Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.

Background: In Phase II trials, carfilzomib (Cfz) was associated with dyspnea (34%), hypertension (14%), renal insufficiency (24%), and peripheral edema (24%) with cardiac events reported in 7% of patients (pts). In order to better understand these toxicities, we prospectively instituted detailed cardiac evaluation in 62 Cfz treated multiple myeloma (MM) pts. Methods: Pts received Cfz between 8/11-5/14. Parameters recorded included Cfz dose, concurrent chemotherapy, hydration, blood pressure, day 1 and 2 creatinine, troponin and NT-proBNP, baseline and cycle 4 echocardiograms with EF, strain and compliance. Notable cardiac events were examined for attribution. Results: Median age was 65 years, with 60% male. 20 pts had no prior therapies, 42 were relapsed; mean 4 prior therapies (range 1-10). 20 received induction chemotherapy (Cfz, dex, thalidomide, cyclophosphamide). At relapse, Cfz was given alone in 21 pts, with added cyclophosphamide in 10, and with an IMiD in 10. Cfz dose was 20mg/m2 days 1,2 and ranged from 27-45mg/m2in subsequent treatment days. Dex was given at 20-40mg weekly in 77% pts. Hydration (250-500ml) was delivered in 89% of patients pre and 63% post treatment. Baseline hypertension (>140mmHg) was present in 20% of pts and rose ≥10mmHg in 26% on day 2, but dropped ≥10mmHg in 36%. On day 8, more pts (32%) had hypertension pre-treatment. Baseline creatinine was elevated in 25% pts. 7 of 55 (13%) pts had a creatinine rise (≥0.3 mg/dL) on day 2, 5 of whom had elevation at baseline. Thus, with normal baseline creatinine and pre-treatment hydration 2/45 (4%) pts had a creatinine rise. Troponin levels on day 1 were normal in all 16 tested patients. 2/25 pts had an elevated troponin on day 2, one with associated MI on day 4. In these 2 pts, symptomatic pre-existing ischemic heart disease and severe cardiac amyloid were confounding factors. Mean baseline NT-proBNP (n=22) was elevated at 565 pg/mL (range <50-3666; normal <77) with normal baseline values in only 41%. On day 2 (n=25), the mean was significantly higher at 1580 pg/mL. Between day 1 and 2, 72% of pts had a rise ≥50 pg/mL; mean change 1387 (range 0 to +6187). On day 2, 52% had a NT-proBNP ≥500 pg/mL, while 36% were ≥1000 pg/mL. 30 pts had baseline and post-C4 treatment echocardiograms, all with normal pre-treatment EFs. Three pts (10%) developed impaired systolic function (EF<50%), however, 2 had plausible concurrent alternative etiologies (VTE/PE, hospitalized multilobar pneumonia) while one patient (during C2) had an asymptomatic unexplained decline in EF (56 to 42%) detected pre-op while hospitalized for hip fracture. Thus, 1/30 (3%) had an EF change in absence of concurrent acute illness. A fourth patient had normal echo at C4 but was hospitalized at C10 with severe sepsis and a diminished EF was documented. All 4 pts with low EF were pre-treated (≥2 therapies plus SCT). Changes in cardiac strain often precede an EF fall. Only 14/25 pts had normal baseline cardiac strain (≥ -18%). Post treatment strain measurement significantly improved in 4 pts and worsened in 4 pts, the latter accompanied by EF decline within the normal range in 2 pts (68/60%, 65/58%). 28 pts had E/e’ ratio (LVEDP) reviewed as a marker of ventricular compliance. 46% had abnormal ratios (≥ 15), prior to Cfz treatment. 20% of patients experienced worsening parameters post treatment, however, an equal number of pts demonstrated improvement. There was no consistent correlation with change in EF. Conclusions: MM pts frequently have baseline elevated cardiac peptides (59%) and abnormal cardiac strain (15% of newly diagnosed and 36% at relapse). A frequent, and sometimes dramatic, rise in the NT-proBNP occurs immediately following Cfz based chemotherapy. Acute structural cardiac events were however uncommon (3%) in the absence of confounding illness. Overall 5/62 (8%) patients had serious cardiac events during treatment with Cfz (4 EF decline, 1 MI). These toxicities were considered probably attributable to Cfz in 3/62 (5%) patients. Prospective controlled studies with longer term follow up and bortezomib treated controls are necessary to accurately document the cardiovascular impact of Cfz and the role of proteasome inhibition. Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Stewart:Celgene Novartis Array BioPharma BMS, research funding Millenium: Consultancy, Research Funding.