Our better understanding of the complex interaction of multiple myeloma (MM) cells with their bone marrow microenvironment and the signaling pathways that are dysregulated in this process has resulted in a dramatic increase in the therapeutic agents available for this disease. A number of these new agents have demonstrated significant activity in patients with MM. Over the past 5 years, three drugs have received approval from the US Food and Drug Administration for therapy in MM—bortezomib, thalidomide, and lenalidomide. To date, the choice of therapy for MM is not individualized according to the biologic characteristics of the disease, but future studies should enable us to identify patients who may benefit most from certain therapeutic interventions, and thus develop individualized therapy for MM. In this review, we will present some of the treatment algorithms currently developed for patients with MM and focus on established advances in therapy, specifically with thalidomide, bortezomib, and lenalidomide. We will also discuss some of the emerging novel therapeutic agents showing promise in phase I/II clinical trials in MM.
This article is a review of Novel Therapeutic Avenues in Myeloma: Changing the Treatment Paradigm
The past decade has witnessed the most dramatic improvement in the treatment of multiple myeloma since the introduction of melphalan (Alkeran) and prednisone in the 1960s and high-dose therapy in the 1980s. There has been a paradigm shift in the way we manage every aspect of the disease, from diagnosis and prognosis to treatment. Introduction of the free light chain assay as well as sensitive molecular and flow-based techniques have enabled more sensitive and specific estimates of tumor burden for both diagnosis and treatment monitoring.[2,3] The International Staging System has provided us with a simple but powerful method of determining prognosis and will allow us to tailor therapy in the future.
One could argue that the most critical development in the past decade has been an understanding of the genetic heterogeneity underlying this disease and its prognostic implications, which in turn resulted from widespread use of fluorescence in situ hybridization (FISH) techniques. Most importantly, therapeutic advances in myeloma have kept pace with developments in other areas and have led to risk-adapted treatment strategies for myeloma, thereby improving outcome for patients with myeloma.
A Series of Therapeutic Advances
In this issue, Ghobrial et al have provided a succinct review of the recent developments in the therapeutic arena for this disease. The current revolution in therapeutic advances in myeloma started with the introduction of thalidomide (Thalomid), guided by knowledge of the antiangiogenic properties of thalidomide and the recognition of relevance of bone marrow angiogenesis in myeloma.[7,8] This eventually led to large phase III trials of thalidomide and dexamethasone in the setting of relapsed as well as newly diagnosed myeloma and its approval for use in this disease.
This was followed by the introduction of the proteasome inhibitor bortezomib (Velcade), which has shown remarkable efficacy in the treatment of myeloma, both relapsed refractory and newly diagnosed disease. The next major improvement came in the form of the immunomodulatory drug lenalidomide (Revlimid), which, in combination with low doses of dexamethasone, is highly efficacious and has led to an unprecedented decrease in early deaths after diagnosis.
The authors have reviewed the various classes of novel drugs that are being evaluated in the setting of myeloma based on their mechanisms as well as the current understanding of disease biology. This impressive lineup of targeted therapies predicts for a brighter future for patients with this currently incurable malignancy.
-Shaji Kumar, MD
-Robert A. Kyle, MD
1. Rajkumar SV, Kyle RA: Multiple myeloma: Diagnosis and treatment. Mayo Clin Proc 80:1371-1382, 2005.
2. Katzmann JA, Abraham RS, Dispenzieri A, et al: Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem 51:878-881, 2005.
3. Sarasquete ME, Garcia-Sanz R, Gonzalez D, et al: Minimal residual disease monitoring in multiple myeloma: A comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. Haematologica 90:1365-1372, 2005.
4. Greipp PR, San Miguel J, Durie BG, et al: International staging system for multiple myeloma. J Clin Oncol 23:3412-3420, 2005.
5. Fonseca R, Barlogie B, Bataille R, et al: Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res 64:1546-1558, 2004.
6. Dispenzieri A, Rajkumar SV, Gertz MA, et al: Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): Consensus statement. Mayo Clin Proc 82:323-341, 2007.
7. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.
8. Rajkumar SV, Leong T, Roche PC, et al: Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6:3111-3116, 2000.
9. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005.
10. Rajkumar SV, Hayman SR, Lacy MQ, et al: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106:4050-4053, 2005.