CLINICAL NEWS

While clinical trials of the proteasome inhibitor carfilzomib for the treatment of multiple myeloma ( MM ) showed varying incidence rates of cardiovascular adverse events ( AEs ), a review of data from the phase I , II , and III trials leading to its approval suggest that the improvements in patient survival are worth the relatively low risk of cardiac failure or hypertension .

“ Carfilzomib-based regimens have produced clinically meaningful responses and [ have ] shown significant improvement in the depth and duration of responses in [ this setting ] … including a nearly eight-month increase in overall survival ,” lead author Ajai Chari , MD , of the Icahn School of Medicine at Mount Sinai in New York , told ASH Clinical News . “ While optimization of cardiovascular health is important for all patients , the findings of this study demonstrate the risk of cardiovascular events is far outweighed by the benefit of carfilzomib treatment – as evidenced by improvements in overall survival ,” he said .

The pooled analysis , which was published in Blood Advances , included data from 11 clinical trials evaluating carfilzomib in patients with relapsed / refractory MM that reported incidence of cardiovascular-related AEs , comprising a total of 2,044 patients who received at least one dose of carfilzomib .

The researchers analyzed studies for all grade and grade ≥3 cardiovascularrelated AEs of interest , including cardiac failure , dyspnea , hypertension , and ischemic heart disease . For the purposes

– AJAI CHARI , MD

TABLE . Treatment-Emergent Cardiovascular Adverse Events

Carfilzomib ( KRd ) ( n = 392 )

ASPIRE ENDEAVOR FOCUS

Control ( Rd ) ( n = 389 )

Carfilzomib ( Kd ) ( n = 463 )

Control ( Vd ) ( n = 456 )

Carfilzomib ( carfilzomib ) ( n = 157 ) of the study , treatment-emergent AEs were defined as events that began on or following the first day of therapy or AEs that presented at baseline and worsened in severity following treatment .

Three trials ( ASPIRE , ENDEAVOR , and FOCUS ) also included analyses of the cardiac safety profile in 1,012 carfilzomib-treated patients compared with 998 patients in control arms who were treated with either lenalidomide plus dexamethasone , bortezomib plus dexamethasone , or best supportive care , respectively .

In the pooled analysis of all 11 trials , the most frequently reported cardiovascular-related AEs included anygrade incidences of :

• cardiac failure ( 6.7 %)

• hypertension ( 18.5 %)

• dyspnea ( 31.9 %)

Grade ≥3 incidences of cardiac failure , hypertension , and dyspnea were reported in 4.4 percent , 5.9 percent , and 4.5 percent of patients , respectively .

Across the three phase III trials , the incidence of cardiac AEs was numerically higher in carfilzomib than control groups , but , after adjustment for duration of

Control ( BSC ) ( n = 153 )

Cardiac failure and hypertension events are listed as standardized MedDRA query , narrow scope , and ischemic heart disease is listed as standardized MedDRA query , broad scope . All data are n (%), unless indicated otherwise . treatment exposure and follow-up , the incidences were similar between the treatment groups ( TABLE ).

Small proportions of patients in each of the phase III trials experienced cardiac failure events that led to missed doses of carfilzomib ( 2.6 %, 3.5 %, and 3.2 % in ASPIRE , ENDEAV- OR , and FOCUS , respectively ). Most of these patients also were able to restart carfilzomib ( 70 %, 75 %, and 80 %, respectively ). Mortality related to cardiac failure was low across studies , the authors reported , ranging from 0.4 to 1.3 percent . “ Treatment with carfilzomib in more than 1,000 patients in phase III studies was associated with low rates of cardiac events ; however , the rates of treatment reduction and / or discontinuation and deaths due to cardiac events were very low and comparable in both arms ,” Dr . Chari added .

In a substudy of 159 cardiopulmonaryevaluable patients enrolled in the phase III ENDEAVOR trial ( 80 who received carfilzomib plus dexamethasone and 79 who received bortezomib plus dexamethasone ), the incidence of left ventricular ejection fraction ( LVEF ) reduction also was low : One patient in the bortezomib group experienced a > 10 percent reduction in LVEF at 24 weeks , and three patients in each arm experienced a significant LVEF reduction at any time during the study period .

“ As hematologist-oncologists , we are tasked with optimizing the risk-benefit profile of treatments for our patients ,” Dr . Chari remarked . “ This study highlights the difficulties in studying toxicities observed in single-arm studies in a disease like MM , where patients have comorbidities due to aging and myeloma itself .”

Limitations of the analysis included the lack of double-blind studies available for assessment and the lack of cardiologybased AE reports in each study analyzed . While the randomized design of the phase III trials worked to address confounding variables , Dr . Chari noted , the lack of blinding ; coding of nonhematologic toxicities by hematology / oncology staff ; and longer therapy times in the experimental arm relative to the control arm presented additional challenges in assessing attributable risk .

The researchers added that “ careful monitoring and management of cardiovascular risk factors , including blood pressure and volume status , are recommended for all myeloma patients as good clinical practice .” ●

The authors reported a financial relationship with Onyx Pharmaceuticals , which funded the study .

REFERENCE

Chari A , Stewart AK , Russell SD , et al . Analysis of carfilzomib cardiovascular safety profile across relapsed and / or refractory multiple myeloma clinical trials . Blood Advances . 2018 ; 2:1633-44 .

26 ASH Clinical News October 2018