Most patients with multiple myeloma are symptomatic at the time of initial diagnosis and require treatment with cytotoxic chemotherapy. Treatment with the combination of the alkylating agent melphalan and prednisone (MP protocol) has been a standard regimen for nearly 30 years. About 40% of patients respond to the MP combination, and the median duration of remission is 2–2.5 years.
In patients who are considered candidates for high-dose therapy with stem cell transplantation, melphalan and other alkylating agents are to be avoided, as they can affect the success of stem cell harvesting.
Thalidomide is a well-established agent for treating refractory or relapsed disease, and about 30% of patients will achieve a response to this therapy. More recently, thalidomide has been used in combination with dexamethasone, and response rates approaching 65% have been observed. Studies are now under way to directly compare the combination of vincristine, doxorubicin, and dexamethasone (VAD protocol) with the combination of thalidomide and dexamethasone. In some patients, especially those with poor performance status, single-agent pulse dexamethasone administered on a weekly basis can be effective in palliating symptoms. Lenalidomide and pomalidomide are two immunomodulatory analogs (IMiDs) of thalidomide. Lenalidomide is approved in combination with dexamethasone for multiple myeloma patients who have received at least one prior therapy, and clinical data show that this combination is effective as first-line therapy. Pomalidomide is the most recent IMiD to receive approval, and this drug may be able to overcome resistance to thalidomide and lenalidomide. The side-effect profiles of these IMiDs appear to be similar, although neurotoxicity is observed more commonly with thalidomide, somewhat less often with pomalidomide, and rarely with lenalidomide.
Bortezomib was first approved for use in relapsing or refractory multiple myeloma and is now widely used as first-line therapy. This agent is thought to exert its main cytotoxic effects through inhibition of the 26S proteosome, resulting in downregulation of the nuclear factor kappa B (NF-κB) signaling pathway, which is thought to be a major signaling pathway for this disease. Of note, inhibition of NF-κB has also been shown to restore chemosensitivity. One potential advantage of bortezomib is that it can be administered by the intravenous or subcutaneous route. Carfilzomib is an epoxyketone 26S proteosome inhibitor that is approved for patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent. This agent is important as it is able to overcome resistance to bortezomib, and preclinical and clinical studies suggest that it has broad-spectrum activity in hematologic malignancies and solid tumors. Ixazomib is the newest proteosome inhibitor to be approved in multiple myeloma, and in contrast to the other proteosome inhibitors, it is orally administered with good oral bioavailability. This agent can cause peripheral sensory neuropathy, but it is also associated with GI toxicity in the form of diarrhea and nausea and vomiting, thrombocytopenia, and hepatotoxicity.
The management of primary breast cancer has undergone a remarkable evolution as a result of major efforts at early diagnosis (through encouragement of self-examination as well as through the use of cancer detection centers) and the implementation of combined modality approaches incorporating systemic chemotherapy as an adjuvant to surgery and radiation therapy. Women with stage I disease (small primary tumors and negative axillary lymph node dissections) are currently treated with surgery alone, and they have an 80% chance of cure.