Treatment advances focus on the potential use of Bortezomib and Lenalidomide in the front-line setting to improve patients' response rates.
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Advances in the Treatment of Multiple Myeloma
Focus on Bortezomib and Lenalidomide
A Growing Body of Evidence Suggests Efficacy in the Front-Line Setting
Both bortezomib (Velcade) and lenalidomide (Revlimid) are FDA-approved treatments for use in patients with multiple myeloma (MM) who have received at least one year of prior therapy. Lenalidomide is approved for use in combination with dexamethasone. Both agents—bortezomib with or without dexamethasone and lenalidomide with dexamethasone— are currently being investigated for use in the front-line setting, and a growing body of evidence suggests these agents can provide high response rates and consistently high rates of complete response (CR) in high-risk patients with no prior therapy.
Bortezomib is a 26S proteasome inhibitor. The 26S proteasome is a large protein complex that degrades ubiquinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. The mechanism of action of lenalidomide—a thalidomide analogue with antiangiogenic, immunomodulatory, and antineoplastic properties—is less well characterized.
Single-Agent Therapy With Bortezomib
In a Phase II study of bortezomib as a single agent in the front-line setting in patients eligible for stem-cell transplantation (SCT),1 the response rate was 40%, with a 10% complete and near-complete response (CR/nCR) rate. This is a considerable CR/nCR rate for a single-agent therapy in the front-line MM setting. Substantial single-agent activity was also demonstrated in patients with high-risk multiple myeloma (elevated b2-microglobulin, high plasma cell labeling index, or chromosome 13 deletion).2
Combination Therapy With Bortezomib Plus Dexamethasone
Combination therapy with bortezomib plus dexamethasone has been investigated as induction therapy in three studies.3—5 In a Phase II study conducted by the Intergroupe Francophone du Mye’lome (IFM), the combination of bortezomib plus dexamethasone in patients with newly diagnosed MM resulted in a response rate of 67%, including a 21% CR/ nCR rate, prior to SCT.3 Among patients who proceeded to SCT, the post-SCT response rate was 90%, with a 33% CR/nCR rate.
Substantial activity was also reported in another study—one in which patients with newly diagnosed MM and were deemed eligible for SCT received bortezomib alone initially, with dexamethasone added later if response was suboptimal.4 In this study, the response rate was 90%, with a 19% CR/nCR rate. Among patients who proceeded to SCT, the one-year overall survival (OS) rate was 100%.
Preliminary results from an IFM Phase III study5 of bortezomib plus dexamethasone versus vincristine, doxorubicin, and dexamethasone (VAD) as induction therapy prior to SCT showed a greater postinduction response rate (82% vs. 67%) and CR/nCR rate (20% vs. 9%) with bortezomib plus dexamethasone. In addition, among patients who underwent a single SCT, a greater proportion of those who had received induction with bortezomib plus dexamethasone achieved a very good partial response (VGPR) or better (78% vs. 55%), eliminating the need for a second SCT.
An Alternating Regimen of Bortezomib and Dexamethasone
Results of the first study in which bortezomib and dexamethasone were administered on an alternating basis were reported recently.6 Study enrollees were younger patients (<66 years of age) with newly diagnosed MM who were deemed eligible for SCT. The response rate was 82%, with 12% of patients achieving a CR and 10% achieving a VGPR. In general, response was rapid, with an 82% M-protein reduction achieved with the first 2 cycles.
Bortezomib in Combination with Other Antineoplastic Agents
A Phase I/II study of bortezomib in combination with melphalan and prednisone (MP) was conducted in patients >65 years of age who were eligible for SCT.7 Approximately 50% of the study enrollees were >75 years of age. The response rate was 89%, with a CR/nCR rate of 43%. At 16 months, the rates of progression-free survival (PFS), event-free survival (EFS), and OS were 91%, 83%, and 90%, respectively. Approximately one-half of the patients who achieved a CR were determined to have achieved immunophenotypic remission (i.e., here were no detectable myeloma cells by multiparametric flow assay). Based on these excellent results, the triple regimen is now being compared with MP in an international Phase III trial.
The combination of bortezomib, doxorubicin, and dexamethasone (PAD) has been investigated as induction therapy prior to SCT.8,9 The response rate to PAD was 95%, including a 29% CR/nCR rate, prior to SCT.8 Among patients who proceeded to SCT, the response rate remained at 95%, but the CR/ nCR rate increased to 57%.8 Similar results were obtained with a reduced-dose PAD regimen. 9 An international Phase III trial is currently being conducted to compare PAD with VAD as induction therapy prior to SCT in patients with newly diagnosed MM.
In a study evaluating PAD with liposomal doxorubicin instead of conventional doxorubicin, the response rate was 81%, with a CR/nCR rate of 29%.10 In a study of bortezomib plus pegylated liposomal doxorubicin, the response rate was 80%, with a CR/nCR rate of 13%.11
Bortezomib has also been studied in combination with thalidomide and dexamethasone (VDT) as induction therapy prior to SCT.12 The response rate was 92%, and response was achieved rapidly. A Phase I study evaluated VDT in combination with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as induction therapy prior to SCT.13 After just two cycles, 83% of patients exhibited a partial response (PR) or better.
Combination Therapy With Lenalidomide Plus Dexamethasone
The combination of lenalidomide plus dexamethasone (Rev/Dex) as initial therapy of MM was evaluated in a Phase II trial.14 Objective response was defined as a decrease in serum monoclonal protein level by ≥50% and a decrease in urine M protein level by at ≥90% or to a level less than 200 mg/24 hours. Ninety-one percent of patients achieved an objective response, including a CR in 6% and a VGPR or nCR in 32%. Based on these results, two randomized, Phase III trials are currently evaluating the combination of lenalidomide plus dexamethasone as front-line therapy in patients with newly diagnosed MM.
Lenalidomide is also being studied in combination with MP in elderly patients with newly diagnosed multiple myeloma. Preliminary results show that treatment with this regimen results in a response rate of 85% after a median of seven treatment cycles, including a 17% rate of CR/nCR.15
As the results of numerous clinical trials have demonstrated, both bortezomib and lenalidomide, in the front-line setting, have the potential to substantially improve response rates in patients with MM. It will be interesting to see whether the promising results observed in trials to date are maintained in Phase III trials that are currently ongoing. If they are, it may be time for a paradigm shiin the way we approach induction therapy in patients with MM, particularly those with high-risk disease.
1. Anderson K, Richardson P, Chanan-Khan A, et al: Single-agent bortezomib in previously untreated multiple
J Clin Oncol
myeloma: Results of a phase II multicenter study. 2006;24:423s. Abstract.
2. Dispenzieri A, Blood E, Vesole D, et al: A phase II study of PS-341 for patients with high-risk, newly diagnosed
multiple myeloma: A trial of the Eastern Cooperative Oncology Group (E2A02). 2005;106:715a. Abstract.
3. Harousseau J-L, Attal M, Leleu X, et al: Bortezomib plus dexamethasone as induction treatment prior to autologous
stem cell transplantation in patients with newly diagnosed multiple myeloma: Results of an IFM phase II study.
4. Jagannath S, Durie B, Wolf J, et al: Bortezomib therapy alone and in combination with dexamethasone for patients
with previously untreated multiple myeloma. 2005;106:231a. Abstract.
5. Harousseau J-L, Marit G, Caillot D, et al: VELCADE/ dexamethasone (Vel/Dex) versus VAD as induction treatment
prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): An interim
analysis of the IFM 2005-01 randomized multicenter phase III trial. 2006;108:21a. Abstract.
6. Rosiñol L, Oriol A, Mateos A, et al: Final results of a phase II PETHEMA trial of alternating bortezomib and
dexamethasone as induction regimen prior autologous stem cell transplantation (ASCT) in younger patients with
J Clin Oncol
multiple myeloma (MM): Efficacy and clinical implications of tumor response. 2007;25(suppl):8024.
7. Mateos MV, Hernández JM, Hernández MT, et al: Bortezomib plus melphalan and prednisone in elderly untreated
patients with multiple myeloma: Results of a multicenter phase 1/2 study. 2006;108:2165-2172.
8. Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and
Br J Haematol
dexamethasone) for previously untreated patients with multiple myeloma. 2005;129:755-762.
9. Popat R, Oakervee HE, Curry N, et al: Reduced dose PAD combination therapy (PS-341/bortezomib, Adriamycin
and dexamethasone) for previously untreated patients with multiple myeloma. 2005;106:717a. Abstract.
10. Friedman J, Al-Zoubi A, Kaminski M, et al: A new model predicting at least a very good partial response in patients
with multiple myeloma after 2 cycles of velcade-based therapy. 2006;91:273. Abstract.
11. Orlowski RZ, Peterson BL, Caligiuri MA, et al: Bortezomib and pegylated liposomal doxorubicin as initial therapy
for adult patients with symptomatic multiple myeloma: CALGB Study 10301. 2005;90:151. Abstract.
12. Wang M, Delasalle K, Giralt S, et al: Rapid control of previously untreated multiple myeloma with bortezomib-
thalidomide-dexamethasone followed by early intensive therapy. 2005;106:231a. Abstract.
13. Badros A, Goloubeva O, Fenton R, et al: Phase I trial of first-line bortezomib/thalidomide plus chemotherapy for
Clin Lymphoma Myeloma
induction and stem cell mobilization in patients with multiple myeloma. 2006;7:210-216.
14. Rajkumar SV, Hayman SR, Lacy MQ, et al: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex)
for newly diagnosed myeloma. 2005;106:4050-4053.
15. Palumbo A, Falco P, Benevolo G, et al: Oral lenalidomide plus melphalan and prednisone (R-MP) for newly
J Clin Oncol
diagnosed multiple myeloma. 2006;24:426s. Abstract.