Myeloma therapy: the future is bright

Comment on Rajkumar et al, page 4050

In a phase 2 study of lenalidomide combined with dexamethasone as front-line therapy for multiple myeloma, Rajkumar and colleagues report an excellent rate of responses, including 38% complete remission or near complete remission.

Over the past decade, new insights into the biology of multiple myeloma have provided the framework for the development of novel therapies to reverse drug resistance and improve patient prognosis. In particular, recognition of the pivotal role of the bone marrow microenvironment in promoting myeloma cell growth, survival, drug resistance, and migration has allowed for identification of specific therapeutic strategies targeting myeloma-host stromal cells interactions, as well as the secretion of cytokines and their sequelae in the bone marrow milieu.¹  Examples of novel drugs that have quickly translated from the bench to the bedside include the first-in-class proteasome inhibitor bortezomib and immunomodulatory analogs of thalidomide, known as immunomodulatory drugs (IMiDs).

Thalidomide, an old drug with a tragic past due to its teratogenicity, has redeemed itself as the third noncross-resistant active antimyeloma agent and actually represents a new treatment paradigm for patients refractory to multiple prior therapies and with newly diagnosed disease.²  However, marked activity of thalidomide is limited by dose- and duration-related side effects, which include peripheral sensory neuropathy, sedation, constipation, and skin rashes. In addition, when used as front-line therapy in combination with dexamethasone or anthracyclines, thalidomide is associated with an increased risk of deep vein thrombosis, which requires prophylactic or therapeutic anticoagulation.^2,3 

The toxicity profile of thalidomide has prompted the search for more effective analogs with reduced toxicity. Based on promising preclinical data showing that the nonteratogenic IMiD lenalidomide (also known as CC-5013 or revlimid) is more potent than thalidomide in stimulating T-cell proliferation and increasing the production of interleukin-2 and interferon-γ, as well as at decreasing the secretion of tumor necrosis factor-α; phase 1, 2, and 3 clinical trials of this agent were performed in patients with advanced refractory or relapsed myeloma.^4,5  Favorable results of these studies ultimately led to incorporation of lenalidomide into front-line treatment strategies for multiple myeloma.

In this issue of Blood, Rajkumar and colleagues report on 34 previously untreated myeloma patients who were primarily treated with oral lenalidomide 25 mg/day for 21 days/month and oral dexamethasone 40 mg/day on days 1 to 4, 9 to 12, and 17 to 20, every month. Using the criteria of the European Group for Blood and Marrow Transplant, the overall rate of responses (partial and complete remissions) was 91%, including 38% of patients who achieved at least a near complete remission. Grades 3 to 4 side effects observed in more than 10% of patients included fatigue (15%) and neutropenia (12%). Toxicities commonly related to thalidomide were mild and well manageable; a single patient (3%) developed pulmonary embolism. Notably, lenalidomide was not toxic to hematopoietic stem cells that were adequately collected in a subgroup of patients who underwent this procedure. Although these results are exiciting, formal validation of the role of lenalidomide as primary therapy for multiple myeloma has yet to be established. Two large randomized studies currently under way in the United States will address this important issue, and their conclusions are eagerly awaited.

After more than 3 decades without new active agents to treat multiple myeloma, the future is bright. Over the past few years, 2 new classes of drugs with the ability to sensitize myeloma cells to chemotherapy and/or to overcome drug resistance have entered the clinical practice. Although the impact of these novel treatment strategies and their combination with old drugs on the ultimate outcome of myeloma patients is still undefined, targeted therapies have greatly expanded the armamentarium in the management of this still uncurable disease. The new millennium has been an encouraging time for patients with myeloma, but the best is still to come. ▪