IPOPRIN 2

Indications

• Treatment of relapsed and refractory multiple myeloma in patients who have received at least two prior treatment regimens
• Used in combination with dexamethasone for enhanced therapeutic effect

Dosage

Adults: 4 mg once daily for 21 consecutive days in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least one prior therapy.

Mechanism of action

Pomalidomide primarily targets the protein cereblon, inhibiting its ubiquitin ligase activity. This leads to altered protein degradation pathways, enhancing T cell and NK cell-mediated immunity and inducing apoptosis in tumor cells. Additionally, pomalidomide inhibits the production of pro-inflammatory cytokines such as TNF-alpha and IL-6 by monocytes. Its action is linked to both direct antiproliferative effects on malignant cells and modifications in immune responses.

Pharmacodynamics

Pomalidomide is significantly more potent than its predecessors, thalidomide and lenalidomide, exhibiting approximately 100-fold and 10-fold greater efficacy, respectively. This enhanced potency translates to more effective suppression of tumor growth and improved immune modulation, which is crucial for its role in treating multiple myeloma.

Pharmacokinetics

Pomalidomide is administered orally and has a bioavailability that allows for effective systemic absorption. It is metabolized primarily in the liver, with a half-life that facilitates once-daily dosing. The pharmacokinetics may be affected by various factors, including liver function, and dose adjustments may be necessary based on patient response and tolerability.

Contra-indications

• Hypersensitivity to pomalidomide or any of its excipients
• Pregnancy
• Severe hepatic impairment

Adverse effects

• Neutropenia
• Thrombocytopenia
• Anemia
• Increased risk of venous thromboembolism
• Fatigue
• Nausea
• Diarrhea
• Constipation
• Rash
• Peripheral neuropathy

Interactions

• Combined hormonal contraceptives: severe interaction, increases risk of venous thromboembolism
• Ciprofloxacin: unknown interaction, increases exposure
• Fluvoxamine: unknown interaction, increases exposure

Precautions

• Regular monitoring of blood counts (complete blood count) is recommended
• Risk of hepatotoxicity, particularly in patients with a history of liver disease
• Patients should be advised to avoid pregnancy during and after treatment
• Patients should be monitored for signs of thrombosis

Pregnancy

Pomalidomide is contraindicated in pregnancy due to the risk of teratogenic effects. It is classified as a category X medication.

Breast-feeding

It is not known whether pomalidomide is excreted in human milk; however, due to the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Pomalidomide 1 mg capsules
• Pomalidomide 2 mg capsules
• Pomalidomide 3 mg capsules
• Pomalidomide 4 mg capsules

Mechanism of action

Promalidomide is an immunomodulatory agent with antineoplastic activity. It is shown to inhibit the proliferation and induce apoptosis of various tumour cells. Furthermore, promalidomide enhances T cell and natural killer (NK) cell-mediated immunity and inhibited the production of pro-inflammatory cytokines, like TNF-alpha or IL-6, by monocytes. The primary target of promalidomide is thought to be the protein cereblon. It binds to this target and inhibits ubiquitin ligase activity. It is also a transcriptional inhibitor of COX2. In vitro studies have identified a molecular mechanism for the pleiotropic effects of pomalidomide in multiple myeloma (MM) and in T cells. Specifically, pomalidomide bound to the protein cereblon (CRBN), part of an E3 ligase complex, and the expression levels of CRBN in myeloma cells was linked to both the efficacy of pomalidomide and to the acquisition of resistance to lenalidomide. Pomalidomide was claimed to have direct antiproliferative activity against B cell lines derived from MM and Burkitt's lymphoma patients. Pomalidomide in combination with dexamethasone increased this effect in a dose dependent manner. Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-alpha (TNF-a) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance. The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects. In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1

Pharmacodynamics

Pomalidomide is more potent than thalidomide (100-times) and lenalidomide (10-times).