An Integrated Analysis of Cardio-Vascular Adverse Events of Carfilzomib, Cyclophosphamide and Dexamethasone in Elderly Newly Diagnosed Myeloma Patients Enrolled in 3 Phase I/II Trials

Cardio-vascular (CV) events are common in patients (pts) with myeloma (MM) and may occur as a result of age-related comorbidities, the disease itself or as a complication of anti-MM treatment, including proteasome inhibitors.Carfilzomib is a novel second generation proteasome inhibitorapproved as a single agent and in combination with lenalidomide and dexamethasone for the treatment of relapsed MM.

Here, we present the results of an integrated CV safety analysis of 148 newly diagnosed, elderly or transplant-ineligible pts enrolled in 3 phase I/II studies with the combination of Carfilzomib, cyclophosphamide and dexamethasone(IST-CAR-506, IST-CAR-561, IST-CAR-601).In all trials cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, 15 and dexamethasone 40 mg was administered orally once weekly. Carfilzomib was administered intravenously at the dose of 36 mg/m2 on days 1, 2, 8, 9, 15, 16 in the IST-CAR-506 trial; at 3 dose levels escalated from 45 to 70 mg/m2 on days 1, 8, 15 in the IST-CAR-561 trial and on days 1, 2, 8, 9, 15, 16 in the IST-CAR-601 trial. In all studies, after completing 9 28-day cycles, pts received 28-day maintenance cycles with Carfilzomib until disease progression or intolerance. Adverse events (AEs) were graded based on NCI-CTCAE v4.

Median age was 72 years (range 55-85), 38 pts (26%) were older than 75 years. The median follow-up was 21 months. Overall, any grade CV AEs were reported in 62 pts (42%): 40/110 pts (36%) younger than 75 years and 22/38 (58%) older than 75 years (p=0.02). The more frequent events were hypertension, aggregated cardiac failure events, thromboembolic events and arrhythmia (Table 1). Grade ≥ 3 events occurred in 29 pts (30%): 17/110 pts (15%) younger than 75 years and 13/38 (34%) older than that (p=0.01). Aggregated cardiac failure events of any grade were reported in 10 pts (7%), thromboembolic events in 5 pts (3%), hypertension in 4 pts (3%) and arrhythmia 2 pts (1%). In pts younger than 75 years, the most frequent grade ≥ 3 AEs were hypertension (10 patients, 9%) and dyspnea (11 patients, 10%). In pts older than 75 years, the most frequent grade ≥ 3 AEs were hypertension and pulmonary edema (5 pts each, 13%). Importantly, 34% of pts who experienced CV AEs had hypertension at baseline or developed it during treatment compared to 14% of pts who did not experience CV AEs. Diabetes was more frequent (33%) in pts older than 75 years who developed CV AEs compared to 10% of pts older than 75 years who did not report any CV AEs or those younger than 75 years. No difference was observed among different doses or different schedules of Carfilzomib. Among pts who developed a CV AE, one third had a Carfilzomib dose reduction or discontinuation (Table 1) compared to 12-18% of pts who did not experience CV toxicity (p<0.0001). Overall, the risk of CV toxicity was lower during maintenance: 21 pts of 97 who started maintenance (22%) developed any grade CV events. This improvement was evident only in pts younger than 75 years: 11/75 patients younger than 75 years (15%) had CV events compared to 10/22 (45%) older than 75 years (Figure 1). The most frequent CV AE during maintenance was hypertension (12%), regardless of age. Only 5 pts (5%) reduced Carfilzomib dose during maintenance. Five (3%) CV-related deaths were documented: 4 during induction and 1 during maintenance. All of them were possibly related to Carfilzomib (atrial fibrillation, heart failure, cardiac arrest, sudden death, pulmonary embolism). The occurrence of any CV AE during induction increased the mortality for any cause by twofold, regardless of age: the 2-year overall survival was 70% in patients who experienced CV AE and 82% in those who did not (HR 2.01, 95% CI 0.99-4.07, p=0.04).

The risk of CV AEs during treatment with Carfilzomib is significantly higher in pts older than 75 years and the most important risk factor, regardless of age, is hypertension. Developing CV toxicity increases the need for dose reduction or drug discontinuation with a negative impact on overall survival. Elderly pts should be carefully assessed before starting treatment with 24 hour blood pressure monitoring. During treatment, baseline vital signs should be recorded and medications of blood pressure should be targeted promptly to keep blood pressure below 140/80 mmHg. With these simple actions, these AEs may be prevented or managed proactively and pts can derive maximum benefit from their treatment with Carfilzomib.

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