Noopur Raje, MD, Massachusetts General Hospital Cancer Center; Division of Hematology and Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA

Although multiple myeloma (MM) remains an incurable bone marrow cancer, survival rates have improved markedly over the past decade. An understanding of MM pathobiology (Figure 1) and improvement in stem cell transplantation, better supportive care, and novel therapies with higher efficacy and lower toxicity are all responsible for this improvement. The availability of a rich pipeline of novel agents undergoing early-phase clinical trials in MM is an exciting and active area of research.¹

Current treatment

Over the past several years, five therapeutic strategies have received US Food and Drug Administration (FDA) approval either as monotherapy or in combination for treating MM, with thalidomide (Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade) as important backbone drugs in these approaches. In the upfront setting, thalidomide with dexamethasone² and bortezomib in combination with melphalan and prednisone³ increased the overall response rate and significantly prolonged time to disease progression and are FDA approved. For treatment of relapsed MM, bortezomib alone⁴ and in combination with pegylated liposomal doxorubicin (Doxil),⁵ as well as lenalidomide/dexamethasone,⁶ have been approved. Results of a recent phase III randomized clinical trial suggest that lower doses of dexamethasone provide a survival advantage, at least in the upfront setting, mainly due to the increased toxicity of high doses of dexamethasone.⁷

The availability of these novel agents has not only provided us with several treatment options but has had an important impact on the overall survival of our patients. To improve upon current outcomes, optimal combinations of bortezomib, thalidomide, and lenalidomide are currently under evaluation in phase II/III clinical trials.

Novel approaches

The preceding review refers to recent data on pomalidomide, the newest immunomodulatory drug (IMiD) analog, which has shown single-agent activity in phase I studies and was subsequently tested in a phase II trial in combination with low-dose dexamethasone in patients with relapsed or refractory MM. Pomalidomide/dexamethasone was found to be highly active and well tolerated, providing a clinical benefit in 47% of patients and no grade 3 neuropathy. These findings have led to a large phase II study, which has completed accrual and is awaiting analysis.

Another promising agent discussed here is the novel proteasome inhibitor carfilzomib. Although bortezomib is an effective agent in MM, about 20% of newly diagnosed patients are resistant to bortezomib, and, ultimately, all patients relapse and develop resistance to the drug. Carfilzomib irreversibly blocks chymotrypsin-like activity and in phase I studies achieved more than 80% proteasome inhibition. Encouraging data presented at the 2010 annual meeting of the American Society of Hematology demonstrated that it was well tolerated and had an overall clinical benefit rate of 36% in relapsed/refractory MM.⁸ In the upfront setting, carfilzomib combined with lenalidomide led to a 100% response rate.⁹

This combination with low-dose dexamethasone is currently undergoing testing in a phase III registration trial. These data, therefore, provide important therapeutic options among the armamentarium of current and future antimyeloma therapies, helping transform MM into an even more chronic disease than it is today and ultimately leading to a cure.

References

1. Cirstea D, Vallet S, Raje N. Future novel single agent and combination therapies. Cancer J 2009;15:511-518.

2. Rajkumar SV, Rosinol L, Hussein M, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol 2008;26:2171-2177.

3. 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.

4. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-2498.

5. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007;25:3892-3901.

6. 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.

7. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29-37.

8. Siegel DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

9. 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 2010;116:862.

Dr. Raje can be reached at nraje@partners.org.