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
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
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
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
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.