Carfilzomib Induced Cardiotoxicity in a Multiple Myeloma Patient

Abstract Proteasome inhibitors such as carfilzomib are indicated in multiple myeloma patients showing relapse and/or refractoriness of clonal activity. However, this therapy has been associated with a significant incidence of cardiotoxicity, especially in patients with known cardiovascular risk factors. Here we report a case of a 60-year-old woman with multiple myeloma, who developed severe congestive heart failure with positive myocardial injury biomarkers together with impaired LVEF and GLS, after treatment with carfilzomib. Therefore, chemotherapeutic drug was discontinued and neurohormonal blocking and diuretic therapy was started resulting in amelioration of symptoms, without changes in LVEF but with significant GLS improvement. Although high-grade cardiotoxicity is relatively rare in patients with non previous cardiac risk factors, it was a predictable side effect of carfilzomib use. Recognition of this syndrome is critical to instauration of appropriate therapy and prevention of morbimortality

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Carfilzomib Induced Cardiotoxicity in a Multiple Myeloma Patient

10.21203/rs.3.rs-33846/v1 ◽

2020 ◽

Author(s):

Arnold Mendez Toro ◽

Candida Diaz-Brochero ◽

Estivalis Acosta-Gutierrez

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Diuretic Therapy ◽

Proteasome Inhibitors ◽

Severe Heart Failure ◽

Cardiac Risk ◽

Chemotherapeutic Drug ◽

Pharmacological Management ◽

Multiple Myeloma Patient ◽

Appropriate Therapy

Abstract Proteasome inhibitors such as carfilzomib are indicated in multiple myeloma patients showing relapse and/or refractoriness of clonal activity after initial treatment. However, this therapy has been associated with a significative incidence of cardiotoxicity, especially in patients with known cardiovascular risk factors. Here we report a case of a 60-year-old woman with multiple myeloma, who developed congestive severe heart failure with positive myocardial lesion biomarkers and LVEF and strain reduction, after treatment with carfilzomib. Therefore chemotherapeutic drug was discontinued and neurohormonal blocking and diuretic therapy was started resulting in amelioration of symptoms, without changes in LVEF but with significant GLS improvement. This case illustrates the behavior of carfilzomib induced cardiotoxicity and the expected response to the appropriate pharmacological management. Although high-grade cardiotoxicity is relatively rare in patients with non previous cardiac risk factors, it was a predictable side effect of carfilzomib use. Recognition of this syndrome is critical to instauration of appropriate therapy and prevention of morbimortality.

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Arterial Hypertension and Multiple Myeloma: Physiopathology and Cardiovascular Risk and ‘Practical’ Indications in Patients Receiving Carfilzomib

Current Hypertension Reviews ◽

10.2174/1573402114666180611110547 ◽

2019 ◽

Vol 15 (1) ◽

pp. 47-53 ◽

Cited By ~ 1

Author(s):

Alberto Milan ◽

Giulia Bruno ◽

Ilaria Maffei ◽

Andrea Iannaccone ◽

Agnese Ravera ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Cardiovascular Risk ◽

Arterial Hypertension ◽

Proteasome Inhibitors ◽

Good Control ◽

Cardiovascular Complications ◽

Uncontrolled Hypertension ◽

Refractory Multiple Myeloma ◽

Current Guidelines

The introduction of carfilzomib in the treatment of relapsing and refractory multiple myeloma has allowed a significant increase in survival. The most frequent adverse effect of Carfilzomib treatment is arterial hypertension, even though the exact physiopathological mechanism are still unclear. MM patients, on the other hand, often present significant cardiovascular risk factors and comorbidities. Uncontrolled hypertension is frequently the cause of cardiovascular complications. It has been estimated that up to 50% of subjects in the general population are unaware of their hypertensive condition and only half of those who are aware of this risk factor present good control of blood pressure. Although the management of arterial hypertension is clearly important in reducing the risk of cardiovascular events, and is well described by the current guidelines, no clear indications are provided on how to approach and treat specifically MM patients undergoing treatment with proteasome inhibitors. The aim of our work is to summarize a practical approach to the stratification of cardiovascular risk of hypertensive in patients who are candidates for or actively treated with carfilzomib for refractory multiple myeloma (MMR). MM patients eligible for carfilzomib treatment should preliminary undergo a careful cardiovascular risk stratification. Perspective studies will help to better identify the specific risk factors that should be considered and treated in these patients.

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Myocardial injury after gynecologic oncology surgery in septuagenarians and octogenarians: Is there a role for routine postoperative cardiac biomarker monitoring?

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.220 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 220-220

Author(s):

Tharani Anpalagan ◽

Kathy Huang ◽

Maura Marcucci ◽

Sarah Mah ◽

Millie Walker ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Injury ◽

Angiotensin Receptor Blockers ◽

Frailty Index ◽

Gynecologic Oncology ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Cardiac Risk ◽

Improvement Program ◽

Surgical Complexity

220 Background: Accumulating evidence correlates myocardial injury after noncardiac surgery (MINS), even when asymptomatic, with increased cardiac and non-cardiac morbidity and mortality. There is no literature on MINS specific to Gynecologic Oncology. We sought to evaluate the incidence and risk factors of MINS in patients aged ≥70. Methods: Elective laparotomies between 01/2016-09/2020 for patients aged≥70 at a tertiary hospital in ON, Canada, were reviewed using prospectively-collected National Surgical Quality Improvement Program (NSQIP) data. MINS was defined as peak serum high-sensitivity troponin-T concentration ≥0.04ng/mL within 30 days postoperatively. Logistic regression analysis was performed. Results: In this cohort of 258 patients, of 242 (93.8%) who underwent postoperative troponin screening, 40 (16.5%) experienced MINS without exhibiting ischemic symptoms or ECG changes. The diagnosis of MINS led to a prescription or optimization of cardiovascular medications for 35 patients (87.5%). On univariate analysis, Revised Cardiac Risk Index (RCRI) of 3-5(p = 0.002), history of coronary artery disease (p = 0.003) or insulin-dependent diabetes (p = 0.006), preoperative use of antiplatelets (p = 0.009), beta-blockers (p = 0.02), ACE-inhibitors (ACEI) or angiotensin-receptor blockers (ARB)(p = 0.002) and frailty as defined by the NSQIP modified frailty index-5 (p = 0.02), were associated with greater risk of MINS. Factors reflecting surgical complexity including surgical complexity score, operative duration, blood loss and advanced oncologic stage were not predictive. Multivariable analysis using backward selection procedure identified elevated RCRI and preoperative ACE/ARB as significant risk factors (OR 5.93, 95% CI 1.52-24.31, p = 0.01 and OR 2.4, 95% CI 1.18-5.06, p = 0.02). Conclusions: One in 6 patients in our cohort experienced asymptomatic MINS irrespective of surgical complexity. Our analysis highlights a possible opportunity to optimize cardiac risk factors and to potentially improve perioperative patient safety by reducing morbidity. Routine preoperative cardiac risk-stratification and postoperative cardiac biomarkers monitoring should be considered in elderly patients with gynecologic malignancies.[Table: see text]

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Cardiac and Pulmonary Safety Profile of Single-Agent Carfilzomib From Four Phase 2 Studies in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4037.4037 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4037-4037 ◽

Cited By ~ 2

Author(s):

Sagar Lonial ◽

Ruben Niesvizky ◽

Leanne McCulloch ◽

Kanya Rajangam ◽

Ravi Vij

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Research Funding ◽

Cardiac Event ◽

Pulmonary Infection ◽

Cardiac Risk ◽

Phase 2 ◽

Pulmonary Infections ◽

Cardiac Events ◽

Cardiac Component

Abstract Abstract 4037 Background: Cardiac and pulmonary events are common comorbidities in patients (pts) with multiple myeloma (MM) that typically affect older adults (Robin J, et al. J Med Case Rep. 2008) and are aggravated by chronic anemia and cardiotoxicity of anti-MM agents such as anthracyclines and hematopoietic stem cell transplantation (Chow AW, et al. Intern Med J. 2012). Pts with MM are also predisposed to pulmonary infections, with pneumonia being one of the most common causes of death (Augustson BM, et al. J Clin Oncol.2005). The following abstract summarizes details of the cardiac and pulmonary safety profile from 4 phase 2 studies of carfilzomib (CFZ), a next generation proteasome inhibitor recently approved for the treatment of relapsed and refractory MM. Methods: Included in this analysis were 526 pts with relapsed and/or refractory MM treated with CFZ in the following trials: 003-A0, 003-A1, 004, and 005. In all studies, CFZ was dosed on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses could be escalated from 20 mg/m2 in C1 to 27 mg/m2 in C2 for all studies except 005 (15 mg/m2 in C1, 20 mg/m2 in C2, and 27 mg/m2in C3). Pts with NYHA class III-IV heart failure and recent MI/unstable angina were excluded. A comprehensive strategy based on Standardized MedDRA Query preferred terms was used wherein clinically related event terms were grouped to determine the most comprehensive occurrences of adverse events (AEs). The cardiac grouping included cardiac arrhythmias, cardiac failure, cardiomyopathy, and ischemic heart disease (IHD). Medical history was analyzed for relevant comorbid conditions, and baseline cardiac risk factor was defined as pts on ≥1 prior cardiac medication. Multiple dyspnea AE terms were grouped as were pulmonary infections from the Infections and Infestations System Organ Classes. Pulmonary AE analyses included dyspnea time-to-event and duration-of-event analyses. Results: In all, 73.6% pts had a medical history of a cardiac event and 70.0% demonstrated baseline cardiac risk factors. The most common cardiac AEs were arrhythmias, the majority of which were low-grade, benign, supra-ventricular events such as tachycardia and palpitations. Congestive heart failure (CHF) events were predominantly Grade (G) 3. There were 4 (0.8%) G5 cardiac SAEs, all cardiac arrest. An additional 4 pts had a cardiac component to their death for a total of 8 (1.5%) deaths on study or within 30 days of treatment with a cardiac component. Of note, 7 of the 8 deaths occurred in pts with baseline cardiac risk factors. Overall, 6 pts (1.1%) had a CFZ dose reduction and 23 (4.4%) discontinued treatment due to a cardiac AE. Cardiac events leading to discontinuation included CHF (1.7%), arrhythmia (1.1%), and IHD (1.0%). In general, the rate of cardiac events decreased over time with increased of number of cycles (C1 52/526 pts, 9.9%; C9–11 3/154 pts, 1.9%). The most commonly reported pulmonary AE was dyspnea (42.2%). Of note, the majority of the dyspnea events were G1 or G2 with 1 G5 dyspnea occurring in the clinical setting of CHF. Dyspnea was reported by a higher percentage of pts in earlier cycles vs later cycles (11.8% in C1; 3.2% in C6), suggesting it is likely not associated with cumulative toxicity. The median duration of a dyspnea event was 8 days and the majority of episodes were transient, with 64% lasting <2 weeks. Notably, no interstitial lung disease (ILD) or pulmonary fibrosis AEs were reported. At least 1 pulmonary infection AE was reported for 18.8% of pts; pneumonia was the most common AE (67 pts, 12.7%) as well as the most common SAE (52 pts, 9.9%). Pulmonary infections resulted in the death of 2 pts. Conclusion: Cardiac event deaths and deaths with a cardiac etiology are not unexpected in this heavily pretreated, late-stage population. Rates reported here are comparable to those noted in the literature for this population. While dyspnea was frequently observed, events were mainly G1 or G2 and transient, and there were no AEs of ILD or pulmonary fibrosis. Pulmonary infection rates were comparable to those previously reported in the literature. Importantly, CFZ discontinuations and dose reductions due to these AEs were uncommon. Cardiac and pulmonary AEs are being further characterized in ongoing randomized clinical trials. Disclosures: Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx Pharmaceuticals: Consultancy; Merck: Consultancy. Off Label Use: Carfilzomib for the treatment of Multiple Myeloma. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding. McCulloch:Onyx Pharmaceuticals: Employment. Rajangam:Onyx Pharmaceuticals: Employment. Vij:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding.

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332 CARDIAC RISK FACTORS AS PREDICTORS OF MYOCARDIAL INJURY AFTER NON CARDIAC SURGERY

Journal of Hypertension ◽

10.1097/01.hjh.0000420087.57497.53 ◽

2012 ◽

Vol 30 ◽

pp. e97

Author(s):

John Mooney ◽

Graham Hillis ◽

Jagnoor Jagnoor ◽

Juuso Makinen ◽

Richard Halliwell ◽

...

Keyword(s):

Risk Factors ◽

Cardiac Surgery ◽

Myocardial Injury ◽

Cardiac Risk ◽

Cardiac Risk Factors

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Abstract 898: Expression of immunoglobulin and its receptor are major determinants of multiple myeloma patient sensitivity to proteasome inhibitors

10.1158/1538-7445.am2014-898 ◽

2014 ◽

Cited By ~ 1

Author(s):

Brian B. Tuch ◽

Andrea Loehr ◽

Jeremiah D. Degenhardt ◽

Kevin A. Kwei ◽

Eric Lowe ◽

...

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitors ◽

Myeloma Patient ◽

Multiple Myeloma Patient

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Early detection of cardiotoxicity during chemotherapy using biomarkers

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.19521 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 19521-19521 ◽

Cited By ~ 3

Author(s):

D. J. Lenihan ◽

M. R. Massey ◽

K. Baysinger ◽

D. Steinert ◽

L. Fayad ◽

...

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Myocardial Injury ◽

Cardiac Risk ◽

Left Ventricular ◽

Cardiac Biomarkers ◽

Cardiac Risk Factor ◽

Cardiac Events ◽

Before And After ◽

The Mean

19521 Cancer chemotherapy (CHEMO), especially anthracycline-containing regimens, may result in heart failure and left ventricular dysfunction (LVD) due to cardiotoxicity (CVTx). The ability to detect CVTx currently utilizes techniques to assess LVD, such as MUGA or echocardiography (Echo), which have substantial limitations and only detect LVD well after it occurs. Cardiac biomarkers, troponin (Trop I) and B-Type Natriuretic Peptide (BNP) are well established for detecting myocardial injury and LVD in patients without cancer. Limited evidence suggests that these may be important predictors of subsequent CVTx during CHEMO, but these markers have not been systematically investigated prospectively. Methods: Patients undergoing anthracycline-containing combination CHEMO were evaluated at baseline with: history and physical; electrocardiogram; Echo; and BNP and Trop I. Biomarkers were repeated before and after up to 6 cycles of CHEMO. ECHO was repeated after 6 cycles or at 6 months from baseline. Cardiac events (heart failure, LVD, sudden death, or arrhythmia) were documented, if present. Results: To date, 111 (53M/58F) patients, age 56±14 (mean±SD), with either lymphoma (n=39, 35%), sarcoma (n=60, 54%), or breast cancer (n=12, 11%) were enrolled. At least one traditional cardiac risk factor was identified in 77 (69%) and 2 or more risk factors noted in 46 (41%). Baseline ECHO parameters including ejection fraction (EF) and biomarkers were normal. With CHEMO, the mean post CHEMO BNP value (pg/ml) for the group did not change significantly; however, in the 8 patients with cardiac events, the BNP post CHEMO was elevated. The Trop I values were not abnormal except in 2 patients with events. Conclusion: Preliminary data collected to date indicates that BNP values during CHEMO remain normal unless cardiac events occur. Additionally, elevated BNP levels appear to detect CVTx, but LVEF did not. Furthermore, patients receiving CHEMO frequently have cardiac risk factors that may promote CVTx. [Table: see text] No significant financial relationships to disclose.

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Tumor-Lysis Syndrome in Relapsed or Refractory Multiple Myeloma Patients Treated with Proteasome Inhibitors

Blood ◽

10.1182/blood-2018-99-114822 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5631-5631

Author(s):

Kazuhito Suzuki ◽

Kaichi Nishiwaki ◽

Tadahiro Gunji ◽

Mitsuji Katori ◽

Rika Hosoba ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Prognostic Factors ◽

Odds Ratio ◽

Tumor Lysis Syndrome ◽

Proteasome Inhibitors ◽

Cytotoxic Agents ◽

Tumor Lysis ◽

Number Of Patients ◽

Significant Difference

Abstract <Introduction> Tumor-lysis syndrome (TLS) describes a group of metabolic disturbances caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells. TLS is a potentially life-threatening complication in rapidly proliferating, bulky tumor, or highly chemo-radiosensitive cancers. In contrast, TLS is the rare complication among patients with multiple myeloma (MM). TLS seems to occur more frequently in MM patients receiving bortezomib (BOR) and carfilzomib (CFZ) than in those receiving other cytotoxic agents. We retrospectively investigated the frequency, risk factors, and clinical outcome among the relapsed or refractory MM (RRMM) patients treated with proteasome inhibitors (PI), such as BOR, CFZ, and ixazomib (IXA), in our institute. <Methods> Between November 2005 and December 2017, seventy-two RRMM myeloma patients treated with BOR, CFZ, or IXA, in our institute. The number of patients treated PI was defined as below. Relapse or refractory disease and response criteria were defined according to the International Myeloma Working Group criteria. Patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and primary plasma cell leukemia were excluded. We evaluated TLS by the Cario-Bishop grading classification. After starting of PI, the following parameters were recorded and evaluated for prognosis: serum hemoglobin concentration (Hb), serum level of lactate dehydrogenase (LDH), creatinine (Cr), uric acid (UA). The cutoff levels of LDH, Cr, and UA were the upper normal limit. Anemia was defined by the CRAB criteria. Hepatosplenomegaly and plasmacytoma were evaluated using computed tomography. We analyze these two groups in terms of patient characteristics, laboratory findings, response, and survival. Fisher's exact tests were used to compare differences between the two groups. We analyzed prognostic factors for survival in significant poor predictors of laboratory parameters and well-established prognostic factors by Cox regression analysis. Overall survival (OS) and time to next treatment (TTNT) were analyzed by the Kaplan-Meier method. <Results> Median age of the patients was 71 years (range, 41-86) at the time of PI treatment. Median number of prior treatments was 2 (range, 1-8). The number of patients treated 53 of BOR, 10 of IXA, 4 of BOR + CFZ, 3 of CFZ + IXA, 1 of BOR + IXA, and 1of BOR + CFZ + IXA, respectively. TLS occurred in 13 patients (18.1%); such as 8 of BOR (13.3%), 4 of CFZ (40.0%), and 1 of IXA (6.7%). TLS occurred more frequently in the patients treated with twice weekly CFZ plus dexamethasone (CFZ 56mg/m2) than twice weekly CFZ, lenalidomide, plus dexamethasone (CFZ 27mg/m2); 50% and 25%, respectively. Median day of TLS after PI was 8 (range, 4-21). Median day of TLS in BOR, CFZ, and IXA were 7.5, 5.5, and 13 days, respectively. Two patients received rasbricase after TLS occurred. There was no patient who underwent hemodialysis for TLS. The mortality related with TLS was none. The significant factors associated TLS were anemia, high LDH level, prior treatments of 2 or more and hepatosplenomegaly according to univariate analysis. In multivariate analysis, high LDH level (Odds ratio; 12.9, P=0.027) and hepatosplenomegaly (Odds ratio; 13.4, P=0.035) was related with TLS significantly. There was no significant difference between overall response rate in the TLS group and non-TLS group (46.4% vs 64.8%, P=0.117). In median follow-up was 12.9 months, the median TTNT of the TLS group was significantly shorter than that of the non-TLS group (1.9 vs 7.0 months, P = 0.009, Figure 1a). The median OS of the TLS group was significantly shorter than that of the non-TLS group as well (5.8 vs 46.4 months, P = 0.017, Figure 1b). <Conclusion> Our analysis revealed that 18.1% of RRMM patients treated with PI developed TLS although TLS was manageable by prophylaxis.gh LDH level and hepatosplenomegaly were identified with significant risk factors for TLS. TLS was not associated with good response of treatment. The TTNT and OS in the TLS group was significantly shorter than those in the non-TLS group. We considered that TLS might be related with progressive disease without activity of treatment in RRMM patients treated with PI. Among the RRMM patients with high LDH level, TLS is one of common adverse events in first cycle of PI but tolerable. Disclosures No relevant conflicts of interest to declare.

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Hypercalcemia-Induced Hypokalemic Metabolic Alkalosis in a Multiple Myeloma Patient: The Risk of Furosemide Use

Case Reports in Oncology ◽

10.1159/000439377 ◽

2015 ◽

Vol 8 (3) ◽

pp. 389-393 ◽

Cited By ~ 1

Author(s):

Ira W. Reiser ◽

Slamat Ali ◽

Vladimir Gotlieb ◽

Samuel Spitalewitz

Keyword(s):

Multiple Myeloma ◽

Metabolic Alkalosis ◽

Loop Diuretic ◽

Laboratory Finding ◽

Diuretic Therapy ◽

Thick Ascending Limb ◽

Metabolic Derangement ◽

Multiple Myeloma Patient ◽

Calcium Sensing ◽

Severe Hypercalcemia

Hypercalcemia is often seen in patients with malignancies, and in the past treatment for this has traditionally included loop diuretics. Clinically, patients with hypercalcemia frequently present with polyuria and volume contraction which may be further exacerbated by diuretic therapy. In the lab, hypercalcemia has been shown to activate the calcium-sensing receptor in the thick ascending limb of Henle and inactivate the 2 chloride sodium potassium co-transporter and induce a hypokalemic metabolic alkalosis, an effect similar to that of the loop diuretic furosemide. We now report what may well be the first clinical correlate of this laboratory finding in a patient who developed a hypokalemic metabolic alkalosis as a consequence of severe hypercalcemia due to multiple myeloma and whose metabolic derangement was corrected without the use of a loop diuretic which may have exacerbated the electrolyte abnormalities.

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