This article reviews the hematologic safety profile of carfilzomib in patients with relapsed/refractory multiple myeloma, as assessed in a cross-trial safety analysis of four phase II studies, and makes recommendations for the appropriate management of hematologic adverse events.
Table 1: CTCAE Grading for Hematologic AEs of Interest
Table 2: Treatment-Emergent and Treatment-Related Hematologic AEs in the Cross-Trial Safety Analysis (N = 526)
Table 3: Shift of Hematologic Laboratory Values From Baseline Normal or Baseline Grade 1 to Grade 3 or Grade 4 in the Cross-Trial Safety Analysis (N = 526)a
Table 4: Recommendations for the Management of Hematologic AEs Associated With Carfilzomib
Hematologic adverse events (AEs) are commonly encountered in patients with multiple myeloma (MM) owing to the nature of the disease and the adverse effects related to myeloma treatment. Immunomodulatory drugs (eg, thalidomide, lenalidomide, and pomalidomide) and the proteasome inhibitor bortezomib have all been associated with increased rates of anemia, neutropenia, and thrombocytopenia, as well as greater incidences of infection caused by associated immunosuppression. The proteasome inhibitor carfilzomib was recently approved in the United States for the treatment of patients with relapsed and refractory MM. This article reviews the hematologic safety profile of carfilzomib in patients with relapsed/refractory MM, as assessed in a cross-trial safety analysis of four phase II studies, and makes recommendations for the appropriate management of hematologic AEs.
At diagnosis, patients with symptomatic multiple myeloma (MM) present with one or more of the MM-defining characteristic clinical/radiologic features, including hypercalcemia, renal insufficiency, anemia, and bone lesions (so-called “CRAB” features), or recurring respiratory infections. Since 75% to 79% of MM patients are older than 70 years at the time of diagnosis, many have other comorbidities, such as heart disease and renal disease.
Hematologic complications are particularly common in patients with MM, and approximately three-quarters of patients present with anemia (typically normochromic) at diagnosis.[3,4] The underlying pathophysiologic causes of anemia in patients with MM are often multifactorial and may be attributable to chronic disease, bleeding, or hemolysis, as well as relative deficiency of erythropoietin due to renal impairment with progressive disease, overcrowding of marrow space by plasma cells, or cytokine-induced inhibition of normal red blood cell (RBC) maturation.[5-7] If left untreated, anemia can have a profound effect on a patient’s quality of life, including severe anemia-related fatigue that may impede normal work and activities of daily life.[8,9]
Other hematologic comorbidities commonly found in patients with advanced MM are thrombocytopenia and neutropenia (including febrile neutropenia). During the course of the disease, the majority of patients will experience some degree of myelosuppression, resulting in dysfunction in both cellular and humoral immunity, secondary to T-cell dysfunction, hypogammaglobulinemia, and granulocytopenia.
The myelosuppression of MM and its consequences can be further exacerbated by current therapeutic regimens, which often include an immunomodulatory drug (IMiD), such as thalidomide and the thalidomide analogs lenalidomide[12-14] and pomalidomide,[15,16] or a proteasome inhibitor (PI), such as bortezomib or carfilzomib. Currently, the PI bortezomib is indicated for previously untreated patients with MM and for those with relapsed MM, while the PI carfilzomib is currently indicated for patients with MM who have relapsed after at least two previous therapies, including bortezomib and an IMiD.
All of these agents have the potential to cause hematologic adverse events (AEs). Bortezomib causes cyclical neutropenia and thrombocytopenia with nadir after the last dose and recovery before the next cycle without cumulative toxicity.[17,19-22] In a phase III randomized trial comparing bortezomib (n = 331) with dexamethasone in heavily pretreated patients with relapsed or refractory MM (RRMM), the most frequently reported (≥ 10%) grade 3/4 hematologic AEs in the bortezomib arm were thrombocytopenia (29%), neutropenia (14%), and anemia (10%).
Neutropenia is one of the most common hematologic AEs associated with IMiD treatment.[11,14,16,24] In a phase II, randomized, open-label study evaluating pomalidomide alone (n = 107) vs pomalidomide + low-dose dexamethasone in RRMM, the most common (≥ 10%) grade 3/4 AEs in the pomalidomide arm were neutropenia (47%), anemia (22%), thrombocytopenia (22%), and pneumonia (16%).[16,25] Febrile neutropenia (defined as temperature ≥ 38.5°C [101.3°F] and absolute neutrophil count [ANC] < 1,000/µL) was observed in 5% of patients in the pomalidomide-alone arm. In an analysis of data from two phase II studies in patients with RRMM comparing lenalidomide + dexamethasone (n = 353) with dexamethasone alone, the most common (≥ 10%) grade 3/4 AEs in the lenalidomide combination arm were neutropenia (33%), thrombocytopenia (12%), and anemia (10%).[13,14,26]
Immunosuppression as a consequence of neutropenia caused by treatment for MM is also often associated with an increase in viral (particularly varicella-zoster virus [VZV]) and bacterial infections, including upper and lower respiratory tract infections (eg, “colds” and pneumonia).[27,28] In the phase III Assessment of Proteasome Inhibition for Extending Remissions (APEX) clinical trial of bortezomib in patients with relapsed MM, a significant increase in reactivation of VZV infection was reported in the bortezomib arm relative to the high-dose dexamethasone arm (13% vs 5%; P = .0002).
Bortezomib has been in clinical use for close to a decade, and the AE profile is well established; however, comparatively less is known about the hematologic safety profile of carfilzomib. It is of further clinical interest at this time because an increasing number of patients exposed to bortezomib in first-line regimens receive carfilzomib as second- or third-line therapy.[30-32] Moreover, because patients with MM often relapse multiple times during the course of their disease and may receive long-term maintenance therapy, appropriate management of treatment-related hematologic AEs is crucial.
The purpose of the current review is to summarize the hematologic safety profile of carfilzomib, as determined from a cross-trial safety analysis of the four phase II clinical trials of single-agent carfilzomib, upon which the approval by the US Food and Drug Administration was based, and to provide practical recommendations for the management of potential hematologic AEs associated with its use.
A cross-trial safety analysis was undertaken on data from four phase II studies to assess single-agent carfilzomib: PX-171-003-A0, PX-171-003-A1,[31,32] PX-171-004,[31,33] and PX-171-005. These grouped analyses examined the incidence, frequency, and severity of hematologic AEs (thrombocytopenia, lymphopenia, neutropenia, and anemia).[35,36] The severity of these events was defined by the Common Terminology Criteria for Adverse Events (CTCAE, v3.0), which is described in Table 1.
Hematologic criteria for entry into these phase II studies were adequate bone marrow function, including white blood cell count ≥ 2,000/µL, ANC ≥ 1,000/µL, hemoglobin (Hb) level ≥ 8.0 g/dL (≥ 7.0 g/dL in study PX-171-005), and platelet count ≥ 50,000/µL (≥ 30,000/µL in study PX-171-005). Patients in these studies were heavily pretreated at baseline, with a median of 4 (range 1–20) previous regimens. All study protocols included dose reduction guidelines for patients in whom prolonged hematologic AEs developed, including grade 3 neutropenia, grade 4 thrombocytopenia, and lymphopenia.
Safety data were available for 526 patients with RRMM who were participating in these studies. At baseline, hematologic AEs were present in 4.6% (grade 1), 15.0% (grade 2), 36.5% (grade 3), and 14.3% (grade 4) of patients; and 153 patients (29.1%) reported a history of any type of herpesvirus infection.
Over the course of the studies, 70.3% (n = 370) of patients experienced a hematologic AE, most commonly anemia (46.8%) and thrombocytopenia (36.3%). Grade 3/4 hematologic AEs were generally reversible. Overall, dose reductions owing to hematologic AEs in the phase II studies were rare (≤ 1.1%), and ≤ 1% of patients discontinued treatment with carfilzomib because of a hematologic AE (Table 2).
Approximately one-half (46.8%) of patients in the cross-trial safety analysis reported anemia of any grade, which usually presented as grade 1/2 (see Table 2). However, patients in the PX-171-004 study had fewer previous therapies (median of 2, range 1–13), and anemia AEs were less frequent (39.6%) in this study.
For all four studies, grade ≥ 3 anemia was reported in 22.4% of patients (see Table 2). However, no patients shifted from normal at baseline to grade 3/4 anemia; from grade 1, 14 patients shifted to grade 3, and 2 patients shifted to grade 4 (Table 3). Hb levels remained stable throughout the treatment cycle, with mean and median nadirs remaining at grade 1.
The incidence of thrombocytopenia of any grade was 36.3%, and grade ≥ 3 thrombocytopenia was reported in 23.4% of patients overall (see Table 2). Median platelet counts, which were observed to be cyclic, decreased from baseline to reach a grade < 1 nadir at day 8 and returned to normal by day 1 of the next cycle. Clinically significant episodes of bleeding associated with concurrent thrombocytopenia were rare. There was limited to no evidence of cumulative or grade 4 thrombocytopenia observed (see Table 3).
The incidence of lymphopenia of any grade was 24.0%, and grade ≥ 3 lymphopenia was reported in 18.1% of patients overall (Table 2). Similar lymphopenia rates with single-agent bortezomib (any grade, 67%; grade ≥ 3, 34%) were observed in mantle cell lymphoma patients in the PINNACLE study, suggesting a class effect. Median lymphocyte counts generally did not fluctuate; 10 of 182 (5.5%) patients shifted from normal at baseline to grade 3/4 lymphopenia.
The incidence of neutropenia of any grade was 20.7%, and grade ≥ 3 neutropenia was reported in 10.3% of patients overall (see Table 2). Similar to the pattern of thrombocytopenia, neutrophil counts were cyclic during carfilzomib treatment. However, it was uncommon (3.7%; 7/187) for patients with normal neutrophil counts at baseline to shift to grade 3/4 neutropenia (see Table 3). Febrile neutropenia occurred infrequently (reported in 6 [1.1%] patients).
Leukopenia of any grade developed in 71 patients (13.5%), and grade ≥ 3 leukopenia was reported in 27 patients (5.3%) overall (see Table 2).
During the course of the phase II studies, low rates (4.8%; n = 25) of herpesvirus infections were reported, and the risk of opportunistic viral infections did not increase. Overall, VZV infection was reported in 2.3% (n = 12; 8 with a history of VZV infection) of patients, and herpes simplex virus (HSV) infection was reported in 2.7% of patients (n = 14; 4 with a history of HSV infection). Episodes of infections were predominantly mild to moderate in severity. Herpesvirus infections often resolved within the usual time course with standard medical management and rarely resulted in dosage interruptions.
AEs attributable to respiratory tract infection (grade ≥ 1) were reported in 18.8% of patients. The most commonly reported respiratory tract infection AE (all grades) was pneumonia (67 patients [12.7%]), which was also the most commonly reported serious AE (52 patients [9.9%]).
Hematologic AEs occurring as a result of treatment with single-agent carfilzomib and/or as a result of an underlying comorbidity are generally manageable (Table 4). Proactive management of these events may help improve the ability of a patient to continue receiving the target dose of carfilzomib, reducing the need for dose reductions or discontinuation, with a concomitant improvement in quality of life.
In patients who present with anemia, possible causes (including MM) should be investigated. For anemia that is not attributable to absolute or functional iron deficiency, only two methods (erythropoietin-stimulating agents [ESAs] and RBC transfusions) have been proved to increase Hb levels, and both approaches have their own risks and benefits.
Grade 1/2 anemia may be managed with an ESA (see Table 1), and transfusions are rarely required. High response rates (25%–85% improvement) have been demonstrated in patients with MM following treatment with ESAs, including increases in Hb levels, reduced need for transfusions, and improved quality of life.[6,39] The ESAs epoetin alfa and darbepoetin alfa are considered to be equivalent by the National Comprehensive Cancer Network (NCCN) anemia panel. For Hb levels ≤ 10 g/dL, 40,000 units subcutaneous (SC) epoetin alfa weekly or 300 µg SC darbepoetin alfa every 2 weeks or 500 µg every month may be administered. The benefits of ESAs include avoidance of RBC transfusions and gradual improvement in fatigue, but these agents may pose an increased risk of thrombotic events, especially in combination with IMiDs. ESAs may also decrease survival and lead to a shorter time to tumor progression.[7,41] Caution should be used when prescribing ESAs; if given, the recommendation is to hold the ESA if the Hb level is > 12 g/dL.
For grade ≥ 3 anemia (see Table 1), RBC transfusions (leukoreduced) are usually required, and dose modifications or interruptions of the chemotherapeutic regimen may also be needed. To avoid withholding treatment because of anemia (Hb level < 8 g/dL), carfilzomib may be administered and followed by transfusion of packed RBCs, as needed. The decision to transfuse is a clinical judgment that requires careful evaluation of the benefits and risks in comparison with those of alternative treatments.
Patients with symptomatic anemia should always receive RBC transfusions. Because of the swift increase in Hb level and hematocrit following RBC transfusions, this approach is associated with a rapid improvement in fatigue and shortness of breath. However, RBC transfusions may be associated with transfusion-related reactions (eg, hemolytic or febrile, non-hemolytic reactions; lung injury), fluid overload, viral transmission, bacterial contamination, iron overload, increased thrombotic events, and decreased survival.
Fatigue is rarely an isolated symptom and may be associated not only with anemia but also with a host of other conditions, such as pain, distress, and/or sleep disturbances. Therefore, patients should be screened for all reasonable clinical causes of fatigue and treated accordingly. Patients with and without anemia-related fatigue may benefit from nonpharmacologic interventions such as energy conservation via structured and paced daily routines, brief daytime naps, and nutritional assessment and intervention. Effective management of concomitant symptoms and morbidities, such as depression, anxiety, and pain, can also ameliorate fatigue.
Because approximately one-third of patients have > 50% plasmacytosis in their bone marrow prior to carfilzomib initiation, platelet counts may be reduced before the start of treatment. Platelet counts should be monitored frequently during treatment with carfilzomib, and doses should be reduced or interrupted as clinically indicated. Platelet counts follow a cyclical pattern and are usually expected to decrease during the dosing cycle and return to baseline before the next cycle; they are also generally manageable with dose reduction. Thrombocytopenia following the administration of carfilzomib resulted in a dose reduction in 1% of patients and discontinuation of the drug in < 1% of patients.
For platelet counts < 25,000/µL (grade 4 thrombocytopenia), transfusion with platelets is generally required, and the carfilzomib dose should be withheld until the platelet count rises above 25,000/µL. If the patient fully recovers before the next scheduled dose, treatment may resume at the same dose level. For patients recovering to grade 3, the dose should be reduced by one dose level (from the target dose level of 27 mg/m2 to 20 mg/m2, or from 20 mg/m2 to 15 mg/m2). If the new reduced dose is tolerated, the dose may be escalated to the target dose at the physician’s discretion. Patients should be taught to recognize and report to their healthcare team the signs and symptoms of thrombocytopenia (ie, unexpected bruising, petechiae, bleeding from the nose or gums, severe headaches, dizziness, and increased fatigue). Platelet transfusions are required for thrombocytopenic bleeding; however, patients should not be routinely transfused in the absence of signs of bleeding unless the platelet count is < 10,000/µL. Irradiated products are suggested for patients who have undergone a transplant. Cytomegalovirus (CMV)-negative blood products are recommended whenever possible for CMV-negative patients who have undergone a transplant.
The risk of developing severe neutropenia during treatment with PIs and IMiDs is related to patient characteristics, disease stage, type of current and previous treatment, and ANC at baseline. Although prophylactic growth factors are not usually necessary with carfilzomib, since the risk of neutropenia is < 50%, physicians may consider these agents for patients at high risk, such as those with a history of neutropenia during previous chemotherapy regimens, low performance status, or multiple comorbidities.
Grade 1/2 neutropenia does not usually require dose adjustment or treatment. However, for grade 3/4 neutropenia, the carfilzomib dose should be withheld until the ANC is restored to ≥ 1,000/µL (usually 1–2 days). If the neutropenia resolves before the next scheduled dose, carfilzomib may be continued at the same dose level. If the patient recovers to grade 2 neutropenia, the dose should be reduced by one dose level (for example, from the target dose level of 27 mg/m2 to 20 mg/m2, or from 20 mg/m2 to 15 mg/m2). In patients who are able to tolerate the reduced dose, carfilzomib may be escalated to the target dose at the physician’s discretion. Grade 3/4 neutropenia may also be treated with growth factors, including filgrastim at 300 µg or 480 µg SC for 1 to 3 days. Therapy can be resumed with no dose modification if ANC increases to > 1,000/µL after growth factor administration.
Bacterial infections in MM tend to follow a biphasic pattern, with Streptococcus pneumoniae and Haemophilus influenzae infections predominating early in the disease and a higher incidence of infections with Staphylococcus aureus and gram-negative pathogens during refractory or advancing disease.[44,45] Patients with RRMM and lymphopenia are often at high risk for urinary tract infections, pneumonia, and other infections; therefore, they may be candidates for antibacterial prophylaxis, usually with a fluoroquinolone, such as moxifloxacin, levofloxacin, or ciprofloxacin, or trimethoprim-sulfamethoxazole. According to NCCN guidelines, RRMM patients with recurrent and life-threatening bacterial infections may also benefit from intravenous immunoglobulin therapy. It is difficult to predict which patients with neutropenia will have complications, but the depth and duration of neutropenia are critical determinants of a patient’s risk of infection; thus, current recommendations for anti-infective prophylaxis are determined by these factors.
In the absence of fever (oral temperature ≥ 38.3°C [100.9°F]), the NCCN guidelines do not recommend prophylactic antibiotics for patients with neutropenia unless the ANC is expected to remain below 1,000/µL for more than 7 days. The American Society of Clinical Oncology has even more stringent criteria and recommends antibiotic prophylaxis only for patients with profound neutropenia (< 100/µL) that is expected to last more than 7 days. However, it should be noted that occasionally patients with neutropenia will have signs or symptoms of infection without fever (eg, severe mucositis), and these patients should be considered to have an active infection. Infection in the absence of fever may be more common in patients who are taking a concomitant corticosteroid (eg, dexamethasone), which is frequently coadministered with carfilzomib. These patients and those who have fever should be carefully assessed for their risk of serious complications, including inpatient/outpatient status at the time of fever development, performance status, renal and hepatic function, comorbidities, expected duration of neutropenia, and Multinational Association for Supportive Care in Cancer (MASCC) Risk Index. The MASCC Risk Index score is a validated means of distinguishing between patients at low or high risk of infection-related complications and determining whether or not they are candidates for intensive or less-intensive antibiotic therapy. The choice of antibiotic will depend on the site of infection and likely organism. Consultation with infectious disease specialists may be indicated.
In the phase II clinical trials that are summarized above, antiviral prophylaxis was used at the discretion of the treating physician to prevent reactivation of VZV infection. For patients who have a history of VZV infections, antiviral prophylaxis may be considered. The NCCN guidelines recommend antiviral prophylaxis during active treatment with PIs in patients who are at high risk for such infections.
In the cross-trial safety analysis of 526 heavily treated patients with RRMM, the hematologic safety profile following use of single-agent carfilzomib was favorable in relation to other anti-myeloma agents.[15,16,48] In particular, there was a notable lack of cumulative thrombocytopenia and an overall low rate and mild severity of myelosuppression, including grade 3/4 thrombocytopenia (10%), which is similar to rates reported from other phase II studies of patients treated with lenalidomide/dexamethasone (12%)[13,14,26] and lower than rates reported from phase II studies with pomalidomide (22%)[16,25] and a phase III study with bortezomib (29%). Data from the cross-trial safety analysis also showed that rates of febrile neutropenia were low (1.1%) in relation to rates reported following use of lenalidomide/dexamethasone (2.3%)[13,14,26] and pomalidomide (5%).[16,25] Febrile neutropenia was not reported in a phase III study that investigated bortezomib in patients with relapsed MM. The rate of grade 3/4 anemia, which was reported in 22% of patients who received single-agent carfilzomib, is similar to rates reported with pomalidomide (22%)[16,25] and higher than rates reported with lenalidomide/dexamethasone (10%)[13,14,26] and bortezomib (10%). The incidence of VZV infection in patients who received single-agent carfilzomib (2.3%) was low in comparison with the rates reported for the high-dose dexamethasone arm (5%) and bortezomib arm (13%) in the APEX study. Although the cross-trial safety analysis reveals that carfilzomib has a favorable safety profile in relation to other antimyeloma agents, in the absence of head-to-head trials, comparisons across studies should be interpreted with caution.
The cross-trial safety analysis of patients treated with single-agent carfilzomib showed that hematologic AEs are infrequently dose-limiting and grade 3/4 events are generally reversible. By utilizing appropriate strategies to help manage or prevent common hematologic events, the frequency and severity of AEs and the need for carfilzomib dose reductions or interruptions may be reduced, allowing patients to continue receiving carfilzomib at the target dose. In doing so, patients with RRMM will be more likely to receive the maximum clinical benefit from their treatment with single-agent carfilzomib.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgment: Medical writing and editorial assistance was provided by BlueMomentum, a division of KnowledgePoint360 Group, San Bruno, California, and funded by Onyx Pharmaceuticals, Inc.
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