Multiple myeloma thalidomide

Lenalidomide was approved recently for the indication of myelodysplastic syndrome where the 5q deletion is present. Since lenalidomide is an analog of thalidomide, all the same precautions must be taken to prevent phocomelia. The time to maximum lenalidomide concentrations occurs 0.5 to 4 hours after the dose. The terminal half-life ranges from 3 to 9 hours. Approximately 65% of lenalidomide is eliminated unchanged in the urine, with clearance exceeding the glomerular filtration rate. To date, no pharmacokinetic studies have been done in patients with renal dysfunction. Lenalidomide is used in the treatment of myelodysplastic syndrome and multiple myeloma. Other side effects are neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary embolus. 

The primary goal in the treatment of multiple myeloma is to decrease tumor burden and minimize complications associated with the disease. A watch and wait approach is an option for asymptomatic patients who have no lytic lesions in the bone. Once symptoms occur, treatment is required. Chemotherapy can be used to reduce tumor burden in patients with symptomatic disease, but increasingly, immunomodula-tors such as thalidomide and dexamethasone are initial therapy. Almost all patients will become refractory to initial treatment and will require the use of salvage therapies such as bortezomib. Autologous stem cell transplantation prolongs overall survival in patients who can tolerate high-dose chemotherapy and may be the treatment of choice for many patients. 

Thalidomide as monotherapy or combination therapy is beneficial in the treatment of multiple myeloma. The precise mechanism of action of thalidomide is unknown, but its antimyeloma activity may be due to its antiangiogenic and... 

Lenalidomide is an immunomodulating agent related to thalidomide that was recently approved for the treatment of patients with multiple myeloma and myelodysplastic syndrome (MDS). Lenalidomide lacks the common side effects of thalidomide, such as constipation and peripheral neuropathy. Interim analyses of two phase III trials show that lenalidomide in combination with dexamethasone produces higher response rates than dexamethasone alone in relapsed and refractory myeloma. Adverse effects of lenalidomide include diarrhea, nausea, muscle cramps, hematologic side effects and deep vein thrombosis.42... 

Newly diagnosed, asymptomatic patients may be observed without treatment. This asymptomatic period may last for months to a couple years. All patients with multiple myeloma will become symptomatic, and once this occurs, treatment is required. First-line treatment may be one of several therapies, including VAD, thalidomide plus steroids, and autologous transplant. Nearly all patients will progress at some point, and second-line therapy usually will include bortezomib. All patients who have bone lesions should receive monthly bis-phosphonates, with the hope of reducing pain and fractures. 

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner. 

Kumar, S. and Rajkumar, S.V. (2006) Thalidomide and lenalidomide in the treatment of multiple myeloma. European Journal of Cancer, 42, 1612-1622. 

Thalidomide was in 2006 approved by the FDA for the treatment, in combination with dexametha-sone, of newly diagnosed multiple myeloma patients. Thalidomide was sold in the late fifties as an hypnotic, with the infamous epidemic of birth defects as a result. Thalidomide is racemic and the S enantiomer is teratogenic. However the enantiomers interconvert in vivo, so giving only the R enantiomer cannot be a solution. After oral administration peak levels are reached in 2-A hours. It is eliminated mainly by biotransformation with a halfiife of about 6 hours. The most common side effects observed with use of thalidomide in myeloma include drowsiness or fatigue, constipation, dizziness, dry skin or rash, low white blood cell counts, and peripheral neuropathy. 

Lenalidomide, a derivative of thalidomide, was introduced in 2004. Patients with multiple myeloma stage II/III, who have undergone at least one previous treatment can be treated with bortezomib or with lenalidomide in combination with dexamethasone. There is good oral absorptin with peak plasma levels at 0.5-4 hours. Lenalidomide is maily eliminated by the kidneys with a half-life of circa 3-9 hours. Teratogenicity cannot be excluded. Side effects include thrombosis, pulmonary embolus, and hepato-toxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. 

Thalidomide is currently used in the treatment of multiple myeloma at initial diagnosis and for relapsed-refractory disease. 

A 44-year-old man with an initial TSH concentration within the reference range took thalidomide 400 mg/ day for multiple myeloma and within 4 weeks developed cold intolerance, fatigue, depression, dizziness, and bradycardia, and had a markedly raised TSH (1114). He was given levothyroxine and the dose of thalidomide was reduced to 200 mg/day, after which he became euthyroid. 

A 70-year-old man with no family history of diabetes or known diabetes took thalidomide 400 mg/day for refractory multiple myeloma. He developed... 

Badros AZ, Siegel E, Bodenner D, Zangari M, Zeldis J, Barlogie B, Tricot G. Hypothyroidism in patients with multiple myeloma following treatment with thalidomide. Am J Med 2002 112(5) 412-3. 

Thalidomide (Thalomid] Multiple myeloma Peripheral neuropathy dizziness drowsiness Gl distress (nausea, diarrhea, stomach pain] contraindicated in pregnant women because of teratogenic potential... 

Kumar S, Anderson KC. Drug insight thalidomide as a treatment for multiple myeloma. Nat Clin Pract Oncol. 2005 2 262-270. 

Suppiah R, Srkalovic JG, Hussein MA. Immunomodulatory analogues of thalidomide in the treatment of multiple myeloma. Clin Lymphoma Myeloma. 2006 6 301-305. 

Significant efforts are currently focused on developing novel agents for multiple myeloma. These include CC5013, a small molecule analog of thalidomide with immunomodulatory effects the proteasome inhibitor PS341 and arsenic trioxide. 

Mood changes are common with thalidomide (612). Three cases of paranoid reactions have been reported in patients with multiple myeloma taking thalidomide however, causality was not proved (613). 

Reversible dementia occurred in a patient with multiple myeloma taking thalidomide 200 mg/day plus dex-amethasone (614). Memory deficit and mania occurred... 

Morgan AE, Smith WK, Levenson JL. Reversible dementia due to thalidomide therapy for multiple myeloma. N Engl J Med 2003 348(18) 1821-2. 

DOXORUBICIN THALIDOMIDE t risk (up to sixfold) of deep venous thrombosis in patients with multiple myeloma compared with those treated without doxorubicin Uncertain. Attributed to doxorubicin contributing to the thrombogenic activity Avoid co-administration - except in clinical trials... 

Holstein, S.A., Tong, H., and Hohl, R.J. (2010). Differential activities of thalidomide and isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells. LeukRes 34 344-351. Tong, H., Wiemer, A.J., Neighbors, J.D., and Hohl, R.J. (2008). Quantitative determination of farnesyl and geranylgeranyl diphosphate levels in mammalian tissue. Anal Biochem 378 138-143. 

Plasmocytoma Extramedullary plasmocytic lymphoma likewise has its origin in immunoglobulin-secreting B-lymphocytes. It is also termed multiple myeloma. The condition occurs most frequently in 7 decade of life and ends fatally after 1-2 (-3) years. In the liver, there are sometimes sinusoidal and portal infiltrations of B-lym-phocytes and plasmocytic tumour cells nodular formation can also occur. Generally, however, liver involvement is found in 40% of cases. (47, 61) (s. fig. 38.12) Recently, patients with non-response or relapse after high-dose chemotherapy were treated successfully with thalidomide (starting with 200 mg daily, the dose was increased by 200 mg every two weeks until it reached 800 mg per day). (48, 56) Plasma cell leukaemia is a rare complicative variant which tends to have its own individual course. 

Of 50 patients with multiple myeloma, 14 developed a deep venous thrombosis after taking thalidomide 400 mg/day, compared with two of 50 patients who did not take it (24) All the episodes occurred during the first 3 cycles of therapy. One patient taking thalidomide had a pulmonary embolus. Most of the patients continued to take thalidomide with the addition of low molecular weight heparin followed by warfarin and there was no progression of deep venous thrombosis. 

The incidence of deep venous thrombosis is increased by the co-administration of doxorubicin, as suggested by a study in 232 patients with multiple myeloma who received a combination of thahdomide and chemotherapy in two protocols that differed only by the inclusion of doxorubicin in one DT-PACE (dexamethasone -I- thahdomide -I-cisplatin -I- doxorubicin + cyclophosphamide -I- etoposide) and DCEP-T (dexamethasone + cyclophosphamide -I-etoposide -I- cisplatin + thalidomide) (25). There was an increased risk of deep venous thrombosis in those who received DT-PACE but not in those who received DCEP-T. Multivariate analysis confirmed that those who received thahdomide + doxorubicin had an increased risk of deep venous thrombosis. In two separate trials in patients taking thahdomide for multiple myeloma, deep venous thrombosis occurred in four of 15 patients who received concomitant treatment with doxorubicin -I- dexamethasone compared with three of 45 who received dexamethasone only (26). 

In patients with leprosy, HIV infection, and multiple myeloma, the incidences of somnolence, fatigue, and weakness were 36-43%, 48%, and 6-22% respectively (21). Administration of thalidomide at bedtime minimizes appreciation of the drowsiness that it produces, and daytime drowsiness usually abates over several weeks. 

In six patients with multiple myeloma who developed a thalidomide-induced sensory polyneuropathy, spinal cord MRI showed high-signal intensity in the posterior columns in only one patient, with abnormal central conduction time at somatosensory-evoked potentials (38). These results suggest that thalidomide can induce either an axonal length-dependent neuropathy or, less often, a ganglionopathy. 

Reversible dementia occurred in a patient with multiple myeloma taking thalidomide 200 mg/day plus dexa-methasone (59). Memory deficit and mania occurred about 2 months after the start of therapy and did not resolve on withdrawal of dexamethasone and administration of risperidone. The memory loss worsened and proceeded to disorientation, apraxia, and tremor 4 months after the start of therapy. The dementia... 

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