Carfilzomib: A New Agent in the Treatment Armamentarium for Multiple Myeloma

Introduction

A 1998 study by the Myeloma Trialists’ Collaborative Group compared conventional chemotherapy (CCT) with melphalan plus prednisone (MP)—the previous standard of care for the treatment of patients with multiple myeloma (MM).¹ This analysis included 6633 patients from 27 randomized trials. Researchers found no difference in mortality between treatment with CCT and treatment with MP.¹ Since this analysis was reported nearly 14 years ago, the landscape of MM has changed dramatically—and for the better. It has been well described by many authors that median overall survival (OS) rates among patients with MM are on the rise.² This is due, in part, to improved treatment and supportive care, as well as an enhanced understanding of the biology of the disease. Insight into the ways in which myeloma cells thrive has given researchers the ability to develop novel, targeted agents that are now regarded as the new standard of care for the treatment of MM. These include the first-generation immunomodulatory drug, thalidomide, its analog, lenalidomide, and the first-in-class proteasome inhibitor, bortezomib.

Novel Targeted Agents for Multiple Myeloma

The antitumor activity of thalidomide in patients with relapsed and/or refractory MM was first reported by Singhal and colleagues in 1999.³ When individuals who had been previously treated with high-dose chemotherapy received this drug, 8 of the 84 patients treated experienced a ≥90% reduction in serum or urine levels of paraprotein.³ In 2006, the US Food and Drug Administration (FDA) granted approval for thalidomide in combination with dexamethasone for newly diagnosed MM patients.⁴ Over the past several years, thalidomide has become an important drug in the treatment armamentarium for myeloma, and is used in both the frontline and relapsed and/or refractory settings.

Bortezomib was the next targeted agent to demonstrate efficacy in myeloma. The international, randomized, phase 3 APEX trial led to the approval of bortezomib in 2005 for the treatment of patients with MM who had received at least 1 prior therapy.⁵ Patients who received bortezomib in this study had a significantly longer median time to progression (TTP) than those who received dexamethasone (6.2 vs 3.5 months, respectively; P <.001), as well as higher response rates (38% vs 18%, respectively; P <.001) and improved survival (1-year survival rate: 80% vs 66%, respectively; P =.003).⁵ Subsequently, bortezomib has also received FDA approval as an initial treatment for patients with MM, based on results of the pivotal phase 3 VISTA trial.⁶

Dimopoulos and colleagues published results of studies assessing OS among heavily pretreated patients with relapsed and/or refractory MM who received lenalidomide plus dexamethasone or dexamethasone plus placebo.⁷ The MM-009 and MM-010 studies were 2 large, placebo-controlled, randomized, phase 3 trials that included more than 704 patients. Individuals treated with lenalidomide plus dexamethasone exhibited a significantly improved median TTP compared with those who were treated with dexamethasone alone (13.4 vs 4.6 months, respectively; P <.001).⁷ In addition, lenalidomide plus dexamethasone versus dexamethasone plus placebo significantly improved overall response rates (60.6% vs 21.9%, respectively; P <.001) and complete response rates (15.0% vs 2.0%, respectively; P <.001).⁷ Since 2006, lenalidomide has been FDA-approved for use in combination with dexamethasone for patients with MM who have received at least 1 prior therapy.⁸

Figure

Carfilzomib, a next-generation proteasome inhibitor, is showing encouraging efficacy as single-agent treatment in patients with relapsed and/or refractory MM.^9,10 The activity of this agent also appears to be enhanced when it is combined with antimyeloma drugs such as lenalidomide and dexamethasone.^11,12 The safety profile of carfilzomib is impressive, especially the low rates of neuropathy reported in recent trials (Figure). Peripheral neuropathy (PN) is a challenging adverse event associated with several novel therapies for MM, and it can be especially problematic in the relapsed and/or refractory setting. From a nurse’s perspective, the ability to offer patients therapy that will not significantly increase the risk of PN is especially appealing, as it allows better quality of life and increases the possibility that they will remain on treatment.

Conclusion

Over the past 12 years, I have had the opportunity to participate in the care of numerous patients with MM and have acquired firsthand knowledge of the benefits of novel agents. Through the context of clinical trials, many established and investigational agents have been evaluated for the disease. It is gratifying to know that an agent such as carfilzomib may soon be available for patients whose myeloma continues to progress despite prior therapy. We continue to welcome research and encourage clinical trial participation to develop additional therapeutic strategies that will benefit patients in the future.

References

1. Myeloma Trialists’ Collaborative Group. Combination therapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998;16:3832-3842.
2. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.
3. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565-1571.
4. Thalomid [package insert]. Summit, NJ: Celgene Corporation; August 2010.
5. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110:3557-3560.
6. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.
7. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23:2147-2152.
8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; October 2010.
9. Singhal S, Siegel DS, Martin T, et al. Integrated safety from phase 2 studies of monotherapy carfilzomib in patients with relapsed and refractory multiple myeloma (MM): an updated analysis. Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 1876.
10. Vij R, Kaufman JL, Jakubowiak AJ, et al. Final results from the bortezomibnaïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 813.
11. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial. Blood (ASH Annual Meeting Abstracts). 2010;116: Abstract 862.
12. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in multiple myeloma (MM). Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 631.