Carfilzomib a New Option for the Treatment of Patients with Relapsed, Refractory Multiple Myeloma Previously Treated with Bortezomib and an Immunomodulatory Agent

Lynne Lederman, PhD, Medical Writer

September 2012, Vol 3, No 6 - Drug Updates


Multiple myeloma (MM), a clonal malignancy of plasma cells, is responsible for 10% to 15% of all hematologic malignancies and for 20% of deaths resulting from hematologic cancers.1,2 In most patients, MM evolves from monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic plasma-cell disorder. In some patients, MGUS progresses through an intermediate, asymptom­atic, premalignant stage, smoldering MM, before the disease is diagnosed.1,2 Although the cause of MM is not known, it is more common in older individuals aged >65 years than in younger persons, is more common in blacks than in whites, and is slightly more common in men than in women. Other factors associated with MM include exposure to certain chemicals, being overweight or obese, having been exposed to radiation, or having another plasma-cell disorder.3

The Burden and Impact of Multiple Myeloma
In 2012, the American Cancer Society estimated that there would be 21,700 patients diagnosed with MM and 10,710 deaths would occur from MM.4 Patients with MM frequently experience fatigue, bone pain, osteo­lytic bone lesions, and/or compression fractures.5 End-organ damage, including hypercalcemia, anemia, renal dysfunction, or bone lesions caused by proliferation of myeloma cells, is considered diagnostic of symptomatic MM.6 Patients with MM experience leukopenia and thrombocytopenia in addition to anemia, and they are at risk for recurrent infections. Also, peripheral neuropathy (PN) can be present at diagnosis. This is important, because cytopenias and PN are significant toxicities associated with some anti­myeloma therapies.2

The median survival for patients with MM was less than 1 year before the introduction of alkylating agents in the 1960s. Median survival increased with the introduction of high-dose chemotherapy and autologous stem-cell transplant (ASCT) in the 1980s.7 Supportive therapies, such as growth factors, bisphosphonates, and im­proved modalities to treat fractures, have also played a role in increasing survival.2,7

Much of the increased survival for patients with MM since approximately 2000 can be attributed to the development of novel, targeted therapies, including the immunomodulatory agents thalidomide and lenalidomide, and the proteasome inhibitor bortezomib.7

Current treatment approaches for newly diagnosed or relapsed MM are based on patient-specific factors, such as eligibility for ASCT and the presence of comorbidities, and disease-related factors, such as high-risk characteristics.2 Almost all patients with MM will eventually experience a relapse. The duration of remission in patients with relapsed MM is shorter with each successive treatment regimen.8 Once MM relapses, it tends to become more resistant to chemotherapy over time, and patients are likely to require continuous treatment with one regimen after another as their disease progresses.2 Therefore, despite the pro­gress in developing novel, tar­geted therapies, MM remains incurable.7

Carfilzomib Fills an Unmet Need

On July 20, 2012, the US Food and Drug Administration (FDA) granted accelerated approval for carfilzomib for injection (Kyprolis; Onyx Pharmaceuticals), which is indicated for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an im­munomodulatory agent (thalidomide or lenalidomide), and have demonstrated disease progression on or within 60 days of the completion of the last therapy.9

Currently, the median survival for patients with MM that is refractory to bortez­omib is 9 months; for those with MM refractory to lenalidomide, the median survival is only 5 months.8 As the second-in-class– approved proteasome inhibitor, carfilzomib should provide a new option for patients whose MM has become resistant to bortezomib, the first-approved proteasome in­hibitor for MM.10

The approval of carfilzomib was based on the response rate determined in a single-arm clinical trial and is not based on survival. Furthermore, a clinical benefit (eg, increased survival or improved symptoms) has not been confirmed.9,11

As a condition of the accelerated approval, Onyx Pharmaceuticals
will submit the results of an ongoing phase 3 randomized trial comparing lenalidomide plus low-dose dexa­methasone with lenalidomide plus low-dose dexamethasone plus carfilzomib in patients with MM that has relapsed or is refractory after 1 to 3 prior therapies. The primary end point of this phase 3 trial is progression-free survival.9 Carfilzomib is not currently indicated for the treatment of newly diagnosed MM.

According to Jamie Shapiro, PharmD, BCOP, Clinical Coordinator at H. Lee Moffitt Cancer Center, Tampa, FL, “Carfilzomib is an exciting new option for our patients with progressive disease after receiving treatment with bortezomib and lenalidomide. Carfilzomib is an important addition to our antimyeloma therapies and meets an unmet need in our patients with progressive multiple myeloma.”

Page Bertolotti, RN, BSN, OCN, of Cedars-Sinai Outpatient Cancer Cen­ter at the Samuel Oschin Comprehen­sive Cancer Institute, Los Angeles, CA, commented that, “Carfilzomib is an important treatment option for our patients with refractory multiple myeloma. We had several patients who missed the clinical trial enrollment and waited anxiously for the approval.”

Clinical Pharmacology
Mechanism of ActionCarfilzomib is in the epoxyketone class of proteasome inhibitors and irreversibly binds to the proteolytic core particle within the 26S proteasome. Carfilzomib has selectivity for the chymotrypsin-like activity of proteasome, and in preclinical studies it has induced cell-cycle arrest and programmed cell death and activated stress response pathways.10,11

Pivotal Phase 2 Clinical Trial
Carfilzomib was approved by the FDA based on the results of a single-arm, multicenter phase 2 clinical trial enrolling 266 patients with relapsed MM who had received at least 2 pre­vious therapies that included bor­tezomib and either thalidomide or lenalidomide.9 The results of this trial have recently been published.12

Trial Design
The trial included patients with MM who had a response rate of ≤25% to the most recent therapy or had disease progression during or within 60 days of the most recent therapy they received before enrolling in the trial.

Patients received carfilzomib by intravenous (IV) infusion over 2 to 10 minutes on 2 consecutive days weekly for 3 weeks followed by a 12-day rest period (one 28-day cycle) until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. The carfilzomib dose was 20 mg/m2 for the first cycle and was escalated to 27 mg/m2 for subsequent cycles.

Premedication with 4 mg of dexamethasone was administered before each dose during cycle 1 and during the first dose escalation cycle and subsequently, when needed, to reduce the incidence and severity of infusion reactions.11

Table 1
Disease Characteristics and Patient Baseline Demographics.
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Patient Population
Key baseline patient demographic and disease characteristics are listed in Table 1.

Safety Profile
The most common adverse reactions experienced by ≥30% of patients in clinical trials included fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

The safety of carfilzomib as monotherapy or with premedication with dexamethasone has been assessed in 526 patients with relapsed and/or refractory myeloma. This patient population includes the 266 patients treated in the phase 2 approval trial. Patients received a median of 4 treatment cycles of carfilzomib.

Of the total population, there were 37 deaths (7%) within 30 days of the last carfilzomib dose, including 21 from disease progression; 5 from cardiac issues (eg, acute coronary syndrome, cardiac arrest, and cardiac disorder); 4 from end-organ failure (ie, multiorgan, hepatic, and renal); 4 from infection; and 1 each from dyspnea, intracranial hemorrhage, and un­known causes.11

Serious adverse reactions were reported in 45% of patients receiving carfilzomib—the most common being pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). In addition, 15% of the patients had serious adverse reactions that led to the discontinuation of carfilzomib monotherapy.11

Peripheral neuropathy. PN is often associated with MM therapies. Any-grade PN occurred in 14% of patients enrolled in carfilzomib clinical trials, but only 1% of patients experienced grade 3 PN. Serious PN events resulting in dose reductions or treatment discontinuations occurred in <1% of patients.11

The incidence of PN associated with carfilzomib is lower than that associated with thalidomide or with bortezomib, and the low rate of new-onset or worsening PN suggests that patients with PN associated with other therapies may be able to tolerate treatment with carfilzomib.12

Commenting on carfilzomib, Dr Shapiro noted that, “One of the most beneficial aspects with carfilzomib is the low incidence of peripheral neuropathy.”

Renal events. The most common renal adverse reactions of any grade were increased blood creatinine (24%) and renal failure (9%). Grade 3 renal events occurred in 6% of patients and grade 4 in 1%. Discontinuations resulting from increased blood creatinine and acute renal failure, each, occurred in 1% of patients. Furthermore, 1 patient died from concurrent sepsis and worsening renal function.11

Response
Response rates for the phase 2 ap­proval trial population were determined by an independent review committee.11 The overall response rate was 22.9% (n = 61); of these, 17.7% of pa­tients (n = 47) achieved a partial re­sponse (PR); 4.9% (n = 13) achieved a very good PR, and 0.4% (n = 1) achieved a complete response. The median duration of response was 7.8 months.11

Overall survival (OS) was 15.6 months in this group of patients with heavily pretreated MM refractory to or intolerant of bortezomib and lenalidomide, and compares favorably to an OS of 9 months in similar settings. Response and survival may have been affected by treatment discontinuation resulting from progressive disease in almost 23% of patients in the first 2 treatment cycles.12

Table 2
Carfilzomib Dosing Regimen.
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Dosing and Administration
Carfilzomib is administered intravenously over 2 to 10 minutes on 2 consecutive days each week for 3 weeks on days 1, 2, 8, 9, 15, and 16, followed by a 12-day rest period from days 17 to 28. These 28 days constitute 1 treatment cycle.11 This dosing regimen is shown in Table 2.

The dose for cycle 1 is 20 mg/m2 using the baseline patient’s body surface area. If this dose is tolerated, the dose is increased to 27 mg/m2 beginning at cycle 2, and the dose is maintained at this level for subsequent cycles.11

Hydration and Premedication
Patients should be hydrated with IV normal saline or with another appropriate IV fluid before each dose of carfilzomib in cycle 1 and after administration, as needed, to reduce the risk of renal toxicity and tumor lysis syndrome. Maintaining adequate hydration and monitoring blood chemistries is recommended. Hydration can be continued for subsequent cycles if needed.11

To reduce the incidence and severity of infusion reactions, patients should receive premedication with 4-mg oral or IV dexamethasone before all doses in cycle 1 and the first cycle of escalation to the higher dose. Pre­medication with this dose of dexamethasone may be administered if infusion reactions occur or recur during treatment.11

Dose Modifications Based on Toxicity
The dose of carfilzomib may be modified if hematologic or nonhematologic toxicities occur, in­cluding grade 3 or grade 4 cytopenias; cardiac, hepatic, or renal toxicities; pulmonary complications; PN; or other toxicities. In general, carfilzomib is withheld until resolution, followed by restarting therapy at the same or at a reduced dose, depending on the type of toxicity and whether it was attributable to carfilzomib.11

Table 3
Carfilzomib Warnings and Precautions.
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Warnings and Precautions
A number of adverse reactions associated with carfilzomib are discussed in the “Warnings and Precautions” section of the prescribing information (Table 3).11 These reactions, which may require dose modification, include cardiac arrest, congestive heart failure, myocardial ischemia, pulmonary hypertension and other complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, and hepatic toxicity and failure.11

Women of child-bearing potential are advised to avoid becoming pregnant during treatment with carfilzomib, because it has been shown to cause fetal harm in animal studies.11

References

  1. 1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962-2972.
  2. Laubach J, Richardson P, Anderson K. Multiple my­el­oma. Ann Rev Med. 2011;62:249-264.
  3. American Cancer Society. Multiple myeloma over­view. 2011. www.cancer.org/acs/groups/cid/documents/webcontent/003065-pdf.pdf. Accessed August 28, 2012.
  4. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epidemiologsurveilance/documents/document/acspc-031941.pdf. Accessed August 28, 2012.
  5. Rajkumar SV. Multiple myeloma. Curr Probl Cancer. 2009;33:7-64.
  6. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757.
  7. Kumar SK, Rakjumar SV, Dispenzieri A, et al. Im­proved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.
  8. Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2010;86:57-65.
  9. US FDA Drug Approvals and Databases. Carfilzomib. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm312945.htm. Accessed July 21, 2012.
  10. Moreau P, Richardson PG, Cavo M, et al. Protea­some inhibitors in multiple myeloma: 10 years later. Blood. 2012;120:947-959.
  11. Kyprolis (carfilzomib) for Injection [prescribing information]. South San Francisco, CA: Onyx Phar­maceuticals, Inc; July 2012.
  12. 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 Jul 25. [Epub ahead of print.]