Mechanisms of Action

Thalidomide influences the production of and cellular effects of inflammatory cytokines, particularly those involved in  angiogenesis. It has also been shown to activate cytotoxic T-lymphocytes, a process involving the release of interleukin-2 (IL-2) and  interferon (IFN)-γ. Thalidomide enhances IL-4 and IL-5 production and downregulates IL-12 production, effecting a shift in cytokine profile which is generally considered favorable in the treatment of cancer. Thalidomide may also have direct effects on the growth and survival of malignant cells; e.g., it inhibits the activity of  Cyclooxygenase-2 via inhibition of  nuclear factor κ-B (NF-κB) activity. IMiDs demonstrate a similar range of biological activities to thalidomide, with significantly greater potency in certain activities. For example, CC-4047 exhibits a 20,000-fold higher potency than thalidomide at inhibiting  tumor necrosis factor (TNF)-α production. Several mechanisms of action are shown in Fig. 2, which lead to alterations in the interplay between  multiple myeloma (MM) cells and the bone marrow environment.

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Multiple Myeloma

Early studies using thalidomide in patients with relapsed multiple myeloma described responses in around half of the patients treated, although typically with a duration of less than 12 months. Initial attempts to achieve high target doses (up to 800 mg/day) resulted in frequent dose-limiting toxicity. The reported side effects were dependent on dose and patient age. Somnolence and constipation were common, although manageable in most cases. Peripheral neuropathy occurred in up to a third of patients, particularly with long-term treatment, and it was disabling and irreversible in some cases. Particular concerns were raised concerning patients with multiple myeloma who may develop neuropathies for other reasons, thus increasing the severity of the symptom, e.g., concomitant drugs, amyloid deposition, or paraproteinemia. There was also a significant rate of venous thromboembolism (VTE) complicating treatment with thalidomide.

Only peer-reviewed published data regarding the efficacy of thalidomide in the treatment of multiple myeloma at various stages of the disease are presented.

Based on its activity in relapsed patients, TD has also been tested in patients newly diagnosed with multiple myeloma. The response rate is superior to that obtained using standard infusional chemotherapy with vincristine,  adriamycin, and dexamethasone (VAD) and offers the benefits of an oral regime versus one requiring the insertion of a central venous catheter. These advantages have led to TD being widely adopted as standard first-line therapy in younger patients prior to autologous stem cell transplant (ASCT), although whether the improved response rates will translate into an overall survival advantage is not yet known. In patients not suitable for ASCT, two recent studies have demonstrated that the addition of thalidomide to standard chemotherapy (melphalan and prednisolone) results in improvements in both response rate and survival (Table 1).

Thalidomide has also been investigated in patients with multiple myeloma as maintenance treatment following ASCT. In a single randomized study of patients treated with VAD chemotherapy followed by ASCT, the event free survival was significantly prolonged in patients receiving maintenance compared to those who did not, with a non-significant trend observed toward improved overall survival.

Two IMiDs are currently used in the treatment of multiple myeloma. A phase I study of CC-4047 demonstrated an encouraging response rate of 67% using the drug as a single agent, but the sample size was small. More data are available on the use of lenalidomide. Two phase I studies have demonstrated a maximum tolerated dose of 25–30 mg/day. Subsequent phase II trials have defined the optimal daily dosing schedule and described significant responses in 30–40% of patients, including those previously treated with thalidomide. In 2006, the Food and Drug Administration in the United States of America approved the use of lenalidomide as treatment for relapsed multiple myeloma.

Preclinical data suggesting synergy with steroids have also led to investigation of the efficacy of treatment with a combination of lenalidomide and dexamethasone (Len/Dex). Two large randomized multicenter phase III studies comparing Len/Dex to dexamethasone in relapsed or refractory disease have produced strikingly similar results. Interim analyses of both studies have demonstrated significantly improved response rates and median time to progression following combination therapy versus dexamethasone alone; both trials were therefore prematurely closed to recruitment. Since activity has also been demonstrated in  chronic lymphocytic leukemia and  non-Hodgkin lymphoma,  clinical trials of lenalidomide treatment in patients with these disorders are ongoing.

Myelodysplastic Syndromes (MDS)

There has been considerable international interest in the use of lenalidomide in the treatment of MDS. A phase I-II study in 43 patients defined the optimal dose as 10 mg/day and demonstrated responses in almost half of the patients studied, including a striking response in over 80% of patients with the 5q-syndrome. A subsequent multicenter phase II study of 148 patients, all of whom exhibited the 5q deletion, confirmed the results of the earlier trial. In this trial, 76% of patients responded to lenalidomide treatment, 67% achieved durable transfusion independence (median duration not reached at 2 years), and almost half of all patients attained cytogenetic remission. A second phase II study investigated the use of lenalidomide in 215 patients with low-risk MDS without 5q deletions, of whom 44% responded to treatment and 26% became transfusion independent, although the duration of response was less than that reported in the study in patients with 5q deletions. The results of these studies led the Food and Drug Administration in the United States of America to approve the use of lenalidomide as a treatment for anemia in patients with MDS exhibiting a 5q deletion. The optimal duration of treatment is not currently known.

Solid Malignancies

When compared to the use of thalidomide in the treatment of multiple myeloma, the role of thalidomide in the treatment of solid malignancies is less clear, particularly in view of the somnolence, constipation, VTE, peripheral neuropathy, and fatigue associated with treatment. Whereas therapeutic doses of 50–400 mg/day orally (2–8 mg/kg/day) are currently used for dermatologic and inflammatory diseases, oncological investigators have generally used 100–800 mg/day either as single-agent therapy or in combination with cytotoxic chemotherapy (e.g., carboplatin ( Platinum Drugs), docetaxel ( Taxotere) or irinotecan ( Topoisomerase enzymes as drug targets), or cytokines such as  interferon-α. Thalidomide at a dose of 400 mg/m²/day can be safely administered to children with solid tumors in combination with carboplatin.

Thalidomide (100–600 mg/day) has been studied in patients with a variety of solid tumors. In phase II studies, responses have been observed in patients with glioma, metastatic melanoma, pancreatic cancer, Kaposi’s sarcoma, malignant melanoma, and prostate cancer. Results for patients with renal-cell carcinoma were considered particularly promising, leading to a randomized phase II study in 60 patients with this condition. Patients received either thalidomide or medroxyprogesterone as monotherapy. There was no difference in overall survival between the two groups, leading the investigators to conclude that the risk/benefit ratio did not favor the use of thalidomide as monotherapy in patients with  renal carcinoma. Similarly, phase II studies of the combination of thalidomide and interferon-α have shown minimal efficacy and unacceptable toxicity in patients with metastatic renal cell carcinoma.

Early data would suggest that the palliative response to thalidomide is separate from the objective radiological response and that it may occur earlier. The most promising palliative results have been reported in Kaposi’s sarcoma, malignant melanoma, and prostate cancer, especially when thalidomide is combined with chemotherapy. In a study of 40 heavily pre-treated patients with ovarian cancer, thalidomide appeared to be comparable in symptom response and quality of life to single-agent intravenous chemotherapy.

Of particular note in the palliative treatment of solid malignancies is the potential for thalidomide to treat  cancer cachexia. The postulated mechanism of action is compatible with the probable role of TNF, INF-γ, and IL-6 in the etiology of this debilitating symptom. Randomized, placebo-controlled trials of thalidomide in weight-losing patients with advanced solid malignancies, such as pancreatic cancer, have demonstrated weight gain and improvements in physical functioning.

Future Directions

When one compares IMiDs to thalidomide treatment, in addition to their increased potency in inhibiting the production of cytokines such as TNF-α, one of the most attractive features of the IMiDs is the lack of neurotoxicity caused by drug treatment. Although their safety in long-term administration (i.e., many years) remains to be demonstrated at the phase IV (post-licensing) level of clinical trial development, the toxicity profile of lenalidomide appears compatible with the concept of maintenance treatment for diseases in which its anti-inflammatory properties, anti-angiogenic activity, apoptotic producing activity, or inhibition of  T-cell response would benefit from chronic exposure to the drug. In particular, the ability of IMiDs to inhibit T-regulatory cells (as well as being co-stimulatory) may represent an ideal property for enhancing immunotherapeutic and cancer vaccine approaches to the treatment or prevention of cancer.

Although a large randomized study which was terminated prematurely did not show any significant impact of lenalidomide treatment on overall survival in patients with stage IV malignant melanoma, several anecdotal responses have been observed in this disease. Patients with malignant melanoma in whom objective responses were demonstrated in a phase II study of lenalidomide treatment, who had also been exposed to melanoma vaccines previously, have led to the suggestion that increased responses may be associated with a reduction in T-cell regulatory activity and co-stimulatory abilities. This highlights the possibility that this class of drugs may work even better in combination with other modalities and may be synergistic with cancer vaccines.

A major target for drug development to inhibit the growth and spread of cancer is angiogenesis. Several  small molecule drugs which inhibit multiple tyrosine kinase pathways and angiogenesis are currently in clinical trials. IMiDs inhibit angiogenesis but it is not currently known if they also inhibit  Receptor tyrosine kinase pathways. Indeed, the other immunomodulatory and cytokine modulating properties of IMiDs may in fact be more synergistic in the inhibition of angiogenesis than in the inhibition of multiple tyrosine kinases. Since such drugs are likely to be taken for many years by patients with cancer in order to maintain response, lack of toxicity and convenience of oral dosing are important factors.