days) with data still being collected for planned 6 month study duration, no patients had experienced major hemorrhage or VTE. Two patients experienced clinically relevant, non-major hemorrhage, including one patient with unprovoked epistaxis lasting more than 5 minutes and another patient with mechanical trauma. These events were medically managed, and both patients were able to resume apixaban. One patient stopped therapy shortly after initiation due to allergic reaction to apixaban manifesting as generalized edema. No patients experienced stroke, myocardial infarction (MI), or death. Conclusions In this pilot study of 50 patients, low-dose apixaban was safe and well tolerated as thromboprophylaxis for patients with MM receiving IMiDs. No patients experienced VTE, major hemorrhage, stroke, or MI. Further randomized studies are needed to validate apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs. Disclosures Moslehi: Bristol-Myers Squibb: Consultancy, Research Funding. Jagasia:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.

Risk of skin cancer in multiple myeloma patients: A retrospective cohort study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20044-e20044
Author(s):  
Austin A Robinson ◽  
Alex Kitto ◽  
Simrin K Cheema ◽  
Erik K Madden ◽  
Adam S Norberg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cohort Study ◽  
Skin Cancer ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Time Course ◽  
Alkylating Agents ◽  
Treatment Regimens ◽  
Increased Risk ◽  
History Of

e20044 Background: Multiple myeloma (MM) patients (pts) have shown a higher risk of developing other cancers, although the type, time course, and relationship to MM treatment of these cancers are less clear. In this study, we determined the risk of specific skin cancer (CA) types among MM patients and its relationship to onset of MM and treatment. Methods: MM pts and unrelated age, sex, and race-matched companions (controls) seen at a MM clinic were enrolled in a retrospective cohort study. Information regarding baseline characteristics of MM and history of skin CA was obtained from medical records. Overall skin CA prevalence and types were compared between groups; among MM patients, the occurrence of skin CA was analyzed relative to date of diagnosis and treatment regimens, with stratification according to treatment duration. Results: We enrolled 205 MM pts and 201 controls with 27.3% and 14.9% demonstrating skin CA, respectively (p < 0.001). Specific types of skin CA included 60 and 37 basal cell carcinomas (BCC), 50 and 17 squamous cell carcinomas (SCC), and 9 and 5 melanomas in the MM pts and controls, respectively. The standardized incidence ratios (SIR) were SCC: 2.88 (p< 0.001), BCC: 1.59 (p<0.001), and melanoma: 1.76 (p = 0.074). SCC SIR was elevated (p<0.001) across each yearly time point from 10 years prior to MM diagnosis through 10 years subsequent to MM diagnosis. BCC SIR was elevated (p <0.002) from 7 through 10 years following MM diagnosis. The SIR markedly increased over time following the diagnosis of MM for both SCC and BCC. Relative risk (RR) was determined for pts treated with bortezomib, immunomodulatory agents, alkylating agents, glucocorticoids, and anthracyclines. There was no significant increase in RR overall or for any specific type of skin CA in relationship to the type or duration of MM treatment. Conclusions: MM pts show an increased risk of skin CA (there was no increase in melanoma incidence), including SCC and BCC. SCC occurred before and following the diagnosis of MM whereas BCC followed the diagnosis of MM. The post-MM diagnosis increase in skin CA was not related to specific drugs used to treat MM.

P1575Cardiovascular toxicity following modern multiple myeloma therapy in Japanese cohort

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Shibata ◽  
S Nohara ◽  
K Nagafuji ◽  
Y Fukumoto
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Multiple Myeloma ◽  
Troponin I ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Prior History ◽  
Ventricular Ejection Fraction ◽  
Increased Risk ◽  
History Of

Abstract Background Multiple myeloma (MM) is a plasma cell dyscrasia accounting for approximately 13% of hematologic malignancies. Patients with MM have an increased risk of cardiovascular adverse events (CAEs) due to disease burden and/or anti-myeloma treatment-related risk factors. However, little is known about the incidence of cardiovascular toxicity of patients with MM. Methods We analyzed 42 consecutive patients (Male/Female 22/20, age 67±10 years old) who received anti-MM therapies between October 2016 and September 2018 from our University Cardio-REnal Oncology (CREO) registry. We examined the incidence of CAEs through January 2019 including congestive heart failure and cardiomyopathy (CHF/CM), ischemic cardiac event, newly symptomatic arrhythmias included atrial fibrillation or flutter requiring treatment, and venous thromboembolism (VTE). Results Within the 408-day median follow-up period (range 15–844 days), CAEs occurred in 23.8% (n=10); CHF/CM in 11.9%, newly diagnosed atrial fibrillation in 4.8%, VTE in 4.8%, vasospastic angina in 2.4%, and death in 28.6%. There were no significant differences between CAEs group and non-CAEs group in terms of sex, body mass index (BMI), incidence of hypertension, ischemic heart disease, prior history of heart failure, cardiovascular medications, left ventricular ejection fraction, serum high-sensitivity troponin-I, estimated glomerular filtration rate, blood urea nitrogen and N-terminal pro-brain natriuretic peptide levels at the time of enrollment. The use of various types of proteasome inhibitors and immunomodulatory drugs were not associated with the increased risk of CAEs. By multivariate analysis, a history of prior anti-myeloma therapies was identified as an independent risk factor for CAEs. Conclusion CAEs were significantly associated with the recurrent MM in Japanese MM patients.

scholarly journals Mutations in the Alternative Complement Pathway in Multiple Myeloma Patients with Carfilzomib-Induced Thrombotic Microangiopathy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2708-2708
Author(s):  
Maria Moscvin ◽  
Christine Ivy Liacos ◽  
Tianzeng Chen ◽  
Foteini Theodorakakou ◽  
Despina Fotiou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Biopsy ◽  
Thrombotic Microangiopathy ◽  
Research Funding ◽  
Endothelial Injury ◽  
Alternative Complement Pathway ◽  
Heterozygous Deletion ◽  
Complement Pathway ◽  
Increased Risk ◽  
Alternative Complement

Abstract Introduction Vascular endothelial injury related to treatment with proteasome inhibitors (PI) has been previously described. Carfilzomib is an irreversible PI and has been associated with cardiovascular toxicity, suggesting increased risk of endothelial injury. Thrombotic microangiopathy (TMA) has been described in multiple myeloma (MM) patients receiving PIs; more often with carfilzomib. In the pediatric transplant population, increased risk of TMA was related to heterozygous mutation in the alternative complement pathway. The homozygous deletions enable uncontrolled complement activation and was found three times more frequently in TMA population. We hypothesized that MM patients with complement mutation are at increased risk of PI-related TMA. Materials and Methods We identified ten cases of renal TMA in MM patients receiving carfilzomib from two medical institutions in Greece and in the United States. TMA was diagnosed based on either renal biopsy or acute kidney injury, new-onset anemia, thrombocytopenia and increased LDH in the absence of disease progression. We performed targeted sequencing of the twelve genes implicated in TMA: CFH, CFI, MCP, CFB, CFHR5, C3, THBD, DGKE, PLG, ADAMTS13, MMACHC and G6PD genes. Multiplex Ligation-Dependent Probe Amplification (MLPA) was performed for the analysis of the CFH-CFHR5 region. Results Patient characteristics and laboratory values at TMA diagnosis are presented in Table 1. The median age of patients was 68 years (range, 47-73), with slight male predominance (60%). Median laboratory values at diagnosis included hemoglobin 9.35 g/dL, platelet count 26,500 x 10 6/L, LDH 356,5 U/L and creatinine 2.25 mg/dL. Patients were treated with carfilzomib doses ranging 20-70 mg/m 2. Regimens included carfilzomib-dexamethasone (Kd, 7 patients), carfilzomib-lenalidomide-dexamethasone (KRd, 1 patient), carfilzomib-pomalidomide-dexamethasone (KPd, 1 patient), and carfilzomib-daratumumab-dexamethasone (DaraKd, 1 patient). All patients had previously received at least one line of therapy and seven patients had previously undergone autologous stem cell transplant (ASCT), 1-12 years prior to TMA diagnosis. The median time between carfilzomib initiation and TMA diagnosis was 4.5 months (range, 1-60 months). Diagnosis was confirmed with renal biopsy in four cases. Carfilzomib was discontinued in all patients and five patients were treated with plasma exchange (PLEX) while one patient received eculizumab. Seven patients demonstrated clinical improvement and resolution of TMA at 1 year after discontinuation of carfilzomib. Two patients progressed to end stage renal disease (ESRD) requiring intermittent hemodialysis, and one patient developed multiorgan failure. Results of genetic panel are shown in Table 2. Deletions of the CFHR3-CFHR5 region were present in seven cases (70%): two patients carrying a homozygous deletion of CFHR3-CFHR1, four patients with a heterozygous deletion of CFHR3-CFHR1, and one patient with heterozygous deletion of CFHR1-CFHR4. Direct gene sequencing revealed identifiable mutations in CD46 (MCP) and CFHR5 in two distinct patients. The functional correlation and clinical significance are yet to be investigated. Conclusions In our cohort of ten patients of carfilzomib-induced TMA, deletions of CFHR3-CFHR5 occurred frequently (70%). In the setting of carfilzomib use, heterozygous CFHR3-CFHR1 deletion may represent a risk factor for the development of TMA. Our data set the bases for larger studies assessing complement mutation as a predisposing factor for PI-induced TMA. Figure 1 Figure 1. Disclosures Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Dimopoulos: Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Richardson: AbbVie: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

scholarly journals Non-Secretory Multiple Myeloma with Patchy Marrow Involvement and Aberrant Cytokeratin Expression

2021 ◽  
Vol 34 (13) ◽  
Author(s):  
Miguel Silva ◽  
Joana Martins ◽  
João Pinto ◽  
Teresina Amaro
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Aspiration ◽  
Normal Serum ◽  
Bone Lesions ◽  
Diagnostic Challenge ◽  
Serum Free Light Chain ◽  
Cytokeratin Expression ◽  
History Of ◽  
The Right

Non-secretory multiple myeloma is a rare form of the disease that presents a diagnostic challenge. A 69-year-old woman presented to the emergency department with a pathological fracture of the right clavicle, along with a history of asthenia and middle back pain in the preceding three months. Workup revealed multiple focal lytic bone lesions in the clavicles, ribs, skull and thoracic- lumbar-sacral spine, without evidence of anemia, hypercalcemia or renal failure, with no abnormal immunofixation in the serum or urine and with normal serum free light chain ratios. The Iliac crest bone marrow aspiration and biopsy revealed a scarcely involved marrow, However, biopsy of one of the focal bone lesions revealed a hypercellular bone marrow with phenotypically abnormal plasmocytes, along with an intriguing, albeit aberrant, cytokeratin expression. Non-secretory multiple myeloma is in itself a rare diagnosis. However, the combination of a patchy marrow involvement and aberrant cytokeratin expression makes this a noteworthy presentation.

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