ABSTRACT: In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib(Drug information on bortezomib) (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide(Drug information on thalidomide) (Thalomid), and liposomal doxorubicin(Drug information on doxorubicin). These are commonly used in the treatment of relapsed/refractory (R/R) multiple myeloma (MM), but there is no universally accepted standard treatment. Salvage therapy must be tailored according to an individual patient’s clinical profile, with the risks and potential effects of treatment-related adverse events being major determinants of the choice of therapy. Two novel agents in phase II studies to investigate their potential for the treatment of R/R MM are carfilzomib, a selective, irreversible next-generation PI, and pomalidomide, a next-generation thalidomide analog. This review will discuss the side-effect profiles of the currently approved immunomodulatory agents and bortezomib, as well as those of the newer agents, carfilzomib and pomalidomide.
The rational development of novel targeted therapies is expanding treatment options for patients with relapsed/refractory (R/R) multiple myeloma (MM). The first-in-class proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents thalidomide (Thalomid) and lenalidomide (Revlimid), and liposomal doxorubicin are currently the major approved therapeutic agents in this setting. Other novel agents, such as the next-generation thalidomide analog pomalidomide and the more selective next-generation PI carfilzomib, are under investigation for the treatment of R/R MM.
The newer agents for the treatment of R/R MM have distinct toxicity profiles (Table 1). The effective management of the adverse events (AEs) associated with these agents is crucial to ensure that patients receive the most effective dosing regimen while maintaining an acceptable quality of life.
Important Treatment-Related Adverse Events
Hematologic adverse events
Thalidomide and lenalidomide. Myelosuppression is an AE commonly associated with lenalidomide therapy, mainly manifesting as neutropenia and thrombocytopenia. In two phase III studies in patients with R/R MM, grade 3/4 neutropenia occurred in approximately 30% to 40% of patients treated with lenalidomide + dexamethasone(Drug information on dexamethasone), compared with only 2.3% to 4.5% of patients treated with dexamethasone alone, although grade 3/4 febrile neutropenia occurred in less than 4% of patients.[4,5] In contrast, treatment with thalidomide is associated with only mild neutropenia in 3% to 15% of patients.[3,6] Thrombocytopenia was the second most common hematologic toxicity in patients treated with lenalidomide + dexamethasone, with grade 3/4 thrombocytopenia occurring in 11% to 15% of patients.[4,5]
In one of the earliest dose-finding studies of thalidomide for the treatment of refractory MM, grade 3 or 4 thrombocytopenia or anemia occurred in only 3 of 258 patients (1.2%). In most of the patients who had no response, pretreatment anemia or thrombocytopenia did not worsen, although significant increases in hemoglobin levels occurred in responding patients. Anemia has also been observed following treatment with lenalidomide. In pivotal trials involving > 700 patients, the incidence of anemia was 31.4% with lenalidomide + dexamethasone vs 23.7% in the dexamethasone-only group. In the same studies, the incidence of grade 3/4 anemia was 10.8% in the lenalidomide + dexamethasone groups compared with 6.0% in the dexamethasone-only groups.[4,5]
Thalidomide-based regimens have been reported to impair CD34+ stem-cell yields in patients with newly diagnosed MM.[9,10] A more prominent trend toward lower CD34+ stem-cell yields has been observed in newly diagnosed patients treated with lenalidomide + dexamethasone, so it is recommended that peripheral blood stem cells be harvested before prolonged exposure to lenalidomide.[1,11] Duration of treatment with lenalidomide has also been cited as a reason for decreased stem-cell yields.
Bortezomib. Thrombocytopenia is a prominent hematologic toxicity associated with bortezomib. Grade 3/4 thrombocytopenia was reported in 30% of patients with R/R MM treated with bortezomib in the Assessment of Proteasome Inhibition for Extending Remissions (APEX) study. Platelet levels typically decrease during each cycle of bortezomib treatment, returning toward baseline between cycles without evidence of cumulative thrombocytopenia.[13,14] Predicted time for recovery of platelet counts from nadir to baseline is less than 7 days with bortezomib, whereas other cytotoxic agents typically require 3 to 4 weeks for resolution. Interestingly, a parallel phenomenon observed in murine models has been traced to a bortezomib-induced dose-dependent inhibition of proplatelet formation by megakaryocytes.
Neutropenia associated with bortezomib follows a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering before initiation of the next cycle. In one phase II study of bortezomib in patients with R/R MM, neutrophil counts decreased during the bortezomib dosing period (days 1 to 11) and returned to baseline levels during the 10-day rest period at the end of each treatment cycle. This cyclical pattern of neutrophil decreases and recovery remained consistent over multiple cycles of twice-weekly dosing, with no evidence of cumulative neutropenia. Overall, neutropenia occurred in 19% of patients and was grade 3 in 11% to 12% of patients, with ≥ grade 4 in 2% to 3% of patients.[13,16] Neutropenia was reported as a serious event in < 1% of patients, and < 1% of patients discontinued treatment because of neutropenia. In the same study, the incidence of febrile neutropenia with bortezomib was < 1%.
Anemia was observed in studies evaluating the administration of bortezomib or dexamethasone in patients with relapsed MM, with a slightly increased incidence of anemia in patients treated with bortezomib compared with those treated with dexamethasone (26% vs 22%, respectively).
Regarding CD34+ stem-cell toxicity, a study evaluating the impact of two cycles of bortezomib therapy prior to stem-cell collection showed no adverse effects on stem-cell yields in patients with peripheral blood mononuclear cells mobilized in response to granulocyte colony-stimulating factor.
Pomalidomide. Grade 3/4 neutropenia has been observed in 37% to 55% of patients treated with pomalidomide (2 mg or 4 mg daily) plus low-dose dexamethasone in one study in patients with R/R MM. In the same study, the incidence of grade 3/4 thrombocytopenia was 11% to 13%, while the incidence of grade 3/4 anemia was 9% to 16% across two dose cohorts. Neutropenia and anemia have also been noted as the most common grade 3/4 AEs in a second study evaluating the same combination regimen. In that study, thrombocytopenia was also reported as a serious AE related to pomalidomide. There are no data currently available on stem-cell toxicity related to treatment with pomalidomide.
Carfilzomib. The overall incidence of neutropenia in phase II trials of carfilzomib has been in the range of 17% to 31%, while grade 3/4 neutropenia was observed in 5% to 8% of patients.[20,21] Cyclic thrombocytopenia has also been observed in clinical trials with carfilzomib.[22,23] The overall incidence has ranged from 27% to 38%, and the incidence of grade 3/4 thrombocytopenia has ranged from 9% to 27%.[20,21] However, as with bortezomib, the clinical pattern of thrombocytopenia suggests that the underlying pathophysiology does not involve megakaryocytic or stem-cell injury.
Treatment-emergent anemia was observed in 40% to 44% of patients in the major phase II trials of carfilzomib in patients with relapsed or refractory MM. These events were grade 3/4 in 5% to 20% of patients, although no patients discontinued treatment because of anemia.[20,21]
In a phase I/II study of the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for the treatment of newly diagnosed MM, all 14 patients underwent successful stem-cell harvest. The yields did not appear to be adversely impacted by the CRd regimen and produced a median of 6.15 × 106 CD34+ cells/kg (range, 4.1 to 8.5)..
Management. Initial episodes of thrombocytopenia in the setting of bortezomib therapy are dealt with by withholding the next dose of bortezomib (Table 2). Given the rapid reversibility of bortezomib-induced thrombocytopenia, it has been suggested that some patients with thrombocytopenia during treatment with bortezomib can continue therapy without dose interruptions. Neutrophil counts should be monitored before giving each dose of bortezomib. Patients experiencing severe or prolonged episodes of thrombocytopenia or neutropenia may require a change in the dose and schedule of bortezomib, including dose interruptions.[6,25] Guidelines for the management of hematologic toxicity associated with lenalidomide are detailed in Table 2.
Anemia is commonly associated with MM itself and will often improve with treatment response. Erythropoiesis-stimulating agents (ESAs) should be considered when, despite response to therapy, there has not been an increase in hemoglobin concentration. However, ESAs may increase the risk of thromboembolism associated with immunomodulatory agents.
Thalidomide and lenalidomide. Peripheral sensory neuropathy (PN) is frequently reported with thalidomide therapy.[6,26] The overall incidence of thalidomide-induced PN varies widely among studies (25% to 83%), with approximately 15% of patients needing to interrupt treatment. Thalidomide-induced PN is typically characterized by stinging sensations or numbness in the extremities. It usually occurs after prolonged exposure and may be permanent.[26,27] Symptoms may occur even after thalidomide treatment has been stopped and may resolve slowly or not at all. Motor neuropathy, including trembling, may occur with thalidomide treatment. Deep vibratory sensitivity and proprioceptive changes may occur later in the course of treatment, resulting in progressive ataxia, difficulty in walking, and trembling when still. Sinus bradycardia may occur as a result of autonomic neuropathy in MM patients receiving thalidomide and can be severe enough to cause syncope.
The incidence of PN, however, is relatively low with lenalidomide, suggesting that PN is not necessarily a class effect of immunomodulatory agents. In phase II trials of lenalidomide in patients with R/R MM, PN occurred in up to 10% of patients.[29,30] The incidence of grade 3/4 PN was similar in phase III trials, occurring in < 10% of patients with R/R MM receiving lenalidomide + dexamethasone.[4,5]
Bortezomib. PN is frequently reported with bortezomib therapy.[6,26] In a pooled analysis of 256 patients with R/R MM enrolled in the phase II SUMMIT and CREST trials of bortezomib, treatment-emergent PN occurred in 35% of patients overall, including 13% with grade 3 PN and 0.4% with grade 4 PN. Dose reductions were necessary in 12% of patients, and 5% of patients discontinued therapy because of PN. The clinical profile of bortezomib-induced PN includes neuropathic pain, mainly in the fingertips and toes, which may severely affect normal daily activities.[26,27] The risk of PN reaches a plateau by cycle 5, suggesting a dose threshold rather than a cumulative dose effect.[26,27] It improves or resolves in most patients at a median of 3 months after treatment is discontinued, but it has been reported that resolution can take as long as 2 years after treatment discontinuation. Recent reports have indicated reduction in neuropathy with once-weekly dosing schedules and with subcutaneous administration.[32-34] Grade 1–3 bortezomib-induced motor neuropathy (involving distal weakness in the lower limbs) affects approximately 10% of patients. Isolated cases of life-threatening grade 4 motor neurotoxicity have also been reported.
The true incidence of bortezomib-induced autonomic neuropathy is not known. The fact that both constipation and diarrhea are associated with bortezomib in clinical trials may be relevant. In a phase II study in patients with metastatic neuroendocrine tumors receiving a higher dose of bortezomib than the currently approved dose for MM, 6 of 10 patients with PN also had symptoms such as grade 2/3 dizziness, orthostatic hypotension, syncope, ileus, and abdominal cramps. Pooled data from the phase II SUMMIT and CREST studies of bortezomib in patients with R/R MM revealed orthostatic hypotension in 12% of bortezomib-treated patients (grade 3 in 4% of patients).
Two cases of grade 4 suspected autonomic neuropathy in patients with R/R MM receiving bortezomib included reports of abdominal numbness, distension, and urinary retention in one patient and persistent diarrhea, despite antibiotics and antimotility medication, in another patient. Two additional patients with PN during bortezomib treatment were reported to have developed paralytic ileus, urinary retention, and impotence. A case of complete heart block believed to be directly related to bortezomib was recently reported in a patient with MM. Several of these patients had previously been exposed to other neurotoxic agents (thalidomide and vincristine) and had comorbid conditions associated with neurologic damage.
Pomalidomide. Grade 1/2 PN was observed in 16% to 17% of patients treated with pomalidomide (2 mg or 4 mg daily) + low-dose dexamethasone. No additional data on the overall incidence of PN in patients treated with pomalidomide are available. Similarly, there are no data currently available on the incidence of motor neuropathy or autonomic neuropathy related to treatment with pomalidomide.
Carfilzomib. A low rate of treatment-emergent PN has been reported in clinical trials of carfilzomib,[38-40] suggesting that PN is not a class effect of PIs. To date, there have been no reports of dose-limiting PN in phase I and II trials of carfilzomib in patients with R/R MM.[38-40] In the PX-171-003 (A1) phase II trial of carfilzomib in patients with relapsed and refractory MM, 77% of patients presented with grade 1/2 PN at baseline. Despite this, treatment-emergent PN was uncommon throughout the course of the study, occurring in < 10% of patients overall[20,38]—a rate comparable to that seen with lenalidomide.[29,30] Similarly, in another phase II study (PX-171-004) in patients with relapsed MM, 69.0% of the overall population had a history of neuropathy at baseline, and 53% entered the study with active PN of grade 1/2. Treatment-emergent PN again was infrequent (15.3% in cohort 1 and 17.1% in cohort 2) and did not limit treatment, despite the previous exposure of a significant proportion of patients to thalidomide. Only one patient experienced grade 3 PN. There were no episodes of grade 4 PN and no treatment discontinuations because of PN. The relatively low incidence of new-onset or worsening PN suggests that carfilzomib may be tolerable in patients who previously experienced PN with other therapies. Moreover, prolonged treatment with carfilzomib—in some cases for > 2 years—was not associated with any significant increase in neuropathy. There have been no specific reports of carfilzomib-induced motor neuropathy or autonomic neuropathy in phase II clinical studies of patients with R/R MM.
Management. Clinicians need to educate patients about identifying the early signs of PN to avoid irreversible nerve damage. After starting thalidomide or bortezomib therapy, patients should be monitored regularly for symptoms of neuropathy, such as burning sensations, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, and weakness. Patients being given bortezomib should be examined before each dose for early signs of neuropathy.
There is no effective prophylactic treatment for PN, so dose and treatment schedule modifications are the mainstays of management, as described in Table 3.[6,27,41] Other medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide and/or bortezomib.
Pharmacologic intervention may involve a number of options, including gabapentin(Drug information on gabapentin), pregabalin(Drug information on pregabalin), nortriptyline(Drug information on nortriptyline), duloxetine(Drug information on duloxetine), and topical lidocaine(Drug information on lidocaine) (Table 4). For treatment-emergent PN, the Nursing Leadership Board of the International Myeloma Foundation has specific recommendations based on the severity of the toxicity or symptoms (Table 5). Interdisciplinary management of PN that involves pain specialists, neurology, psychosocial services, and physical therapy is highly encouraged.
Thalidomide and lenalidomide. Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of lenalidomide are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to nonmalignant conditions, lenalidomide starting-dose adjustment is recommended for patients with a creatinine clearance (CrCl) of < 60 mL/min. In clinical studies, patients with MM receiving lenalidomide experienced an increased incidence of thrombocytopenia, required more frequent lenalidomide dose reduction or interruption, and had shorter overall survival than patients with mild or no renal impairment (P = .006).
Bortezomib. Renal toxicity is not a common consequence of treatment with bortezomib, and in clinical trials, worsening of renal function was not observed following bortezomib therapy. A retrospective analysis was conducted of 82 patients with newly diagnosed MM who presented with renal impairment and who were treated with either conventional chemotherapy + dexamethasone or novel agents (bortezomib, lenalidomide, or thalidomide) + dexamethasone. The study found that improvement of renal function was achieved more frequently in patients treated with novel agents (87% for lenalidomide or thalidomide; 94% for bortezomib) than with conventional chemotherapy (64%; P = .024). The study also found that major renal responses were achieved most often in patients treated with bortezomib-based regimens (69%, as opposed to 43% of patients treated with conventional agents and 50% of patients treated with thalidomide- or lenalidomide-based regimens).
Pomalidomide. Limited data are currently available on the incidence of renal toxicity related to treatment with pomalidomide. In a single phase II study of pomalidomide + dexamethasone in patients with dual lenalidomide/bortezomib-refractory MM, the incidence of grade 3/4 renal failure was reported to be < 5%.
Carfilzomib. While there were some concerns about the effects of carfilzomib in patients with renal impairment early in the phase I clinical development program, the institution of hydration guidelines and allopurinol(Drug information on allopurinol) prophylaxis has largely addressed these concerns. In the major phase II clinical studies of carfilzomib in relapsed or refractory MM, the incidence of treatment-emergent renal failure or acute renal failure has been consistently low—in the range of 2.3% to 8.7%. Of these AEs, approximately half (1.5% to 4.3%) were considered to be related to carfilzomib treatment.[20,21,38,49]
Management. The management of renal toxicity or renal impairment in patients with MM routinely involves making sure that the patient receives adequate hydration, and that hypercalcemia and hyperuricemia are corrected and controlled. Specific recommendations for the use of certain drugs (eg, lenalidomide) indicate that the starting dose should be reduced for patients with moderate to severe renal impairment and for those on dialysis. The recommendations for initial starting doses of lenalidomide for patients with MM and renal impairment are displayed in Table 6.