Angela Mayo

Carfilzomib and the cardiorenal system in myeloma: An endothelial effect?

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.

Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma

Sixty‐four transplant‐eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1–28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28‐day cycles (CYKLONE regimen). Carfilzomib was dose‐escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide‐related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression‐free survival and overall survival at 24 months was 76% and 96%, respectively (median follow‐up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.

Phase II Trial of Nab‐paclitaxel in Patients with Relapsed or Refractory Multiple Myeloma

between 0.1% and 0.72%. There was a weak significant negative Spearman correlation between the percentage of these cells and age (r 5 20.232 P 5 0.022). We could not detect significant correlations between hematogones and the IPSS-R score, the number of aberrancies in the granulocytic lineage, or percentage of myeloid progenitors, but there were significant negative correlations with the number of monocytic aberrancies (r 5 20.256; P 5 0.012), the number of abnormalities of CD34 cells (r 5 20.206; P 5 0.044), and the total number of aberrancies detected (r 5 20.334; P 5 0.0008). In the univariate Cox regression, the percentage of B-cell precursors was a significant favorable prognostic factor for overall survival (B 5 26.220; P 5 0.011). In the Kaplan–Meier curve, patients with detectable B-cell precursors in BM had a significant better overall survival (log-rank test: P< 0.001) than patients with undetectable CD34/CD19/CD10 cells. After 5 years, 76.7% of the patients presenting BM hematogones at diagnosis were still alive, whereas this value dropped to 51.9% in patients without detectable B-cell precursors (Fig. 1). In a multivariate Cox regression model, the percentage of hematogones (B 5 25.061; P 50.006), of myeloid progenitors (B 5 0.191; P 50.02), and the IPSS-R score (B 5 0.714; P< 0.001) remained in the final model, thus demonstrating that the percentage of B-cell precursors is an independent favorable prognostic factor in MDS patients. In order to estimate the clinical importance of the variable “hematogones” in the model, we calculated the relative Akaike weights (w) for different models according to the Akaike information criteria. The relative weight for the prognostic model based only on IPSS-R was 0.0179 and raised to 0.112 in a model containing IPSS-R and the percentage of myeloid precursors. The weight was even higher in a model based on IPSS-R and the percentage of B-cell precursors (w 5 0.195), but the best model was achieved joining the variables “percentage of B-cell precursors,” “myeloid progenitors,” and the “IPSS-R score” (w 5 0.675). These data indicate that the percentage of hematogones in BM at diagnosis adds important prognostic information independent from already well-known prognostic features for overall survival in MDS patients. This is in keeping with similar results found in the setting of hematological recovery after allogeneic BM transplantation, where the absence of B-cell precursors in BM on day 130 was associated with a higher non-relapse mortality, a higher frequency of acute graft-versus-host disease and infections [6]. In normal individuals, there is a decrease of B-cell precursors, especially after the age 55 years, but these cells are even more decreased in patients with MDS compared to age-matched persons [5]. All these data indicate that the number of B-cell precursors in BM is not only a good marker of a preserved immune function but also for the integrity of the hemopoietic stem cell.

Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement

Over the last two decades, the utilization of various novel therapies in the upfront or salvage settings has continued to improve survival outcomes for patients with Multiple Myeloma (MM). Thus, the conventional role for hematopoietic stem cell transplantation (HSCT) in MM either in the form of an autologous stem cell transplant (ASCT) or an allogeneic stem cell transplant (Allo-SCT) warrants re-evaluation, given the aforementioned clinical advances. Here, we present a consensus statement of our multidisciplinary group of over 30 Mayo Clinic physicians with a special interest in the care of patients with MM and provide evidence-based recommendations on the use of HSCT in MM. We specifically address topics that include the role and timing of an ASCT for MM in the era of novel agents, eligibility for an ASCT, post-ASCT consolidation, and maintenance options, and finally the utility of an upfront tandem ASCT, salvage second ASCT, and an allo-SCT in MM.

Systolic dysfunction associated with carfilzomib use in patients with multiple myeloma

Proteasome inhibition with carfilzomib (CFZ) has shown to be effective therapy in multiple myeloma (MM), with a response rate of around 87% and improved overall survival, in combination with lenalidomide and dexamethasone in patients with relapsed and refractory disease . Notably cardiac failure have been noted in 6–8% patients in these phase 3 trials, with 3–5% being grade 3 or higher. In a pooled analysis of 4 phase 2 clinical trials, cardiac failure was reported in approximately 7% patients and resulted in treatment discontinuation in 1.5% patients. The exact mechanisms behind cardiac dysfunction with CFZ are unknown. Some have postulated disturbance of endothelial nitric oxide synthase and nitric oxide. In a previous report from our group, the toxicity appeared to be the result of an endothelial effect given the cooccurrence with hypertension and elevation in creatinine. While cardiac toxicity has been reported with bortezomib, it appears to be more frequent with CFZ, possibly because CFZ is more potent and binds irreversibly to the β-subunit of the 20 S proteasome. This potency may also unmask potential protein metabolism consequences of proteasomal inhibition to the myocardium, a muscle in perpetual motion. Thus far, the predisposition, natural history, and reversibility of cardiac dysfunction are not well known. We share our experience of the clinical course of 12 patients who had worsening of cardiac function after initiation of CFZ. We identified 136 patients at Mayo Clinic in Arizona who received CFZ treatment for MM between July 2012 and June 2016. Twelve of those were known to develop worsening of cardiac function upon exposure to CFZ. A decrease in ejection fraction (EF), on transthoracic echocardiogram evaluation, by 5% resulting in EF< 55% with symptoms of congestive heart failure or drop in EF by 10% resulting in EF< 55% regardless of signs or symptoms, was defined as a cardiac event or cardiac dysfunction in this study. For patients who had a baseline EF less than 55%, any decline in EF was noted as the systolic dysfunction. We conducted a retrospective review of patients’ charts to obtain demographic and treatment-related information. Known risk factors for congestive heart failure such as gender, cigarette smoking, overweight, hypertension, history of cardiac disease, previous exposure to anthracyclines were evaluated. The study was approved by Institutional Review Board at Mayo Clinic Arizona.