Posted: Wednesday, January 31, 2018
Since the approval of bortezomib for the treatment of patients with multiple myeloma in 2003,1 the proteasome inhibitor drug class has represented a cornerstone of the therapeutic options included in the NCCN Guidelines for this hematologic malignancy.2 Unlike the other proteasome inhibitors, bortezomib, which is administered by intravenous push or subcutaneously,1 or ixazomib,3 which is orally administered, carfilzomib is administered as an intravenous infusion over 10 or 30 minutes.4 Because it is indicated in second or subsequent lines of treatment4 for patients who have relapsed during or have become refractory to first-line therapy, those who receive carfilzomib may have significant disease- or treatment-related symptoms and/or morbidities when they begin treatment. [Editor’s Note: Although not in the prescribing information, the NCCN has given carfilzomib a 2A designation (in the NCCN Categories of Evidence and Consensus) for newly diagnosed multiple myeloma. This designation signifies that “Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.”]
Although initial approval of carfilzomib was based on a single-agent carfilzomib study, the 003A1 trial,5 current practice almost always incorporates a second agent, such as dexamethasone,6 and very often a third agent, such as an immunomodulating drug (IMiD; eg, lenalidomide or pomalidomide), is added to the combination.7,8 Moreover, NCCN Guidelines also include combinations with cyclophosphamide and dexamethasone, as well as with panobinostat.2
According to David S. Siegel, MD, PhD, Chief, Division of Multiple Myeloma, John Theurer Cancer Center, Hackensack University Medical Center in New Jersey, “Carfilzomib is arguably one of the most active drugs we have for multiple myeloma, with daratumumab being another.”
Inconvenience as a Toxicity?
Carfilzomib is considered by some less experienced providers to be challenging, although that is not justified by reality, Dr. Siegel stressed. “It is a somewhat inconvenient drug, which may very well be its primary toxicity,” he said. The greatest disadvantage of carfilzomib, he noted, may be its schedule. There have been studies looking at once weekly administration9 (vs twice weekly), and some clinicians—especially those who are comfortable with carfilzomib administration—have adopted that schedule. “In my view, once weekly administration is less effective than twice weekly, but for patients who have responded exceptionally well to the drug but who are tired or unable to come to the infusion center twice a week, once-a-week administration is feasible. [Editor’s Note: Results of the phase III ARROW study of once weekly carfilzomib demonstrated that 70 mg/m2 given once a week with dexamethasone resulted in longer progression-free survival compared with twice-weekly administration of standard doses.10] Another schedule that may be tried is twice weekly but only every other week, instead of every week for 3 weeks. This attenuated schedule was built into the original trial as part of an extension for responders,5 so there is a published precedent for that strategy.
Conceding that coming to the infusion center 2 days in a row every week for 3 weeks can be inconvenient for patients, Dr. Siegel said, “There are things we can do to make the 2-day administration a little easier. For instance, at our institution, the IV that is placed on the first day can be retained for the second day of administration.”
Noting that geography can present a hardship for patients who live farther away from the myeloma program, Yi Lisa Hwa, APRN, CNP, DNP, a nurse practitioner in the Hematology Department at the Mayo Clinic in Rochester, Minnesota, said: “We (Mayo Clinic) collaborate with local community hematologists/oncologists. Many times, we get the patient started at our center and make certain the treatment is tolerated; then we can transfer the patient’s therapy for subsequent doses to his or her local clinic or infusion center, providing the recommended dosage and schedule.”
Easier in Combination
Somewhat counterintuitively, the combination of carfilzomib and dexamethasone is better tolerated and effective than carfilzomib alone. According to Dr. Siegel, although some clinicians may be reluctant to dose dexamethasone at 20 mg/day, the regimen is much easier to tolerate than when “baby” doses (eg, 4 mg) are used. Moreover, when the larger dose of dexamethasone is used as part of the combination regimen, premedication with a corticosteroid is not necessary. Today, carfilzomib is almost always used as part of a doublet with dexamethasone, and often it is part of a triplet with dexamethasone and lenalidomide or pomalidomide.2 The NCCN Guidelines for Multiple Myeloma include other carfilzomib-containing combination regiments also, such as carfilzomib/cyclophosphamide/dexamethasone and panobinostat/carfilzomib.2 In addition, studies are ongoing to evaluate combination regimens with daratumumab11 or cyclophosphamide,12 for instance. “It is an easy drug to use in combination because the toxicities don’t overlap with those of other drugs,” Dr. Siegel said.
Ms. Hwa’s experience is similar to that of Dr. Siegel. Although the delivery schedule is less convenient than oral regimens, she noted, from the perspective of adverse events, “carfilzomib may be a good drug option for those patients who have significant neuropathy from previous therapies and/or other comorbidities.”
“Carfilzomib doesn’t make patients sick and doesn’t cause other types of subjective issues,” Dr. Siegel said. Some myeloma teams give antiemetic prophylaxis, he noted, but carfilzomib is not like doxorubicin or other highly emetic regimens.”
Carfilzomib may cause a transient decrease in renal function. This is why, Dr. Siegel explained, there was concern about the potential for tumor-lysis syndrome. Although this is not a significant toxicity of carfilzomib, a dose of corticosteroids “will mitigate this effect, and a larger dose of corticosteroid can often block this effect altogether,” Dr. Siegel said. Contrary to what might be expected, “given that dexamethasone is the most toxic drug we use, the combination of carfilzomib plus 20 mg of dexamethasone is often better tolerated than 4 mg of dexamethasone used as premedication.”
Hydration and Premedication
Dr. Siegel explained that in the early carfilzomib studies,13,14 there was concern about the numbers of patients with congestive heart failure. However, he pointed out, the prescribing information for carfilzomib requires a “significant level of hydration to prevent purported tumor-lysis syndrome. The purpose of the hydration is to protect patients from a consequence that is not likely (ie, tumor-lysis syndrome) but may actually cause an issue (ie, fluid overload and congestive heart failure). Many of those cardiac sequelae observed in the early studies were related to the fluid overload rather than to carfilzomib itself.” Dr. Siegel suggested that the instructions about hydration in the prescribing information are part of the overall challenge with carfilzomib. “We need to use our clinical judgment when making decisions about aggressive hydration,” he said.
We need to use our clinical judgment when making decisions about aggressive hydration.
Infusion reactions are rare when carfilzomib is used with dexamethasone, Dr. Siegel said. “The only time they may be seen is when a 30-minute dose is given over 10 minutes.” He observed that carfilzomib is just one of many drugs used in patients with myeloma, and many different doses are used. The standard dose of carfilzomib is 20 mg/m2 for 2 days; then, if the initial dose is tolerated, 27 mg/m2 is given for each subsequent cycle. But there are also 56 mg/m2 and 36 mg/m2 doses, and those are administered over 30 minutes instead of over 10 minutes. “If you give those larger doses over 10 minutes, you may see substantial localized infusion reactions,” Dr. Siegel cautioned.
According to Heidi D. Finnes, PharmD, BCOP, a pharmacist also with the Mayo Clinic Cancer Center in Rochester, “premedication with dexamethasone and allopurinol is why we don’t see many infusion reactions.”
Because carfilzomib can cause a transient decline in heart function, resulting in congestive heart failure, Dr. Siegel recommended obtaining a baseline echocardiogram before starting treatment. “Then, if the patient complains of shortness of breath after 5 cycles and the echocardiogram shows an ejection fraction of 30%, you’ll be able to assess whether the congestive heart failure is due to the treatment. Multiple myeloma itself can cause congestive heart failure. And you want to make sure the patient doesn’t have amyloid or some type of deposition in the heart,” he cautioned.
Ms. Hwa also explained it may be challenging to distinguish a cardiac adverse effect, such as dyspnea, from anemia-associated shortness of breath. Patients are often already anemic because of progression of disease and may become more so as a result of treatment.
Dr. Siegel recommended that providers individualize hydration and encourage patients to drink 8 glasses of water before and during carfilzomib administration as an alternative to intravenous hydration. "But if you have an 83-year-old woman with a baseline ejection fraction of 35%,” he said, “you don’t want to load her up with too much hydration because she won’t tolerate it well. Contrast that clinical scenario with that of a 50-year-old, 6-foot, 2-inch athlete for whom the hydration question is almost irrelevant.”
According to Dr. Finnes, patients treated at the Mayo Clinic usually receive between 250 and 500 mL of normal saline before the carfilzomib infusion, particularly during Cycle 1 and potentially during Cycle 2, when the dose of carfilzomib is being escalated. Providers will sometimes give fluids after infusion as well, depending on their assessment of whether the patient can keep up appropriate fluid intake at home. However, fluids may need to be restricted in patients with certain comorbidities, for example, renal dysfunction, cardiac disease, or congestive heart failure. “You have to watch for signs of fluid overload and adjust. On the second treatment day, clinicians assess the patient and, if necessary, may have to consider a diuretic, if fluids are accumulating,” she said.
Patient and family education15 is critical to good reporting, Ms. Hwa added. “We teach our patients and caregivers to monitor for the symptoms of fluid overload, such as peripheral edema, ascites, shortness of breath, persistent coughing or wheezing, severe weakness, chest discomfort, and sudden weight gain. We encourage patients to weigh themselves every day. Both subjective reports and objective observation are important for a good assessment. For example, when I ask whether the patient needs to take a rest after a few steps of walking, I also watch to see whether there’s a lot of huffing and puffing going on. A thorough physical exam to check for signs suggesting fluid overload and congestive heart failure should be performed,” she said.
Anyone who will be receiving a proteasome inhibitor should also receive antiviral/anti-zoster prophylaxis with acyclovir, famciclovir, or valacyclovir, Dr. Siegel said. The choice of drug usually is determined by baseline renal function. Dr. Finnes added that “antibacterial prophylaxis with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia (PJP) and with high-dose corticosteroids and thromboprophylaxis during IMiD therapy should also be considered.”
Advice for Myeloma Teams
Ms. Hwa raised an important point, gained through clinical experience. “When we treat patients with carfilzomib in combination with IMiDs, we coordinate the infusion schedule with the timing of IMiDs delivery from the specialty pharmacy. We want patients to start all the drugs on the same day of each treatment cycle so they will have 7 days off all of the therapies. Ideally, this gives the marrow maximal recovery time from drug-induced neutropenia and thrombocytopenia, which are cyclical,” she explained. These patients are often already marrow-depleted from their relapsed or refractory disease and multiple previous treatments. “Myelosuppression can be an issue,” she said. “We monitor complete blood cell counts and modify drug dosages when necessary.”
As her take-home message, Ms. Hwa said: “In addition to the cardiotoxicity and myelosuppression, we should keep in mind the potential for embryofetal toxicity. We should always instruct patients about effective birth control, because these regimens can cause birth defects. I’d also emphasize—because I’ve seen patients who are referred to our center for whom these preventive steps were not implemented—that patients need to be on antivirals, as well as on prophylaxis for PJP and thrombosis when they are receiving combination regimens with steroids and IMiDs.” On the plus side, she added, there is less incidence of peripheral neuropathy with carfilzomib, which may be an advantage for patients with advanced multiple myeloma.
Dr. Finnes pointed out, “Carfilzomib is a nice drug for patients with relapsed, refractory multiple myeloma because it is not metabolized via cytochrome P450 pathways; it can be used in renal dysfunction (even in patients on dialysis), which is not an uncommon finding in patients with advanced multiple myeloma. For patients with mild to moderate hepatic dysfunction, the dosage needs to be reduced by as much as 50%.”
“Carfilzomib is a very important drug in myeloma,” Dr. Siegel said. Providers who treat patients with myeloma will need to become familiar with administering carfilzomib because it will be part of many key treatment regimens. Dr. Siegel’s bottom line is: “Do your baseline echocardiogram; make sure to manage hypertension or work with the patient’s cardiologist or internist to ensure that blood pressure is controlled. It’s a very easy drug to combine with other agents and a very effective drug.”
David S. Siegel, MD, PhD, has served on the speakers bureau and advisory boards for Amgen Inc.
Yi Lisa Hwa, APRN, CNP, DNP, disclosed no relevant relationships.
Heidi D. Finnes, PharmD, RPh, disclosed no relevant relationships.
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