ES is a 72-year-old female diagnosed with IgG kappa Durie-Salmon stage IIIA, International Staging System stage unknown multiple myeloma who presented with a 5-year history of anemia and progressive back pain in April 2002. Her medical history is
significant for asthma. She initially received 4 cycles of pulse dexamethasone therapy followed by high-dose cyclophosphamide and stem cell harvest. The transplant was postponed at the patient’s request, and dexamethasone maintenance (4 days/month) was initiated. In February 2004, because of evidence of progressive disease, the patient began on thalidomide and dexamethasone. After 16 months, the patient showed signs of disease progression as evidenced by an increase in both serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP), with a corresponding increase in the serum free kappa light chain. A repeat bone marrow biopsy revealed high-risk cytogenetics with del(13q) and del(17p–). Lenalidomide and dexamethasone were begun with an initial partial response (PR), but therapy was complicated by a whole body rash and deep vein thrombosis (DVT) while on aspirin for DVT prophylaxis. Lenalidomide was attenuated to 15 mg for rash, and the patient was placed on therapeutic warfarin. The patient continued on therapy until June 2011, at which time disease progression was documented. The patient initiated her 4th line of therapy on bortezomib/lenalidomide/dexamethasone (VRD). After 5 cycles of therapy, she had achieved a PR but began to develop symptoms of peripheral neuropathy (PN), grade 1 with pain. The bortezomib dose was attenuated to 1 mg/m2, and the patient completed a total of 9 cycles of VRD before discontinuing due to progressive disease with stable PN. She then enrolled on a phase 1 clinical trial with stable disease assessment and good subjective tolerance. In August 2012, disease progression was documented along with worsening anemia (hemoglobin 8.9 g/dL) and renal insufficiency (creatinine 1.3 mg/dL, creatinine clearance [CrCl] 48 mL/min). What treatment options are available, and what are the considerations for ES when choosing the next line of therapy?
ES has received 5 prior lines of therapy, with progression of disease documented on her most recent therapy with a rise in SPEP from 1.3 to 2.2 g/dL and in UPEP from 556 to 1342 mg/24 hours. The current clinical considerations include anemia, renal insufficiency, and PN grade 1 with pain.
Multiple treatment options were provided to ES, including enrollment on a clinical trial. After a discussion with her family, ES chose to pursue treatment on single-agent carfilzomib based on the information provided regarding the visit schedule, treatment-related toxicities, and efficacy of the options provided.
Based on the data from the PX-171-003-A1 clinical trial, the overall response rate is 23.7%, with a median duration of response of 7.8 months and a median overall survival of 15.4 months.1 The patient characteristics of the study population are similar to those of ES, with the median number of prior therapies being 5; 95% were refractory to their most recent line of therapy, with 74% progressing on that therapy.1 The most commonly reported adverse events (>30%) associated with carfilzomib include fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.1
ES was concerned about the potential for worsening of her sensory PN using a proteasome inhibitor.
In the PX-171-003-A1 trial, 77% of patients enrolled had grade 1/2 sensory PN at the time of enrollment. During treatment with carfilzomib, 12.4% of patients experienced new-onset or worsening of preexisting PN, with 1.1% grade 3, and only 8.3% attributed to carfilzomib.1 An integrated safety analysis of 4 single-agent carfilzomib phase 2 trials (N=526) showed that PN occurred infrequently at the following rates: grade 1, 7.8%; grade 2, 4.8%; and grade 3, 1.3%. No grade 4 PN was reported, and only 1 patient required discontinuation of drug and 4 patients dose modification.2
ES was scheduled to receive carfilzomib 20 mg/m2 IV over 10 minutes on days 1, 2, 8, 9, 15, and 16 with dexamethasone 4 mg po during 28 days of cycle 1. Hydration with 250 mL over 1 hour was to be given prior to and following carfilzomib for the first cycle as the patient had no cardiac or pulmonary comorbidities aside from asthma. If she tolerated therapy well, the plan was to dose escalate to 27 mg/m2 with cycle 2 on the same schedule with continued dexamethasone premedication but without IV hydration. Based on the data from the PX-171-005 study, no dose modification for renal insufficiency is required as there was no difference in pharmacokinetic assessment or safety profile.3,4
ES presented to the clinic on cycle 1 day 2 stating that the evening before she had a fever with a temperature of 101.3°F, shaking chills, and mild shortness of breath. The on-call physician had instructed her to take Tylenol 650 mg po q4 hours for fever and to call back if her symptoms worsened. She reported that all symptoms resolved within approximately 2 hours of the onset. She was feeling well this morning aside from fatigue, which she attributed to insomnia. IV hydration was initiated at 250 mL/hr, and CBC and a chemistry panel were drawn and resulted prior to carfilzomib administration. The serum creatinine had risen to 2.7 mg/dL, >2x the baseline. A decision was made to withhold the carfilzomib dose and hydrate with 1 L of saline over 4 hours and repeat assessment in 24 hours. The patient was encouraged to maintain oral hydration.
Infusion reactions can be characterized by a cluster of symptoms, which may include some or all of the following: fever, chills, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, and angina. There may also be a transient rise in serum creatinine associated with these symptoms. The reaction may occur either immediately following the administration of carfilzomib or up to 24 hours later. Often the patients will experience these symptoms later in the day or after they have returned home. The administration of dexamethasone 4 mg po prior to dosing is for prophylaxis against this reaction. Symptomatic management is appropriate should the patient experience an infusion reaction. The renal insufficiency is often transient, and the prescribing information recommends withholding carfilzomib until renal function has recovered to grade 1 or baseline. Dosing can resume, but if the reaction is attributable to carfilzomib, dose reduction is recommended with reescalation to previous dose if tolerated, at the discretion of the physician.5
ES returned to clinic on cycle 1 day 3, and repeat creatinine was 1.5 mg/dL. She was sent home and advised to maintain oral hydration and return to clinic on day 8. She returned as instructed and resumed therapy with dose-attenuated carfilzomib at 15 mg/m2. Repeat creatinine on day 9 was stable at 1.4 mg/dL, and a decision was made to complete the remainder of the cycle at
20 mg/m2.
An integrated safety analysis of 4 single-agent phase 2 carfilzomib trials (N=526) showed that many of the patients had renal dysfunction at the time of enrollment, with 71% having a CrCl <50 mL/min. Transient worsening was seen in 6% of patients, with a median of 1 episode/patient. A nontransient change was seen in 7% of patients, with 2% requiring treatment discontinuation due to renal dysfunction.5
ES went on to initiate cycle 2 at the planned escalated dose. Her platelet count had dropped from 102,000 on day 1 to 49,000 on day 8.
The overall rate of thrombocytopenia, all grades, in the integrated safety analysis of 526 patients was 37.8%, with 24.9% reaching grade 3/4. The platelet counts reached a nadir by day 8 of the 28-day cycle, with normalization prior to the start of the next cycle. No significant bleeding events were reported, and only 1.1% of patients required dose reduction and 1% discontinuation of carfilzomib.6
ES was able to complete cycle 2 without dose modification or interruption, with recovery of her platelet count to 115,000 at the start of cycle 3. During cycle 3, she reported that dyspnea, grade 2 in severity, was limiting her instrumental activities of daily living. There were no adventitious sounds on physical exam, and the patient had not experienced any recent asthma exacerbation or change in her chronic medications. Patient was afebrile without any cough or localizing symptoms of infection. She reported the symptoms as transient and resolving approximately 24 to 36 hours post dosing.
Dyspnea was reported in 34% of patients on the PX-171-003-A1 trial.1 The etiology of the dyspnea is currently unknown, but the condition was transient in most patients and did not increase with continued exposure to carfilzomib. Only 17% was attributed to carfilzomib by investigators, and in light of the patient population dyspnea is likely multifactorial and warrants further evaluation.
Further workup ensued. A chest x-ray was nondiagnostic, and pulmonary function tests revealed stable findings to those done prior to carfilzomib initiation. An echocardiogram showed a left ventricular ejection fraction of 55% with mild pulmonary hypertension and moderate to severe mitral regurgitation, all unchanged from the previous exam prior to dosing. Due to the transient weight gain of 3 to 4 lb observed between consecutive days of dosing, ES was prescribed furosemide 20 mg po on the days of and the day after dosing of carfilzomib. Dyspnea improved to grade 1 with this intervention, and ES was able to continue on carfilzomib without dose modification or delay.
Following 5 cycles of therapy, ES has achieved a PR with a reduction in her SPEP to 1.0 g/dL and in UPEP to 194 mg/24 hours. She is tolerating therapy well and continues without dose modification with plans to treat until progression or intolerance.
References
- 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(14):2817-2825.
- Martin T, Vij R, Badros A, et al. Carfilzomib is associated with a low rate of typically mild to moderate, non-dose limiting treatment-emergent peripheral neuropathy. Haematologica. 2012;97(S2). Abstract 0857.
- 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.
- Harvey D, Lonial S, Patel P, et al. Carfilzomib dose and schedule need not be adjusted for baseline renal dysfunction, including patients on hemodialysis. Haematologica. 2012;97(S2). Abstract 0844.
- Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; 2012.
- Nooka A, Badros A, Patel P, et al. Hematologic safety data from four phase 2 studies of single-agent carfilzomib in relapsed and/or refractory multiple myeloma. J Clin Oncol. 2012; 30(suppl). Abstract 8086.