VM is a 72-year-old female who presented with relapsed multiple myeloma (MM). She was initially diagnosed with a monoclonal protein (M protein) spike of 7.6 g/dL of IgG lambda. Cytogenetics revealed an 11q chromosomal abnormality. She was treated with bortezomib, liposomal doxorubicin, and dexamethasone. She had a good response, and after 2 cycles, she was transitioned to bortezomib and dexamethasone. After 3 cycles, she developed grade 3 peripheral neuropathy (PN) attributed to bortezomib. She was switched to lenalidomide and dexamethasone, and her PN improved to grade 2. After 3 cycles of her new regimen, her MM progressed. She presents today for evaluation of treatment with carfilzomib for her relapsed MM and a discussion of expected outcomes of therapy.
Carfilzomib (Kyprolis, Onyx Pharmaceuticals, South San Francisco, CA) is a proteasome inhibitor that recently received accelerated FDA approval as single-agent treatment for relapsed or refractory multiple myeloma (RRMM),1 as well as designation as a “Preferred Regimen” for salvage therapy according to the National Comprehensive Cancer Network (NCCN) guidelines.2 Carfilzomib differs structurally and mechanistically from bortezomib; it functions by irreversibly inhibiting chymotrypsin-like activity of the constitutive proteasome and the immunoproteasome and offers a novel treatment option for patients with advanced MM.3
Accelerated approval of carfilzomib was based on the results of a phase 2, single-arm, multicenter clinical trial known as PX-171-003-A1, which enrolled 266 patients with relapsed MM who had received ≥2 prior therapies, including bortezomib and an immunomodulatory agent.4 Overall response rate, using International Myeloma Working Group Uniform Response Criteria, was 23.7%, and average duration of response was 7.8 months. Median overall survival was 15.6 months. Patients enrolled to study were heavily pretreated, having received a median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide, and 27% had unfavorable cytogenetic profiles.4
Overall, the carfilzomib treatment has resulted in an acceptable safety profile in this patient population, as the majority of adverse events (AEs) were not treatment-limiting. In the PX-171-003-A1 trial, the most common treatment-emergent AEs, regardless of causality, were fatigue (49%), anemia (46%), nausea (45%), thrombocytopenia (39%), and dyspnea (34%). The most common carfilzomib-related AEs were fatigue (37%), nausea (34%), thrombocytopenia (29%), and anemia (22%).4
An integrated safety analysis of all 4 phase 2 studies (N=526) have been reported.5 This analysis showed that a majority of patients experienced at least 1 treatment-emergent AE during the course of treatment, and the most common AEs of any grade were fatigue, anemia, and nausea.5 The most common grade ≥3 AEs were primarily hematologic and included thrombocytopenia (23.4%), anemia (22.4%), lymphopenia (18.1%), and pneumonia (10.5%). Serious adverse events (SAEs) were reported in 45% of patients.1 The most common SAEs regardless of causality were pneumonia, acute renal failure, pyrexia, congestive heart failure, dyspnea, hypercalcemia, and pathologic fracture. AEs resulting in discontinuation of therapy occurred in 15% of patients.1 Other grade 3 or 4 toxicities include hepatic toxicity and liver failure, pulmonary hypertension, new or worsening heart failure, and cardiac ischemia.1
In addition to MM, VM has a medical history significant for hypothyroidism, gastroesophageal reflux disease, New York Heart Association Class II heart failure, and bortezomib-induced PN. How should carfilzomib treatment be initiated in this patient?
Carfilzomib is dosed based on body surface area, which should be capped at 2.2 m2. The approved dosing schedule is days 1, 2, 8, 9, 15, and 16 of a 28-day cycle, at a dose of 20 mg/m2 in cycle 1, escalating to 27 mg/m2 in cycle 2 forward. Carfilzomib pharmacokinetic parameters were not affected by various degrees of renal function, so no dose adjustment is required for baseline renal insufficiency.6 Geriatric patients were enrolled and successfully treated in the PX-171-003-A1 trial, and there was no age-related difference in response.4
Premedication with dexamethasone 4 mg po is recommended for all doses in cycle 1 and the first doses of cycle 2 to reduce the incidence and severity of potential infusion-related reactions. These may occur within the first 24 hours following treatment and include fever, chills, arthralgias, myalgias, facial flushing, edema, vomiting, weakness, shortness of breath, hypotension, chest tightness, and angina. Adequate hydration (250-500 mL) beginning in cycle 1 and continuing throughout treatment is recommended to reduce the potential risk of renal toxicity and tumor lysis syndrome.1
Carfilzomib is provided as lyophilized powder in 60 mg single-dose vials stored at 2-8°C. Each vial is reconstituted with 29 mL of sterile water for injection to yield a 2 mg/mL solution. Doses are administered IV over 2 to 10 minutes, either undiluted or further diluted in 50 mL of 5% dextrose solution. Solutions are stable for up to 24 hours refrigerated or 4 hours at room temperature.1
There are no contraindications to treatment; however, due to the possible SAEs, patients should be counseled about risks and symptoms of infusion-related reactions and on the need to maintain good hydration. Patients should also be advised to contact their physician if they develop fever, chills, rigors, chest pain, dyspnea, cough, or other concerning symptoms.1
VM’s current medication list includes levothyroxine, gabapentin, omeprazole, furosemide, and aspirin. Are there any important drug-drug interactions with carfilzomib that should be considered in this patient?
Carfilzomib is metabolized via peptidase cleavage and epoxide hydrolysis to inactive metabolites,7 with only minor role inhibition of human cytochrome CYP3A4/5 enzymes in vitro.8 Clearance exceeds hepatic blood flow, suggesting extrahepatic metabolism.9 Elimination is biphasic, with a half-life less than 1 hour.9,10 Repeat doses do not appear to result in accumulation. Based on its kinetic profile, carfilzomib is not expected to influence exposure of other drugs.1,11
On day 8 of cycle 1, VM has serum chemistries and hematologic parameters checked. Her serum creatinine has increased by 20% over baseline, and she has grade 3 thrombocytopenia. Her PN remains grade 2.
Treatment-induced thrombocytopenia is a common AE of carfilzomib treatment. Across all phase 2 studies, 10.3% of patients experienced grade 4 thrombocytopenia. Platelet nadirs occur around day 8 of each treatment cycle and typically recover to baseline by the start of the next cycle.5 Platelet counts should be monitored regularly during treatment, but have rarely led to dose reductions or discontinuations.
Across all the phase 2 studies, changes in renal function attributable to carfilzomib were uncommon. In PX-171-003-A1, the most common renal AE was increased serum creatinine (25%); the majority of events was grade 1 or 2, and none led to treatment discontinuation.5 Predose hydration is recommended to mitigate possible treatment-related renal effects and can be continued beyond cycle 1 if warranted.1
Carfilzomib may be better tolerated than other MM therapies with respect to PN. In PX-171-003-A1, 77% of patients had grade 1 or 2 PN at baseline. New or worsening PN occurred in 12.4% of patients.4 Across all phase 2 studies, serious PN (grade 3) occurred in less than 1% of patients, and less than 1% of patients required dose reduction or discontinuation.5
Dyspnea was reported in 35% of patients and was predominantly grade 1 or 2, but included 1 death in a patient with chronic heart failure. In addition, there was 1 death within a day of treatment, and heart failure events were reported in 7% of patients. Consequently, any pulmonary or cardiac symptoms should be evaluated and managed promptly.1
In patients with any clinically significant AEs, including those noted previously, doses should be withheld until the patient recovers. For those AEs where values return to baseline, treatment can be resumed at the same dose. In those cases where values recover, but not to baseline, the dose level can be reduced (from 27 to 20 mg/m2, or from 20 to 15 mg/m2).
Conclusions and Future Directions
Despite recent advances in therapy, MM remains a terminal diagnosis; responses to current regimens are temporary, and the majority of patients eventually relapse.12 Carfilzomib is an important new addition to the array of drugs available to treat patients with RRMM. Based on both the acceptable safety profile and overall response rates seen in the PX-171-003-A1 trial, carfilzomib received accelerated approval in the United States and NCCN designation as a “Preferred Regimen” for salvage therapy in RRMM patients.1,2
Carfilzomib has shown rapid, durable responses and an acceptable tolerability profile in heavily pretreated patients. There has been no evidence of cumulative or significant treatment-limiting toxicity despite prior treatment with bortezomib and immunomodulatory drugs in the majority of patients.4 Additionally, carfilzomib has demonstrated potential for long-term use without the need for dose adjustment or interruption.4 Management measures exist to mitigate the risk for AEs, even in patients with advanced disease or otherwise considered to be at high risk.
Approval is currently limited to patients who have received ≥2 previous treatments that include bortezomib and an immodulatory agent, and who are refractory to the most recent therapy. As a condition for accelerated approval, results from a phase 3 trial comparing progression-free survival in patients treated with lenalidomide and dexamethasone with or without carfilzomib must be submitted to the FDA.13 In addition, carfilzomib shows promise in frontline MM treatment, as well as in the treatment of other malignancies. Until the results of these and other ongoing trials are available, questions remain about the optimal dose, regimen, and ultimate role of carfilzomib in patient care. For now, carfilzomib fills an unmet need in the treatment of RRMM, as it offers an important treatment option for patients who have either failed or cannot tolerate other treatments.
- Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; 2012.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Multiple Myeloma. Version 1.2013. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed October 10, 2012.
- Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011;17:2734-2743.
- Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120: 2817-2825.
- Singhal S, Siegel DS, Martin T, et al. Integrated safety from phase 2 studies of monotherapy carfilzomib in patients with relapsed and refractory multiple myeloma (MM): an updated analysis. Blood. 2011;118. Abstract 1876.
- Niesvizky R, Vij R, Martin T, et al. Carfilzomib pharmacokinetics, safety, and activity in patients with relapsed or refractory multiple myeloma and renal dysfunction: final results. Haematologica. 2011;96(S2). Abstract 0890.
- Yang J, Wang Z, Fang Y, et al. Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats. Drug Metab Dispos. 2011;39:1873-1882.
- Wang Z, Yang J, Fang Y, et al. In vitro and in vivo drug-drug interaction studies of carfilzomib. AAPS J. 2011;13. Abstract T2419.
- O’Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009;15:7085-7091.
- Alsina M, Trudel S, Furman RR, et al. A phase 1 single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012;18:4830-4840.
- Yang J, Wang Z, Kirk C, et al. Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib [published online ahead of print November 1, 2012]. Drug Metab Dispos.
- Anderson KC, Alsina M, Bensinger W, et al. NCCN clinical practice guidelines in oncology: multiple myeloma. J Natl Compr Canc Netw. 2009;7:908-942.
- US Food and Drug Administration. Carfilzomib. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm312945.htm. July 20, 2012.