When was thalidomide approved for myeloma

The exact mechanism by which Thalomid treats myeloma is not known. Thalomid may also suppress the production of tumor necrosis factor-alpha TNFa , which is a cell-signaling protein that plays important roles in cell survival, proliferation, differentiation, and death. However, the effect of Thalomid on TNFa varies widely between different health conditions. Thalomid especially affects rapidly dividing cells, which is why it is able to target cancerous cells.

The efficacy of Thalomid in treating myeloma was demonstrated in a randomized multi-center, open-label clinical trial involving patients who were newly diagnosed with myeloma. The patients were randomly assigned to receive either Thalomid and dexamethasone patients or dexamethasone alone patients. Patients received mg of Thalomid daily, and 40 mg of dexamethasone on days 1 to 4, 9 to 12, and 17 to 20, every 28 days.

Both groups were treated for four day cycles. The primary endpoint was the response rate to treatment. The investigators concluded that lower doses of dexamethasone could greatly reduce the incidence of adverse events without a negative effect on efficacy, and that anticoagulant prophylaxis should be used in all newly diagnosed patients.

No substantial differences in survival were reported. ThaDD indicates thalidomide-pegylated liposomal doxorubicin-dexamethasone; T-VAD doxil, thalidomide-vincristine-pegylated lyposomal doxorubicin; and ND, not determined.

In a continuing study, 35 elderly patients were randomly assigned to TD or oral melphalan and prednisone MP. DVT, neuropathy, and constipation were more frequent in the TD group, whereas hematologic toxic effects were most prominent in the MP group.

A case-control analysis showed that the TD regimen was better than the vincristine-doxorubicin-dexamethasone VAD schema. Offidani and coworkers 21 showed that oral melphalan and thalidomide was better than thalidomide alone Tables 1 , 2.

A total of 3 randomized studies assessed the combination of MP and thalidomide Tables 4 , 5. The PR rates were Median OS was These 3 independent randomized studies showed virtually identical results, and they represent the experimental evidence that supports MPT as the standard of care for elderly patients not eligible for ASCT. Several trials have investigated the combination of thalidomide, pegylated lyposomal doxorubicin PLD , and dexamethasone Tables 1 , 2.

Offidani and coworkers 24 used a VAD-like regimen that substituted vincristine with low-dose thalidomide. Hussein and colleagues 25 added thalidomide to a regimen consisting of PLD, vincristine, and decreased-frequency dexamethasone.

Complete response CR and PR rates were similar between regimens; the toxic effects of these regimens were manageable, although vincristine increased the incidence of severe neuropathy. The association of thalidomide, doxorubicin, and dexamethasone TAD has been studied in newly diagnosed patients Tables 4 , 5. Patients with impaired renal function achieved PR, and renal function was improved or restored. Other studies used vincristine and PLD in association with thalidomide mg and decreased-frequency dexamethasone, 25 or with thalidomide mg and high-dose dexamethasone.

Cyclophosphamide has been associated with thalidomide and corticosteroids for the treatment of advanced MM Tables 1 , 2. A total of 27 percent of patients developed infections, most of which were respiratory, but there were no infection-related deaths.

Other phase 2 studies showed similar results. The combinations of oral cyclophosphamide mg on days 1, 8, and 15 , thalidomide mg , and high-dose dexamethasone CTD have been studied in 27 patients and compared with the combination of cyclophosphamide-vincristine-doxorubicin-methylprednisolone CVAMP in a case-matched analysis Tables 4 , 5.

To assess whether the incorporation of thalidomide into high-dose therapy could improve survival, newly diagnosed patients, who received tandem ASCT, were randomly assigned to receive thalidomide or not.

There was no difference in OS because of a significantly shorter survival after relapse in the thalidomide group median, 1. The delivery of thalidomide at diagnosis significantly extended EFS, but the administration of thalidomide at relapse in the control group probably abrogated the OS benefit. Cardiac pacemakers were implanted in nearly a third of patients with symptomatic sinus bradycardia. The treatment-related mortality rate was similar in both groups. High-dose chemotherapy has increased the response rate in patients with MM, but this treatment is not curative, and effective consolidation-maintenance strategies could extend the duration of response.

Patients received thalidomide for a median of 15 months range, 0. The DVT incidence did not differ significantly in the 3 groups. Factors affecting outcome of patients with MM treated with thalidomide have been assessed. These studies might select patients who most benefit from thalidomide and might allow a risk-based treatment algorithm to be designed. In the first study into the use of thalidomide monotherapy in advanced MM, 9 3 factors were associated with a short EFS: increased LDH, C-reactive protein, and plasma cell labeling index.

Short OS was associated with low albumin, chromosome 13 deletion del13 , and high bone marrow plasma cell infiltration. Barlogie and colleagues 49 treated patients with ASCT with or without thalidomide. Thalidomide was unable to overcome these adverse prognostic factors in terms of OS. The Bologna group 57 reported a significantly reduced probability of response to TD in patients with coexisting del13 or t 4;14 cytogenetics abnormalities, but not in those with a single abnormality.

These negative results were completely offset by subsequent tandem ASCT. Attal and coworkers 54 showed that patients without del13 had a significant benefit from thalidomide, whereas patients with del13 did not. The frequency and severity of thalidomide side effects are dose related and time dependent Tables 2 , 3 , 5.

Generally, once a relation between thalidomide and toxicity is established, no action should be taken if there are nonhematologic grade 1 side effects. Women of childbearing potential should have a negative pregnancy test before starting thalidomide, use 2 effective forms of birth control, and have a pregnancy test every 4 weeks if their period is regular or every 2 weeks in case of irregularity. Men receiving thalidomide must abstain from sexual intercourse or use a latex condom even if they have undergone vasectomy.

The Risk Management Programs are designed to avoid prescription of thalidomide to pregnant women or men with childbearing potential.

Thromboembolic events are one of the most important side effects Table 3. The pathogenic mechanisms of DVT associated with thalidomide have not been clearly established. Acquired activated protein C resistance and a reduction in thrombomodulin level have been associated with an increased risk of DVT. Endothelial injury produced by the combination of thalidomide with chemotherapy and subsequent restoration of endothelial cell PAR-1 expression are probably factors that promote thrombosis. Thromboprophylaxis is not recommended for patients who receive single-agent thalidomide or thalidomide maintenance if no other risk factors for DVT are simultaneously present , but it is strongly recommended in those who receive thalidomide in combination with high-dose dexamethasone or doxorubicin.

Thromboprophylaxis should be tailored according to the presence of other risk factors that could further increase the risk of DVT: individual risk factors age, obesity, comorbidities, surgical procedures , MM-related risk factors diagnosis, high tumor mass , and treatment-related risk factors high-dose dexamethasone, doxorubicin, multiagent chemotherapies.

There are no data to suggest that one anticoagulant is better than another. Although aspirin is more appealing because of convenience and of ease of administration, the rate of thrombosis is relatively high in particular conditions. Until further evidence becomes available, aspirin should only be recommended for patients with low risk of DVT. In high-risk patients, evidence nowadays supports the use of LMWH or full-dose warfarin. The use of warfarin is limited by its long half-life in patients at risk of concomitant thrombocytopenia.

LMWH is a more suitable option because of its short half-life and the decreased risk of secondary bleeding. Ongoing studies will determine which is the most appropriate anticoagulant prophylaxis. Almost all DVT has been reported in the first 6 months of treatment, and all episodes arose within the first 12 months. Sinus bradycardia occurs in patients given thalidomide because of autonomic neuropathy. Bradycardia can be severe enough to cause syncope. Symptoms related to bradycardia can resolve or decrease in severity after either discontinuation or dose reduction, but sometimes a pacemaker needs to be implanted.

Hypotension is a possible although infrequent side effect. The concurrent administration of antidepressants could induce or worsen hypotension.

Peripheral edema is more frequent with coadministration of corticosteroids; it is generally mild, reversible, and usually responsive to temporary discontinuation of the drug. Many patients with MM present with subclinical or even clinical peripheral neuropathy. These patients can be at increased risk of peripheral neuropathy because of thalidomide treatment.

Patients suffer from pinprick sensations, numbness, and tingling that initially affect fingers and toes but later extend proximally. Subsequently, vibration perception, deep sensitivity, and position sense are affected, leading to ataxia, progressive gait disturbance, and postural tremor.

Neuropathy is closely related to duration of treatment 68 , 69 and cumulative dose, 70 , 71 and it is more frequent in elderly patients. A randomized study 17 reported a greater tolerability of thalidomide in patients who received mg than in those who received mg.

Thalidomide discontinuation increases the probability of recovery, which usually occurs within 3 weeks. If treatment is not stopped, the neuropathy progresses and could become irreversible. Patients should be taught to recognize peripheral neuropathy and to immediately decrease the dose or discontinue thalidomide when sensory paresthesia is complicated by pain, motor deficit, or interference with daily function.

Symptomatic therapy for paresthesia includes gabapentin, pregabalin, L-carnitine, and tricyclic antidepressants. Tremors arise quite frequently but rarely interfere with daily activity. Depression has been reported, especially in patients with a previous history of depression. Headache is possible, it is not usually dose-dependent and can be relieved with nonsteroidal anti-inflammatory drugs. This adverse event appears early after treatment is started days , and is most severe in elderly patients and in those receiving opioid analgesics.

Drugs that reduce bowel motility should be avoided if possible. Stool softeners and osmotic laxative are usually sufficient for moderate constipation. Some amount of sedation is universal. It generally appears within 15 days after thalidomide treatment is started and is usually mild and dose dependent. Benzodiazepines, opiates, phenytoin, or sedative neuroleptics can enhance sedation, and thalidomide itself can increase the sedative activity of barbiturates and alcohol, and the catatonic activity of chlorpromazine and reserpine.

Patients should be instructed to take thalidomide in the evening and to expect assumption in late afternoon if somnolence persists the following morning. Cautions should be given in the first 2 weeks for activities requiring great attention eg, driving , and concomitant drugs with sedative activity should be avoided. Adverse dermatologic effects include rash, atrophic lesions, dry skin and mouth, and, rarely, toxic epidermic necrolysis and the Stevens-Johnson syndrome.

The most common dermatologic side effect is a pruritic maculopapular rash, starting on the trunk and extending to the back and proximal limbs; it does not seem to be dose related and has been reported within 10 to 14 days after the start of treatment.

Temporary discontinuation leads to resolution of the rash and allows readministration at a reduced dose. The appearance of a maculopapular rash that covers the entire body is a potential early sign.

Niesvizky et al. With the successful results of combining MP with thalidomide and then with bortezomib in the elderly myeloma population, the addition of lenalidomide to MP was assessed by Palumbo et al.

A number of phase I and II trials are also presently exploring the combination of lenalidomide with other novel anti-myeloma agents. A Mayo Clinic lead randomized phase II trial is comparing the combination of bortezomib, cyclophosphamide, lenalidomide and dexamethasone with either bortezomib or lenalidomide with cyclophosphamide and dexamethasone [ 52 ]. Although initial reports of these studies demonstrate unprecedented overall response rates for the four-drug combinations. It remains to be seen whether the depth of response may lead to similar success, and potentially, cures such as observed in aggressive lymphomas.

Lenalidomide had also shown promising activity as maintenance therapy after autologous stem cell transplant, e. McCarthy et al. Lenalidomide was also evaluated in transplant ineligible patients as part of initial and maintenance therapy.

In this trial patients received melphalan, prednisone, lenalidomide MPR as nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until relapse or disease progression or MPR or MP without maintenance therapy. Pomalidomide is the newest IMiD that is undergoing clinical investigation Table 8. In an ongoing phase II study, patients who had failed both lenalidomide and bortezomib were given pomalidomide and dexamethasone. Treatment benefit with pomalidomide and low dose dexamethasone was also confirmed by another Phase II study in patients with multiple myeloma despite prior use of lenalidomide [ 54 ].

More research is needed to establish the optimal treatment strategy and role of pomalidomide in patients with relapsed and refractory myeloma. After over two decades with limited treatment options, numerous new regimens incorporating novel agents are now available for both transplant eligible and transplant ineligible patients with multiple myeloma. While response rates, adverse reactions and the optimal dosing strategy vary among the various IMiDs, there is increasing data to suggest that these novel agents and regimens are altering the natural history of the disease, improving the quality of life and longevity of patients with myeloma.

Although teratogenicity is a significant concern and careful monitoring and precautions are required when using these agents, recent discoveries on the possible mechanism of thalidomide teratogenicity will hopefully lead to development of safer IMiDs [ 38 ]. Immunomodulatory drugs are a promising class of therapy for patients with multiple myeloma, both as single agents and in combination with conventional chemotherapy. N Engl J Med , — Siegel R, Ward E, Brawley O, Jemal A: Cancer statistics, the impact of eliminating socioeconomic and racial disparities on premature cancer deaths.

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