Incorporating Novel Agents into Upfront Myeloma Therapy

By Kenneth C. Anderson, MD

2008-11-01

Dr. Anderson disclosed that he receives research support from and consults for Millennium.

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;359:906-17.

Thalidomide (thal), lenalidomide, and bortezomib are novel agents that first demonstrated efficacy in treating relapsed and refractory multiple myeloma (MM), but they are now all being utilized as treatment for newly diagnosed disease. Importantly, they are included in the latest iteration of the NCCN guidelines, which have been adopted by CMS as parameters for compensation of care. Thal was first utilized as a single agent to treat relapsed, refractory MM and then combined with dexamethasone (dex) to achieve responses in relapsed MM that was refractory to thal or dex alone. Thal-dex combination therapy achieves increased response compared to dex in newly diagnosed transplant candidates1 and was FDA-approved as first-line therapy in 2006. Thal combined with melphalan and prednisone (MP) for the elderly non-transplant candidate with newly diagnosed MM is superior to MP (including patients >75 years old) and to melphalan 100mg/m2 x 2, each rescued with autologous peripheral blood stem cells.2,3

Lenalidomide-dex was FDA-approved as therapy for relapsed and refractory MM.4,5 As upfront therapy, lenalidomide-low-dose dex is superior to lenalidomide-high-dose dex based on prolonged survival, and allows for collection and transplantation of peripheral blood stem cells.6 Lenalidomide has been combined with MP in the newly diagnosed elderly patient and is superior to MP.7 In the newly diagnosed transplant candidates, bortezomib-dex combination achieves higher extent and frequency of response, both before and after high-dose melphalan, with 60 percent of patients achieving a very good partial response or better8 and therefore not candidates for a second autologous transplant. Thus, use of novel therapies as initial treatment is demonstrating great promise.

Bortezomib inhibits DNA damage repair and sensitizes or overcomes resistance to DNA-damaging agents.9 Combination bortezomib-doxil is superior to bortezomib,10 setting the stage for its FDA approval in relapsed MM. Most excitingly, San Miguel and colleagues have recently reported significantly increased overall and extent of response, as well as progression-free and overall survival, when newly diagnosed non-transplant candidates are treated with MP-bortezomib versus MP, providing the basis for its FDA approval to treat newly diagnosed MM. Of note, partial response or better and complete response were noted in 71 percent and 30 percent of patients, respectively, treated with MP-bortezomib versus 35 percent and 4 percent of patients, respectively, in the MP-treated cohort. This magnitude of response is remarkable, previously achievable only in the context of high-dose therapy. Importantly, this response extent and frequency advantage translated into prolonged duration of response and progression-free survival, as well as decreased death rate. Side-effect profile was as expected and not significantly different in the two arms. MP-bortezomib was superior to MP in patients with renal compromise and across all International Staging System groups. Importantly, high-risk cytogenetics, including t(4;14) or t(14;16) translocation, 17p deletion, or 13q deletion, did not affect response, time to progression, or survival achieved to MP-bortezomib.

Therefore, this study further validates the use of novel therapies as initial therapy for multiple myeloma, achieving unprecedented results. In the era of novel therapies, ongoing and future studies will define patient subgroups most likely to respond, durability of response, and the role of scientifically based combination therapies.

References

  1. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431-6.

  2. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367:825-31.

  3. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370:1209-18.

  4. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-42.

  5. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-32.

  6. Rajkumar SV, Jacobus S, Callander N, et al. Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly dianosed multiple myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008; 26:455s.

  7. Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007;25:4459-65.

  8. Harousseau J-L, Mathiot C, Attal M, et al. Velcade/dexamethasone versus VAD as induction treatment prior to autolotous stem cell transplantation in newly diagnosed multiple myeloma: updated results of the IFM 2005-01 trial. Blood. 2007;110:139a.

  9. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2003;101:2377-80.

  10. 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: 3892-901.

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