Managing Adverse Events of Multiple Myeloma and Anti–Multiple Myeloma Treatment: A Perspective on Carfilzomib

Multiple myeloma (MM) is a malignancy caused by the uncontrolled accumulation of clonal plasma cells, which leads to substantial immunosuppression and a variety of organ dysfunctions. It is the second most common hematologic malignancy, after non-Hodgkin lymphoma, and accounts for 1.3% of all new cancer cases and 1.8% of cancer deaths in the United States.[1] Advances in anti-MM treatment in the last decade, including the development of immunomodulatory drugs and proteasome inhibitors, have led to significant improvements in the duration of survival. Nearly all patients experience relapse, however, and disease progression is typically characterized by diminishing periods of remission with each successive treatment.

Patients with MM, particularly those with relapsed MM, can be challenging to treat owing to a number of patient- and disease-related factors, including that these patients are typically elderly and may present with a greater number of preexisting comorbid conditions, such as history of cardiac events, renal impairment, or cardiac risk factors.

In addition, the natural progression of the disease can result in a spectrum of end-organ damage, including severe hematologic complications as plasma cells replace bone marrow and kidney damage stemming from the deposition of myeloma monoclonal light chains in the kidney. Anti-MM agents themselves may also be associated with a range of toxicities, including hematologic, neuropathic, cardiac, pulmonary, and renal adverse events, although each agent may affect these systems to varying degrees. For example, peripheral neuropathy is one of the most serious adverse effects of thalidomide, bortezomib, and vincristine, while lenalidomide and pomalidomide are associated with lower rates and less severe cases of neuropathy.[2-4] Unlike thalidomide and bortezomib, lenalidomide and pomalidomide are excreted primarily through the kidneys; thus, dose modification is recommended for patients with renal impairment who are receiving lenalidomide.[5] Although ongoing studies are examining the use of pomalidomide in patients with severe renal impairment, it is recommended that patients with serum creatinine levels > 3 mg/dL avoid treatment with this agent.[3]

Because patients with MM typically undergo multiple lines of treatment, it is important to understand the safety profiles of these agents and how adverse events associated with their use may be best managed. Importantly, the development of treatment-related adverse events may necessitate dose reduction or treatment discontinuation, which can prevent a patient from deriving maximum benefit from anti-MM treatment. In addition, cumulative toxicities can also affect later lines of treatment and may inform present and future treatment choices for a patient.

Carfilzomib is a selective proteasome inhibitor that has been approved in the United States as a single agent for the treatment of patients with relapsed and refractory MM. In clinical studies, single-agent carfilzomib has been shown to produce robust and durable activity in heavily pretreated patients with relapsed and refractory MM,[6] and it has proved to be generally well tolerated.[6-10]

The safety of single-agent carfilzomib has been characterized recently in a cross-trial analysis of the four phase II trials (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005) that supported its approval by the US Food and Drug Administration. This analysis allows for a comprehensive examination of the treatment-emergent adverse events and safety profile associated with carfilzomib in more than 500 patients.[11]

Given the challenges inherent in treating patients with MM, the articles in this supplement review the safety profile of carfilzomib as defined in the cross-trial analysis and place the findings in the context of other currently approved agents. In addition, practical recommendations are provided for the management of common complications associated with the disease and its treatment. Dr. Martin reviews peripheral neuropathy, a frequent comorbidity of MM and toxicity associated with several anti-MM treatments. Dr. Nooka discusses the management of treatment-emergent hematologic adverse events, including thrombocytopenia, neutropenia, and anemia. Dr. Shah reviews the impact of MM on the kidney, including the use of agents that are cleared renally and those, such as carfilzomib, that are cleared extra-renally. Finally, Drs. Wang and Cheng discuss the incidence of cardiac and pulmonary adverse events associated with the administration of carfilzomib, and provide guidance on their management.

Together, this series of articles provides clinicians with a resource for the use of carfilzomib in the management of patients with MM.

Financial Disclosure: Dr. Siegel serves on the speakers bureaus and advisory boards of Onyx, Millennium, and Celgene.

Acknowledgment: Medical writing and editorial assistance was provided by BlueMomentum, a division of KnowledgePoint360 Group, San Bruno, California, and funded by Onyx Pharmaceuticals, Inc.

References:

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30.

2. Richardson PG, Delforge M, Beksac M, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia. 2012;26:595-608.

3. Pomalyst (pomalidomide) prescribing information. Summit, NJ: Celgene Corporation; 2013.

4. Vincasar PFS (vincristine sulfate) prescribing information. Sellersville, PA: Teva Pharmaceuticals USA; 2013.

5. Revlimid (lenalidomide) prescribing information. Summit, NJ: Celgene Corporation; 2013.

6. 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;120:2817-25.

7. Jagannath S, Vij R, Stewart AK, et al. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012;12:310-8.

8. Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012;119:5661-70.

9. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739-48.

10. Badros AZ, Vij R, Martin T, et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013;27:1707-14.

11. Siegel DS, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: Experience from 526 patients enrolled in 4 phase 2 clinical studies. Haematologica. 2013 Aug 9. [Epub ahead of print]