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Several agents and molecules are being evaluated either as a single agent or in combination with traditional therapy in multiple myeloma. Thalidomide stands out as it is the only anti-cancer agent that is available which maintains the same high response rate noted in newly diagnosed as well as in the relapsed refractory multiple myeloma patients 1;2.
Thalidomide, also known as alpha-(N-phthalimido) glutarimide, consists of a two-ringed structure with an asymmetric carbon in the glutarimide ring. Thalidomide exists as an equal mixture of S- (-) and R- (+) enantiomers that interconvert rapidly under physiologic conditions. Thalidomide is sparingly soluble in water and ethanol, which to date has prevented the availability of an intravenous formulation 3. At physiologic pH, these isomers interconvert rapidly, making attempts at isolation of the dextro-form, in an effort to eliminate teratogenicity, unsuccessful. Thalidomide is poorly soluble in water, and thus no intravenous preparation is available. One of the unique chemical aspects of thalidomide is that the parent compound undergoes spontaneous hydrolysis in aqueous solution at pH 7•0. Thalidomide degradation results in more than 20 products, and its activity e.g., inhibition of micro-vessel formation or reduction of aortic endothelial cell proliferation—seems to depend on its metabolism 4. The active metabolite seems to be generated by cytochrome P450 2C19 (CYP2C19) isozyme-mediated oxidation of thalidomide. Whether the metabolism of thalidomide contributes specifically to its immunomodulatory activity, therefore, remains unclear 5. Thalidomide undergoes rapid pH¬ dependent hydrolysis in aqueous solution. Maximum serum concentration of a 200-mg dose of thalidomide is reached within a mean of 4 hours, and the drug undergoes spontaneous, non-enzymatic, hydrolytic cleavage to numerous metabolites, which are rapidly excreted in urine, whereas non-absorbed drug is excreted in feces 6. Mean terminal half-lives for a 200-mg dose range from 4 to 9 hours, whereas higher doses of 800 mg have a substantially longer terminal half-life of approximately 8 hours 7. Pharmacokinetics in renal and hepatic dysfunction is not well established; in patients with renal failure secondary to multiple myeloma however the practice continues to use similar dose levels as in patients with non impaired renal function.

Biology and Mechanism(S) of Action
Thalidomide and its class appear to have a broad spectrum of activities and may act as an anti-myeloma agent thorough several mechanisms 8. Thalidomide may have a direct effect on the multiple myeloma cell and/or BM stromal cell through free radical–mediated oxidative DNA damage may play a role in the teratogenicity of thalidomide 9. Another probable target for thalidomide is its ability to interfere with the adhesion of multiple myeloma cells to BM stromal cells which both triggers the secretion of cytokines that augment multiple myeloma cell growth and survival 10-12 as well as conferring drug resistance 13; Thalidomide modulates adhesive interactions 14, thereby, altering tumor cell growth, survival, and drug resistance. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor 2 (bFGF-2) are secreted by multiple myeloma and/or BM stromal cells and may play a role both in tumor cell growth and survival, as well as BM angiogenesis 15;16. The activity of thalidomide directly and/or indirectly could decrease the different angiogenic factors supporting the multiple myeloma environments. This multifaceted activity of thalidomide makes it an attractive agent to use as a single agent or in combination therapy in the treatment of a disease such as multiple myeloma that has a complex tumor micro-environment.

Thalidomide in Multiple Myeloma Therapy

Early studies in relapsed/ refractory disease:
Traditionally drug development starts with phase 1 design trials, however in the case of thalidomide and the treatment of multiple myeloma this was not the case. Thalidomide can inhibit angiogenesis and induce apoptosis of established neovasculature in experimental models 17;18. The bone marrows of multiple myeloma patients show prominent vascularization which correlates positively with high plasma-cell–labeling index disease activity and independently confers poor prognosis 15;19-22. Moreover the plasma levels of various angiogenic cytokines, such as basic fibroblast growth factor and vascular endothelial growth factor, are elevated in patients with active myeloma 15;23-25. In addition to the intriguing preclinical data few cases of advanced refractory multiple myeloma showed a significant response resulting in moving forwards with a phase II trial 26.
The first study of thalidomide in multiple myeloma by Singhal et al included eighty-four previously treated patients with refractory myeloma (76 with a relapse after high¬ dose chemotherapy) who received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or urine that lasted for at least six weeks. The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not significantly change in responding patients. After 12 months of follow-up, Kaplan–Meier estimates of the mean (±SE) rates of event-free survival and overall survival for all patients were 22±5 percent and 58±5 percent, respectively 26. A more recent follow up where the study was extended to 169 patients with advanced myeloma (abnormal cytogenetics (CG), 67%; prior autotransplant, 76%)27. A 25% reduction in the m-protein was noted in 37% of the patients > 50% reduction in 30% of the patients; near-complete or complete remission in 14% which was more frequent in patients with low plasma cell labeling index and normal cytogenetics. Two-year event-free and overall survival rates were 20% ± 6% and 48% ± 6%, respectively. Again the superior 2 year event free and over all survival was in the multiple myeloma patients with normal cytogenetics, plasma cell labeling index and 2-microglobulin of 3 mg/L or less. Considering the advanced status and the heavily pre-treated group of patients treated therapy was over all well tolerated. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare 26. This study was confirmed by several other groups (table 1).

Early studies in newly diagnosed multiple myeloma as a single agent and in combination:
The activity of thalidomide noted in advanced /refractory multiple myeloma patients encouraged moving the compound forwards to newly diagnosed patients. With the available data suggesting that steroids are a critical component of multiple myeloma therapy where it is believed to be the most active single agent in the management of the disease 28;29, absence of overlapping toxicity, and its different mechanism of action, investigators explored its role in combination with thalidomide. The first of such studies was by the group at the MD Anderson 2 where 28 patients with previously untreated asymptomatic myeloma were treated with thalidomide 100 to 200 mg orally at bedtime with serial increments of 50 to 100 mg at weekly intervals, as tolerated to a maximum of 600 mg PO qhs. Forty consecutive previously untreated patients with active myeloma were also treated as above (maximum dose 400 mg) and received dexamethasone 20 mg/m2 for 4 days beginning on days 1, 9, and 17; the second and third cycles of repeated dexamethasone were begun on day 30. Both groups of patients were treated for a minimum of 3 months. The response rate was 36% for patients treated with thalidomide alone and 72% for patients treated with thalidomide-dexamethasone, the latter including complete remission in 16% of patients. The median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide-dexamethasone. Grade 3 toxicity included infections (nine patients) and thrombotic/embolic events (seven patients). Five deaths have occurred as a result of disease progression, infection and thromboembolic event. The authors concluded that thalidomide is effective in early newly diagnosed patients and the addition of dexamethasone improved the rate and quality of response. In another study fifty symptomatic patients with newly diagnosed myeloma were studied. Thalidomide was given at a dose of 200 mg/d orally. Dexamethasone was given at a dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and 40 mg/d on days 1 to 4 (even cycles), repeated monthly 1. A response rate of 62% was noted with the responding patients proceeding to stem-cell collection following their forth cycle of thalidomide/dexamethasone. The majority (26 patients) proceeded to stem-cell transplantation and five chose to cryopreserve the stem-cells for possible future use. Grade 3 or 4 toxicities were observed in 16 patients (32%) with the most frequent side effect were deep vein thrombosis (six patients), constipation (four patients), rash (three patients), and dyspnea (two patients). Three deaths occurred during active therapy secondary to pancreatitis, pulmonary embolism, and infection. The authors in this report confirmed the feasibility and activity of the combination more over they demonstrated that stem cells could be collected and utilized after such therapy.

Early Studies Utilizing Thalidomide in Combination with Chemotherapy
Pegylated Doxorubicin (Doxil) vincristine and dexamethasone (DVd) is an active combination in the management of newly diagnosed multiple myeloma 30. However the response rates and the quality of responses are not improved over VAD therapy 31. Moreover in the relapsed/refractory setting the response rates are modest and only durable when patients achieve a near complete remission or better which is a rare occurrence (overall response rate is 22% and NCR is <5%) 32. DVd significantly reduces the number of abnormal angiogenic activity in the treated patients; however this finding does not impact PFS 33. As previously noted in this review thalidomide has a direct anti¬-myeloma effect in addition to its ability to modulate integrins, rendering the myeloma cell vulnerable and sensitized to different chemotherapeutic agents. With its ability to modulate the multiple myeloma microenvironment could possibly maintain the anti-angiogenic effects of the DVd and thus translates in to a better response rate as well as better quality response thus positively influencing progression free and over all survival. We therefore evaluated the role of thalidomide in combination with DVd in newly diagnosed active multiple myeloma as well as in advanced progressing relapsed/refractory disease with the primary objective of improving the response rate, quality of response and maintain the anti-angiogenic activity achieved with the DVd regimen. The overall CR/ NCR rates were virtually identical for both newly diagnosed (46%) and the relapsed/refractory patients (47%), as was the time to best response (median of 4.2 months for both groups). Stable disease or better occurred in 84% and 89% of the newly diagnosed and the relapsed/refractory group respectively. The study has completed accrual and long term effects are awaiting maturation of data 34. We concluded that DVd in combination with thalidomide and the appropriate supportive care measures resulted in a high response rate as well as an improved quality of response similar to what is achieved with high dose therapy. This regimen was well tolerated and the bone marrow reserves did not seem to be compromised. The results achieved with this combination are comparable to what is noted with autologous bone marrow transplantation. Earlier our group investigated the role of thalidomide in combination with intravenous melphalan and dexamethasone for a group of advanced refractory multiple myeloma patients 35. Intravenous melphalan without stem-cell support often provides rapid responses even in those who have been treated previously with oral melphalan. However, these responses are generally short lived, rarely lasting beyond 3 months. The combination of intravenous melphalan, thalidomide and one pulse of Decadron in an advanced refractory group of myeloma patients resulted in a one year survival of 57% with 38% of the patients in plateau phase. Other studies evaluating the role of thalidomide in combination with other cytotoxic agents such as Cytoxan have been studied 36;37

Reference List

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33. Hussein MA, Wood L, Hsi E et al. A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer 2002;95:2160-2168.
34. Hussein MA. Modifications to therapy for multiple myeloma: pegylated liposomal Doxorubicin in combination with vincristine, reduced-dose dexamethasone, and thalidomide. Oncologist. 2003;8 Suppl 3:39-45.
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36. Kropff MH, Lang N, Bisping G et al. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma. Br.J.Haematol. 2003;122:607-616.
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