PLACE IN THERAPY

Patients with RRMM who have received at least one prior therapy are potential candidates for treatment with carfilzomib. Currently, carfilzomib (dosed at 20/56 mg/m2) combined with dexamethasone and once-weekly dosing of carfilzomib (20/70 mg/m2) combined with dexamethasone and carfilzomib in combination with lenalidomide and dexamethasone are FDA-approved (carfilzomib dosed at 20/27 mg/m2) for RRMM.

Several (combination) treatments are available for RRMM nowadays, as (next-generation) IMiDs, (next-generation) PIs, alkylating agents, monoclonal antibodies, for example. Comprehensive assessment of prior therapies, prior toxicity, and weighting the different therapeutic options available are important determinants in choosing a subsequent therapy. The goal is to provide a treatment option that differs from frontline and/or other prior salvage regimens, with potent myeloma activity and a favorable toxicity profile.


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RECOMMENDATIONS FOR DAILY PRACTICE

In the first administrations of carfilzomib, higher amounts of intravenous fluids (at least 250 mL), in combination with rasburicase in case of high tumor load, high levels of urate or preemptive renal impairment is advised to prevent TLS. Monitor blood chemistries closely, particularly in cycle 1, to anticipate for TLS. In our practice, this currently means obtaining laboratory reports on days 1, 2, 8, and 15 in cycle 1 and before the start of each cycle thereafter. Prophylaxis with allopurinol is not advised, due to possible interactions. Intravenous fluids (250 mL) are recommended before each dose of carfilzomib in the first cycle if the patient is able to tolerate such a fluid challenge. In cycle 2 and beyond, 100 mL of intravenous fluid or even oral hydration is likely adequate.

Cardiac AEs are thought to be a class effect of PIs, because they have been reported with bortezomib, carfilzomib and ixazomib; however, they appear to be more frequent with carfilzomib. At present, there are no strategies to prevent cardiovascular events that have been validated in prospective studies. However, as advised by the European Myeloma Network, cardiovascular risks should be assessed and wherever possible corrected before starting therapy with carfilzomib.46 Therefore, it is advised to measure and correct modifiable risk factors, such as hypertension, high cholesterol levels, hyperglycemia, tobacco use, and incorrect diet. Patients with cardiac risks may benefit from a cardiology review prior to receiving treatment, and should be closely monitored for fluid overload. Before and during treatment, regular clinical surveillance with blood-pressure control and tight treatment of hypertension with antihypertensives is recommended, pursuing normotension during treatment with carfilzomib.

Unfortunately, a good screening method to identify patients at risk for cardiac events is not yet available. Serial monitoring of cardiac function via echocardiography or cardiac biomarkers, such as N-terminal pro-brain natriuretic peptide are considered of limited value in mitigating the risk of carfilzomib-associated cardiac failure.45 In the event of grade 3 or 4 cardiac events, carfilzomib should be withheld until recovery.42 Carfilzomib may be resumed at the physician’s discretion based on a benefit–risk assessment, although preferably at a reduced dose. After the first cycle, caution is advised with regard to administering large amounts of intravenous fluid, especially in cardiac-compromised, hypertensive, and elderly patients. All patients should be routinely controlled for fluid overload. Furthermore, physicians should also be aware of the possible development of pulmonary hypertension.

Dose modifications in patients with baseline renal impairment are not necessary. However, during treatment renal function should be routinely evaluated at the start of each cycle and whenever indicated, as sudden renal insufficiency has been described. Then, further carfilzomib should be discontinued. Carfilzomib is not metabolized via the liver. Therefore, mild liver impairment is no contraindication for treatment; however, patients with severe liver impairment have been excluded from clinical trials. As such, we advise careful monitoring in patients with severe liver impairment.

Immunomodulatory drugs, especially in combination with corticosteroids and chemotherapy, are associated with high frequency of thromboembolic complications. Therefore, for the combination of carfilzomib with lenalidomide and dexamethasone, prophylaxis with cardioaspirin, low-molecular-weight heparin, or warfarin is mandatory. The choice of the most appropriate drug depends on the thrombotic risk: if the probability of venous thromboembolism/pulmonary embolism is high, low-molecular-weight heparin or warfarin should be preferred. Routine evaluations of normal blood levels, especially platelet counts, are the standard of care. Also, as with bortezomib treatment, herpes zoster prophylaxis is recommended.

CONCLUSION

Carfilzomib is a potent selective PI that irreversibly binds to the proteasome. Carfilzomib is generally well tolerated, and seems to be a safe treatment option in patients with renal impairment, patients with liver impairment, and patients with PNP. However, a slightly higher incidence of cardiovascular toxicity is seen, for which further tools for identifying patients at risk are necessary. Altogether, carfilzomib is a welcome addition to the therapeutic arsenal for RRMM. Importantly, a more patient-friendly regimen, dosing once a week instead of twice a week, seems feasible, and has recently been FDA-approved for carfilzomib monotherapy. Ongoing phase II and III trials will help further to define the role of carfilzomib in frontline treatment and the sequence of (combination) treatment schedules in relapsed MM, as well as helping to establish best dosing schemes and supportive-care management during treatment with carfilzomib, further benefiting MM patients.

Disclosure

NWCJD and SZ have received compensation as part of the advisory board of Amgen. The other authors report no conflicts of interest in this work.


K Groen, NWCJ van de Donk, CAM Stege, S Zweegman, IS Nijhof

Department of Hematology, VU University Medical Center, Amsterdam, Netherlands


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Source: Cancer Management and Research
Originally published April 2, 2019.

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