Carfilzomib-Based Therapies for Multiple Myeloma: A Nurse's Perspective

Most of the illnesses that are encountered in medicine are incurable. Diabetes and heart disease are 2 of the common, chronic, and incurable health conditions that require diligent monitoring. In 2013, multiple myeloma (MM) joins diabetes and heart disease in the category of chronic health conditions. Because treatment is required on an ongoing and daily basis, patients with MM rely on the discovery of new drugs to improve survival, quality of life, and the possibility of a cure.

The field of clinical research can be exciting when an agent is discovered and is as effective as (or more than) was anticipated. Much time and effort are required to see a clinical trial through from start to finish. Con­ducting a trial involves many difficult aspects, from writing the clinical protocol and ensuring scientific rigor to accruing patients and maintaining accurate records. The investigators must obtain funding and align themselves with a multidisciplinary team of physicians, nurses, and scientists. Each of these tasks can be daunting for the novice researcher. Even for the best researchers, the majority of the drugs that are developed in the laboratory do not make it to human trials for testing. The reasons for that include a lack of funding or a lack of researchers to carry out the necessary experiments.

Dr Lederman provides a comprehensive review of the clinical trials that feature one of the newest anti-MM agents that has successfully transitioned from the laboratory to the bedside—carfilzomib (Kyprolis). Carfilzomib is a proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects. In July 2012, carfilzomib was approved in the United States for the treatment of relapsed and refractory MM. Despite only having phase 2, nonrandomized data, the US Food and Drug Administration (FDA) recognized the need for patients with MM to have access to all drugs that may provide some benefit. In the PX-171-003-A1 clinical trial, carfilzomib has demonstrated an acceptable safety and efficacy profile in patients with relapsed and/or refractory MM.

Carfilzomib and bortezomib (Velcade) belong to the drug class of proteasome inhibitors. Proteasomes are important components of cellular degradation, and proteasome inhibitors prevent the proteasome from functioning properly and produce conflicting regulatory signals so that the myeloma cells cannot survive. Carfilzomib selectively and irreversibly inhibits the chymotrypsin-like activities of proteasomes via a binding mechanism that is distinct from that of bortezomib. The different mechanisms of the proteasome inhibition of carfilzomib and bortezomib are critical, because patients with MM who have not responded (or have stopped responding) to bortezomib will now have another treatment option with carfilzomib.1

According to the FDA indication, carfilzomib should be given to patients for the treatment of MM if the patient has received at least 2 previous therapies (including bortezomib and an immunomodulatory drug [IMiD], such as lenalidomide or thalidomide), with demonstrated disease progression on or within 60 days of completion of the last therapy. The starting dose of carfilzomib is 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle administered over a 2- to 10-minute period. The dose should be escalated to 27 mg/m2 after the first cycle of therapy if no significant side effects—such as fatigue, cardiopulmonary, or infusion reactions—occur. Carfilzomib, when given according to the FDA indication, can be very effective in patients with previously treated MM.1

Providers should be aware of key considerations when patients begin carfilzomib therapy. In <1% of patients in a phase 2 clinical trial, tumor lysis syndrome occurred. Therefore, oral allopurinol should be given to patients with a high tumor burden. Infusion reactions were rare in the phase 2 registration trial. To minimize the risk of infusion reactions, dexamethasone 4 mg orally or intravenously should be given during the first 2 cycles of carfilzomib administration. Finally, patients with a history of herpes zoster infection should receive concomitant antiviral medications.1

Additional trials in patients with newly diagnosed and relapsed and/or refractory MM are necessary to clarify the role of carfilzomib in MM. It remains unclear in which patient population (newly diagnosed or relapsed and/or refractory MM), and with which drugs carfilz­omib will be safe and effective to use. Dr Lederman provides an excellent overview of some of the trials that are currently under way in patients with newly diagnosed and relapsed and/or refractory MM.

Many oral and poster presentations featured carfilz­omib at the 2012 meeting of the American Society of Hematology. Maturing safety data from the earliest carfilzomib trials were presented in an effort to provide insight into cardiac and pulmonary adverse events (AEs). As was discussed in a poster by Lonial and colleagues, in one analysis of 526 patients with relapsed and/or refractory MM in 4 phase 2 clinical trials of carfilzomib, the rates of cardiac and pulmonary events were considered to be comparable to the rates reported for patients with relapsed and/or refractory MM.2 In addition, Siegel and colleagues presented long-term data that highlighted the safety and tolerability of carfilzomib.3 As carfilzomib is being studied in patients with newly diagnosed MM, it is encouraging to see the long-term tolerability of carfilzomib reported.

Some exciting trials were presented in which carfilz­omib was combined with an IMiD. Preliminary data from 2 clinical trials in patients with newly diagnosed MM involve the regimen of carfilzomib, lenalidomide, and dexamethasone (CRd),4 and cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE).5 The CRd and CYCLONE trials use agents that are already available and approved by the FDA for use in MM. Using carfilzomib in combination with other agents, especially FDA-approved agents, provides an opportunity to optimize disease control. In the CRd and CYCLONE trials, improved responses to treatment were seen with a longer duration of therapy.

The side effects of the CRd and CYCLONE regimens were similar to many anti-MM therapies, although the incidence of elevated liver enzymes, fatigue, dyspnea, and arrhythmias seen in CYCLONE was possibly or probably related to the higher dose of carfilzomib (20/45 mg/m2). Therefore, the maximum tolerated dose in the next cohort of the CYCLONE study will be 20/36 mg/m2. It is also important to note the low incidence of moderate-to-severe peripheral neuropathy. The low evidence of neurotoxicity allows the provider to combine carfilz­omib with thalidomide, as in the CYCLONE study.5

The time of infusion for carfilzomib was the topic of 2 presentations. In the phase 1b clinical trial presented by Badros and collegues, the carfilzomib dose of 20/56 mg/m2, when given in combination with low-dose dexamethasone, was at least as well tolerated and effective as single-agent carfilzomib.6 These study results were consistent with a phase 2 clinical trial presented by Lendvai and colleagues, in which an increased infusion time allowed a higher dose of carfilzomib to be administered.7 The 2 study results are pertinent to providers, because it is a major goal of treatment to minimize AEs and enhance tolerance to the drug. Further evidence that the longer infusion time can improve tolerance may change the way we administer carfilzomib in the future.
Carfilzomib is being studied in combination with new drugs, such as panobinostat, pomalidomide, and the novel kinesin spindle protein inhibitor ARRY-520.8-10 In each of the early-phase trials, the maximum tolerated dose of the combinations and safety are being determined. Although more patients are needed to determine the safety, efficacy, and tolerability profiles of the combinations, the preliminary results are promising.

Conclusion

The accelerated FDA approval of carfilzomib is a benefit to patients who have exhausted many options to treat their MM. At this time, carfilzomib should only be given to patients who have relapsed and refractory MM unless they are enrolled in a clinical trial. We anxiously wait for the safety and efficacy data from previous and ongoing clinical trials to mature. Those results will shed light on the best way to use these drugs and in which combination for optimal benefit.

Author Disclosure Statement

Ms Faiman is on the Speakers’ Bureau and a Consultant of Celgene, Millennium Pharmaceuticals, and Onyx Pharmaceuticals.

References

1. Kyprolis (carfilzomib) for Injection. Prescribing Information. South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

2. Lonial S, Niesvizky R, McCulloch L, et al. Cardiac and pulmonary safety profile of single-agent carfilzomib from four phase 2 studies in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4037.

3. Siegel DS, Wang M, Martin T, et al. A phase 2 study of prolonged carfilzomib therapy in patients with multiple myeloma previously enrolled in carfilzomib phase 1 and 2 clinical trials. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 2962.

4. Korde H, Landgren O. Phase II: carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 732.

5. Mikhael JR, Reeder CB, Libby EN III, et al. Results from the phase II dose expansion cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 445.

6. Badros A, Papadopoulos KP, Zojwalla N, et al. A phase 1b study of 30-minute infusion carfilzomib 20/45 and 20/56 mg/m2 plus 40 mg weekly dexamethasone in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4036.

7. Lendvai N, Landau H, Lesokhin A, et al. Phase II study of infusional carfilzomib in patients with relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 947.

8. Shah JJ, Thomas S, Weber D, et al. Phase 1/1b study of the efficacy and safety of the combination of panobinostat + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4081.

9. Shah JJ, Stadtmauer EA, Abonour R, et al. Multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 74.

10. Shah JJ, Thomas S, Weber D, et al. Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4082.