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Thalidomide (Old Drug for New Indication: Multiple Myeloma)

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The introduction of Thalidomide was quickly abandoned after the revelation of its teratogenic effects. Four decades later, its renewed use in the setting of Multiple Myeloma brought hope.

The dramatic enkindling following its catastrophic fall from grace in the late 1900s resulted in profound teratogenicity. An improved understanding of Thalidomide’s mechanism has propelled its 21st-century renaissance in the field of haematological cancers. 

Thalidomide possesses immunomodulatory, anti-inflammatory and antiangiogenic effects against Myeloma cells. The immunologic effects were observed to vary substantially under different conditions. However, they are primarily related to the suppression of excessive tumour necrosis factor-alpha (TNF-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. 

Thalidomide’s broad spectrum of activity also includes alteration of the expression of cellular adhesion molecules on bone marrow stromal cells and both a direct effect on Myeloma cells and an indirect effect via CD8-positive T-cells and NK cell activity.

In November 2021, 11 years following FDA’s regulatory approval for the same indications, Thalidomide (Domide) received local market authorisation from the HSA for use in:

  1. Untreated multiple Myeloma ≥65 years or ineligible for high dose chemotherapy, in combination with Melphalan and Prednisone;
  2. Induction therapy before high-dose chemotherapy with autologous stem cell rescue, for the treatment of patients with untreated multiple Myeloma, in combination with Dexamethasone

Multiple Myeloma (MM) is a plasma cell neoplasm with substantial morbidity and mortality, characterised by end-organ damage – Renal Impairment, Hypercalcemia, Lytic Bone Lesions, and Anaemia. 

It was estimated to have caused over 2.1 million (95% UI, 1.9-2.3 million) disability-adjusted life years (DALYs) globally in 2016. It is the second most common type of blood cancer and afflicts over 100 people in Singapore every year. 

Once considered a largely incurable disease, therapeutic advances in the last decade have changed the disease landscape, providing vastly improved response rates and novel options to patients following relapses hence improving survival. 

Treatment choice should consider the patient’s age, performance status, comorbid conditions, side effect potential and preferences. Risk stratification has considerable prognostic value and helps guide the selection of initial targeted and risk-adapted therapy. 

Thalidomide Efficacy

Thalidomide-based chemotherapy combinations are currently considered front-line regimens. This is applicable for both transplant-eligible (below 65 years of age, with an acceptable comorbidity profile and performance status) and transplant-ineligible (>65 years of age with significant comorbidities) patients. 

Its use as a single agent was first observed in patients with relapsed and refractory MM by Singhal et al. in 1999. Subsequent trials investigating Thalidomide in combination therapy for relapsed and refractory MM demonstrated response rates between 30 and 76%. The promising results eventually led to its investigation in newly diagnosed untreated MM, where response rates of 48 to 80% were observed. A summary of the key trials relevant to Thalidomide’s local registry approval is highlighted below.

Patient status

  • HSA-registered indication
  • Phase III evidence

Transplant-eligible 

Induction therapy before high-dose chemotherapy with autologous stem cell rescue, for the treatment of patients with untreated multiple Myeloma, in combination with dexamethasone

MM-003 compared Thalidomide and Dexamethasone (Thal/Dex) against placebo and Dexamethasone (placebo/Dex)

  • Thal/Dex was associated with significant improvement in time to disease progression (HR 0.43, 95% CI: 0.32-0.58)
  • The median time to progression was prolonged from 28.3 weeks (placebo/Dex) vs 97.7 weeks with Thal/Dex
  • Progression-free survival (PFS) was improved with Thal/Dex (HR 0.50, 95% CI: 0.38-0.64); median PFS was 64.4 weeks vs 28.0 weeks
  • The overall response rate was also significantly greater with Thal/Dex (63% vs 46%)
  • No improvement in overall survival (OS) was demonstrated

Transplant-ineligible 

Untreated multiple Myeloma ≥65 years or ineligible for high dose chemotherapy, in combination with melphalan and prednisone

ECOG EA100 compared Thal/Dex against placebo/Dex

  • Overall response rate at 4 months with Thal/Dex was significantly higher than placebo/Dex (61.6% vs 39.6%); the response was defined as a decrease in serum and urine M-protein of ≧ 50%

Safety

Thalidomide’s beginnings as an oral sedative and anti-emetic in 1957 were quickly abandoned following the catastrophic revelation of its teratogenic effects. Four decades on, its renewed use in the setting of MM has lent new hope to these patients, yielding impressive overall response rates. 

Notwithstanding, its mechanistic adverse effects remain a cause of concern that must be carefully and closely managed. Thalidomide’s dose-limiting toxicities include somnolence, constipation, peripheral neuropathy and critically, an increased incidence of venous thromboembolism (VTE), especially when combined with dexamethasone. 

Strategies to avoid such complications include administration of low molecular weight heparins, especially in patients receiving Thalidomide in combination with other chemotherapy or in patients with an increased risk of developing deep vein thrombosis. Peripheral neuropathy is managed by limiting treatment duration, and current recommendations vary from 6 to 18 months of Thalidomide use. In addition, Thalidomide is available in Singapore under a restricted distribution programme called the “Domide RMP (risk management program)” where Thalidomide administration is closely monitored based on limiting prescription rights only to authorised prescribers.

In summary, Thalidomide’s high activity in MM must be harnessed in tandem with careful follow-up, close monitoring and timely dose adjustments to mitigate or prevent the development of associated adverse effects. Care of the patient with MM requires attention to factors beyond disease status and attention to the disease and treatment-related complications will ensure holistic patient care, maximising the benefits from treatment.

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