New York, NY—In patients with newly diagnosed multiple myeloma, deep remissions and the prevention of relapse are best achieved by targeted combination therapy very early in the disease, according to Kenneth C. Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, Boston, in a presentation at the National Comprehensive Cancer Network 7th Annual Congress on Hematologic Malignancies.
“Multiple myeloma is a complex disease. The average number of mutations at diagnosis is 58. We have new data showing that at relapse, new mutations arise, copy numbers change, and the translocations change,” Dr Anderson explained.
Because of this, he said, he is “passionate” about choosing the best upfront treatments to overcome poor cytogenetics. “Don’t allow genetic evolution to occur in this hideously complex disease,” Dr Anderson emphasized.
Although the genes expressed in multiple myeloma are becoming known, there is presently no universally applicable genetic profile signature that can predict outcomes related to them.
The necessity to choose the most potent regimen holds true for consolidation after transplant as well, Dr Anderson added. Several drugs and combination regimens have been studied as consolidation therapy, including bortezomib monotherapy; lenalidomide monotherapy; the combination of bortezomib and lenalidomide; and the combination of bortezomib, thalidomide, and dexamethasone.
Dana-Farber Cancer Institute no longer uses interferon-alpha or thalidomide for consolidation and maintenance, he added.
“Strong Case” for Triplet Combination Therapy
Combinations of bortezomib, lenalidomide, dexamethasone, and thalidomide are currently the first-line treatment options.
“Studies have made a strong case for triplet combination therapy using a proteasome inhibitor and a thalidomide analog [IMiD] both pre- and posttransplant,” Dr Anderson said. At Dana-Farber, he noted that lenalidomide, bortezomib, and dexamethasone (RVD) is a favored regimen.
In the pivotal phase 2 study of RVD by Richardson and colleagues, the rate of partial response was 100%, and 74% of patients achieved a very good partial response or better (Richardson PG, et al. Blood. 2010;116:679-686).
In transplant candidates, “a 3-drug regimen is most active. Data suggest that we can use new drugs to consolidate and increase response, prolong progression-free survival, reduce the risk of relapse, and extend survival,” Dr Anderson noted. “In my paradigm, I want to achieve the best response, consolidate it, and maintain it to preempt chromosomal change.”
The newly approved proteasome inhibitor carfilzomib, when combined with lenalidomide and dexamethasone, also achieves universal responses and enables adequate stem-cell collection (Jakubowiak AJ, et al. American Society of Hematology 53rd Annual Meeting; December 10-13, 2011. Abstract 631), said Dr Anderson.
The next-generation proteasome inhibitor, the oral agent MLN9708, is also achieving 100% response rates in combination with lenalidomide and dexamethasone, and Dr Anderson believes this drug will become a valuable option.
Maintenance Therapy
Lenalidomide is currently being used for maintenance after transplant, Dr Anderson said. Data supporting this come from the recently published CALGB 100104 trial, which randomized patients after transplant to placebo or lenalidomide 10 mg/day, with dose adjustments ranging between 5 mg daily and 15 mg daily (McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781). Lenalidomide significantly improved progression-free survival, to a median of 46 months versus 27 months in the placebo arm (P <.001).
Although all patients receiving placebo have crossed over to receive lenalidomide maintenance, a survival advantage is still evident for patients randomized to lenalidomide at the start of the trial. The advantage of lenalidomide maintenance was observed in all subgroups, Dr Anderson noted.
He said that studies have shown that the risk of secondary cancers is highest in the context of treatment with alkylating agents, and therefore patients should “avoid using multiple alkylating agents.”
Dr Anderson mentioned that the new subcutaneous formulation of bortezomib will be studied as maintenance therapy. The drug is associated with a markedly reduced risk for neuropathy, he noted.