Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)

Multiple myeloma is considered an incurable disease so several regimens are available for the management of multiple myeloma.

Among these regimens there is the bortezomib, lenalidomide and dexamethasone (RVd or VRd) regimen which is the preferred induction regimen for most patients with newly diagnosed multiple myeloma (NDMM).

Bortezomib has hematologic and non-hematologic adverse reactions. From the non-hematologic adverse reactions there is the bortezomib-induced peripheral neuropathy (BIPN) that remains the most intractable common adverse reactions that occur during bortezomib treatment with no recommended therapies available for preventing or treating existing BIPN.

Fenofibrate a peroxisome proliferator-activated receptor-alpha (PPARα) agonist that is widely used in the management of hypercholesterolemia and hypertriglyceridemia has been proposed as a key lipid metabolism modulator and regulator of inflammation.

Preclinical studies showed that treatment with fenofibrate partially reversed and prevented the development of mechanical and cold hypersensitivity induced by paclitaxel through the regulation of peroxisome proliferator-activated receptor-alpha (PPAR-α) expression and decrease neuroinflammation in the dorsal root ganglia (DRG) without decreasing the antitumoral effect of paclitaxel.

Inclusion criteria

• Age ≥ 18 years old.
• Newly diagnosed MM patients according to the revised International Myeloma Working Group Diagnostic Criteria for the diagnosis of Multiple Myeloma (IMWG).
• Patients being treated by bortezomib-based VRd chemotherapy regimen.
• Patients with performance status <2 according to Eastern Cooperative Oncology Group (ECOG) score.
• Adequate baseline hematologic values (absolute neutrophilic count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin level ≥ 10 g/dl).
• Patients with adequate liver function (serum bilirubin < 1.2 mg/dl) and adequate renal function (serum creatinine < 1.5 mg/d).

Exclusion criteria

• Patients with prior exposure to neurotoxic agents (Cis-platin, vincristine, taxanes, foscarnet, INH, etc..) in the last 6 months.
• Concomitant use of antioxidant vitamins (vitamin A, C, E), anticonvulsants, tricyclic antidepressants, other medications used for neuropathic pain (gabapentin, lamotrigine, carbamazepine).
• Preexisting peripheral neuropathy resulting from other causes such as diabetes and brain disorders, hypothyroidism, autoimmune diseases, hepatitis C.
• Patients with inflammatory diseases (ulcerative colitis, rheumatoid arthritis).
• Patients with conditions associated with oxidative stress (smoking, tuberculosis, comorbid obesity).
• Patients with active liver disease (cirrhosis, fatty liver, hepatitis C, etc..).
• Patients with myopathy.
• Patients with other malignancies.
• Patients with renal impairment, including those with end-stage renal disease and those receiving dialysis.
• Patients with Gallbladder disease and gallstones.
• Pregnant and breast-feeding women.
• Patients with Known allergy to the fenofibrates.
• Concurrent use of statin, colchicine, Ciprofibrate, idelalisib, enzyme inducers (phenytoin, phenobarbitone, carbamazepine,…), enzyme inhibitors (ketoconazole, clarithromycin,…), drugs with high plasma protein binding capacity (Sulfonamides, valproate, oral hypoglycemic, warfarin,…) to avoid potential pharmacodynamics and pharmacokinetic drug interactions.