What are the uses and dosing of thalidomide in patients with multiple myeloma or erythema nodosum leprosum?

Thalidomide Uses and Dosing

Thalidomide is FDA-approved for erythema nodosum leprosum (ENL) and has established efficacy in relapsed/refractory multiple myeloma, though it is not recommended for smoldering multiple myeloma outside clinical trials due to lack of survival benefit despite prolonging time to progression. 1, 2

FDA-Approved Indication

Erythema Nodosum Leprosum (ENL)

• Thalidomide received FDA approval in 1998 specifically for ENL, a severe inflammatory complication of lepromatous leprosy 2, 3
• The drug is available only through a restricted REMS program due to severe teratogenicity risk 4
• Typical dosing for ENL: 100-300 mg daily, though specific FDA-approved dosing should be confirmed through the prescribing information 5, 2

Multiple Myeloma Applications

Relapsed/Refractory Multiple Myeloma

• Thalidomide as salvage therapy induces responses in 30% of patients with progressive myeloma, with response rates of 34-36% in phase II trials 1
• Standard dosing: 200 mg/day orally, which provides good response rates with better tolerability than higher doses 1
• Response typically occurs within 3-5 weeks of treatment initiation 1
• Thalidomide combined with dexamethasone significantly increases response rates but also substantially increases thromboembolic risk to up to 5% per treatment month 1

Maintenance Therapy Post-Transplant

• Thalidomide maintenance after autologous stem cell transplant is a category 1 recommendation, improving event-free survival (56% vs 44% at 5 years) though not overall survival 1
• Thalidomide plus pamidronate maintenance showed significant event-free and overall survival advantages, particularly in patients achieving only partial response after transplant 1
• Patients experiencing less than very good partial response (VGPR) after autologous SCT benefit most from thalidomide maintenance 1

Smoldering Multiple Myeloma (NOT RECOMMENDED)

• Despite phase II trials showing 42% partial response rates at 4 years with thalidomide 200 mg/day in smoldering myeloma, this drug cannot be recommended for SMM treatment until prospective randomized trials demonstrate survival benefit 1
• Median time to progression was 7 years with thalidomide in SMM, but no overall survival advantage has been demonstrated 1

Mechanism of Action in Multiple Myeloma

• Thalidomide's efficacy in MM depends on homing of myeloma cells in bone marrow and interactions with the bone marrow microenvironment 1
• The drug lacks efficacy against soft-tissue plasmacytomas, supporting its bone marrow-dependent mechanism 1
• Acts through antiangiogenic and immunomodulatory effects, including TNF-alpha inhibition 5, 2, 3

Critical Safety Considerations

Mandatory Prophylaxis and Monitoring

• Prophylactic anticoagulation is mandatory when thalidomide is combined with dexamethasone or chemotherapy 1, 6
• Low-molecular-weight heparin is superior to warfarin or aspirin for DVT prophylaxis 6
• Grade 3-4 venous thromboembolism occurs in 15.3% of patients receiving thalidomide/dexamethasone 6

Peripheral Neuropathy Management

• Grade 3-4 peripheral neuropathy occurs in 10.4% of patients on thalidomide/dexamethasone 6
• Peripheral neuropathy is cumulative, dose-related, and may be irreversible, requiring dose reduction in 86% and discontinuation in 50% of patients on long-term therapy 1, 6
• Monitor for tingling, paresthesia, and numbness at 6-monthly intervals with neurological examination and vibration sensitivity assessment 6
• Baseline neurological assessment is required before initiating therapy 6

Teratogenicity (Absolute Contraindication)

• Thalidomide is absolutely contraindicated in pregnancy due to severe life-threatening birth defects 6, 4
• Mandatory contraception with two reliable methods is required for all patients of reproductive potential 6, 4
• Pregnancy testing must be performed within 10-14 days and within 24 hours prior to prescribing, then weekly during the first month, then monthly thereafter 4
• Males must use latex or synthetic condoms during sexual contact and for 4 weeks after discontinuation 4

Other Significant Adverse Effects

• Common toxicities include somnolence, fatigue, constipation, and rash 1, 5
• Deep vein thrombosis occurred in 20% of patients in one dermatologic series, representing a significant complication 7
• Hepatotoxicity including fatal hepatic failure requires monthly liver function monitoring 4
• Severe cutaneous reactions (Stevens-Johnson syndrome, TEN, DRESS) require permanent discontinuation 4

Dosing Algorithm for Multiple Myeloma

Initial dosing:

• Start at 200 mg orally daily for relapsed/refractory disease 1
• Administer on Days 1-21 of repeated 28-day cycles until disease progression 4

Dose modifications:

• Reduce to lower doses if peripheral neuropathy develops 1
• Consider dose reduction with strong CYP1A2 inhibitors (reduce to 2 mg if unavoidable) 4
• Adjust for renal or hepatic impairment per FDA labeling 4

Common pitfalls to avoid:

• Do not use thalidomide in smoldering myeloma outside clinical trials—no survival benefit demonstrated 1
• Do not combine with pembrolizumab or other PD-1/PD-L1 inhibitors—increased mortality observed 4
• Do not omit anticoagulation prophylaxis when combining with dexamethasone or chemotherapy 1, 6
• Do not delay neurological monitoring—neuropathy may become irreversible 6