Data evaluating a combination therapy of lenalidomide (Revlimid?, Celgene International S?rl), an oral immunomodulatory drug or IMiD, and dexamethasone, a corticosteroid, in patients with high-risk asymptomatic smoldering or asymptomatic multiple myeloma were presented during the 52nd American Society of Hematology Annual Meeting in Orlando, Florida from December 4-7, 2010. The study reported that the combination therapy of lenalidomide and dexamethasone prolonged time to progression.

Multiple myeloma (also known as myeloma or plasma cell myeloma) is a cancer of the blood in which malignant plasma cells are overproduced in the bone marrow. Plasma cells are white blood cells that help produce antibodies called immunoglobulins that fight infection and disease. However, most patients with multiple myeloma have cells that produce a form of immunoglobulin called paraprotein (or M protein) that does not benefit the body. In addition, the malignant plasma cells replace normal plasma cells and other white blood cells important to the immune system. Multiple myeloma cells can also attach to other tissues of the body, such as bone, and produce tumors. Multiple myeloma is the second most common hematological malignancy, with an incidence of 6/100 000 in Europe. The cause of the disease remains unknown.

Patients with smoldering multiple myeloma, a slow-growing form of multiple myeloma, have elevated levels of malignant plasma cells in the bone marrow that produce M protein, however they do not have the clinical manifestations or symptoms of multiple myeloma. Smoldering multiple myeloma accounts for approximately 10% of all myelomas, and the median time to progression to a symptomatic multiple myeloma ranges from 2 to 3 years. The main factors for progression are the plasma cell mass (M-protein size and percent of bone marrow plasma cells), the spinal MRI pattern, the plasma cell proliferative index, and the variant of smoldering or asymptomatic multiple myeloma (?evolving? vs ?nonevolving?). Most patients who develop smoldering multiple myeloma ultimately need treatment for myeloma symptoms. Potential symptoms include bone pain, anemia and bone lesions (cellular abnormalities).

Patients with smoldering or asymptomatic multiple myeloma may initially require nothing more than periodic monitoring of their condition. According to specialists at the MD Anderson Cancer Center these patients may receive a follow-up examination every three to six months.

The Phase III, randomised, multicenter, open-label study evaluated whether early treatment with lenalidomide and dexamethasone in high-risk asymptomatic smoldering multiple myeloma patients prolonged time to progression to symptomatic disease compared to patients that did not receive treatment and were just observed.

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Patients were treated with lenalidomide (25mg daily on days 1-21 of 28-day cycle) and dexamethasone (20mg on days 1-4, 12-15 of 28-day cycle) for nine four-week cycles and then continued treatment with a lower dose of lenalidomide (10mg daily on days 1-21 of 28-day cycle) until progression. The results showed an overall response rate of 75% (43/57), including 51% (29/57) PR, 12% (7/57) VGPR, 5% (3/57) CR and 7% (4/57) stringent CR (sCR). For the patients who completed the initial nine treatment cycles, the overall response rate was 91% (30/33), including 15% (5/33) VGPR, 9% (3/33) CR and 9% (3/33) sCR. For patients who then went on to receive continuous lenalidomide treatment, the sCR rate increased to 16% (5/32).

After a median follow-up of 16 months, disease progression was observed in 3% (4/118) of patients treated with lenalidomide and dexamethasone, while 18% (21/118) of patients progressed to active myeloma in the observation arm. Eleven out of these 21 patients also developed bone lesions due to active myeloma.

The median time to symptomatic myeloma was 25 months in patients in the observation arm and has not yet been reached for patients who received lenalidomide and dexamethasone (P<0.0001).

No Grade 4 adverse events were reported. Grade 3 adverse events included asthenia (7% 4/57), diarrhea (4% 2/57), infection (4% 2/57), anaemia (2% 1/57) and skin rash (2% 1/57). One patient discontinued treatment because of adverse events. Dose adjustments were made as necessary to manage toxicity.

In the countries of the European Community and the Middle-East , Asia and Australia and New Zealand, lenalidomide, in combination with dexamethasone, is indicated for the treatment of multiple myeloma in patients who have received at least one prior therapy. In the US the agent is approved for the treatment of multiple myeloma and myelodysplastic syndromes and transfusion-dependent anaemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Lenalidomide is not approved as a treatment for high-risk smoldering multiple myeloma.

For more information:
– Alexanian R, Barlogie B, Dixon D. Prognosis of asymptomatic multiple myeloma. Arch Intern Med. 1988 Sep;148(9):1963-5.
– Dimopoulos MA, Moulopoulos A, Smith T, Delasalle KB, Alexanian R. Risk of disease progression in asymptomatic multiple myeloma. Am J Med. 1993 Jan;94(1):57-61.
– Weber DM, Dimopoulos MA, Moulopoulos LA, Delasalle KB, Smith T, Alexanian R. Prognostic features of asymptomatic multiple myeloma. Br J Haematol. 1997 Jun;97(4):810-4
– Harousseau JL. Clinical management of myeloma–state of the art. Cancer Treat Rev. 2010 May;36 Suppl 2:S1-2
– Kumar S. Multiple myeloma – current issues and controversies. Cancer Treat Rev. 2010 May;36 Suppl 2:S3-11.
– Summary of Product Characteristics (SPC | EMEA)
– Full Prescribing Information (FDA)

Clinical Trials:
– Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma (NCT01169337)
– QUIREDEX: Revlimid (Lenalidomide) and Dexamethasone (ReDex) Treatment Versus Observation in Patients With Smoldering Multiple Myeloma With High Risk of Progression (NCT00480363)

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