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Brief description/objective

Multiple myeloma (MM) accounts for 1% of all cancers and ∼10% of all hematological malignancies. Despite recent advances in myeloma treatment, including the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs) and stem cell transplantation, myeloma remains an incura-ble disease. The treatment of bortezomib and lenalidomide refractory myeloma is still an unmet medical need. Once
patients have relapsed after IMiD-containing therapies and have become bortezomib-resistant, their prognosis is ex-tremely poor.

Pomalidomide is a third-generation, Swissmedic approved, oral immunomodulatory drug with activity in such patients. Toxicity of pomalidomide in the pivotal MM-003 trial, how-ever, was considerable, with 60% of patients experiencing drug-related G3/4 toxicity. Neutropenia (48% vs 16%) and pneumonia (13% vs 8%) were significantly more common in the pomalidomide arm. This resulted in frequent dose interruptions (67%) and dose reductions (27%). This sug-gests that for the majority of patients the 4 mg daily dosing schedule (4 mg daily on 21 of 28 days) is toxic, and
that strategies to deliver reduced dosing of pomalidomide are of high practical relevance.

Alternative dosing schedules
There are robust data available that lower pomalidomide doses (e.g. 2 mg daily) lead to similar responses and pro-gression free survival with fewer side effects. Due to its unique pharmacological characteristics, pomalidomide is
well suited for alternate day dosing. The decline of the plasma concentration at the terminal phase is slow. These data make pomalidomide an ideal candidate for alternate day dosing. Therefore, a Phase 1 study has already been conducted in 2008 to test the alternating administration of the drug showing excellent responses with a marked re-duction of thrombotic events and less severe myelosup-pression.
The drug costs of pomalidomide are high (Switzerland: 12.400 CHF per 4 week cycle; US: 13.700 US$ per 4 week cycle). Interestingly, the manufacturer chose a pricing model that is independent from the capsule strength (costs for one capsule 1 mg=2 mg=3 mg=4 mg). In patients
requiring dose reductions due to hematologic toxicity, daily dosing of reduced strength pomalidomide (e.g. 2 mg daily) is approved and suggested by the manufacturer. This de-livers 50% less pomalidomide to the patient, albeit at 100% of the price of full dosing.
In summary, the establishment of the modified pomalido-mide schedule would be an interesting option for our pa-tients to achieve similar efficacy with fewer side effects. In addition optimizing the cost-effectiveness of the drug.

The main objective is to establish that alternate day dosing of pomalidomide (4 mg q2d, d1-28) is non-inferior to daily dosing (4 mg d1-21 q28).