Kenneth C. Anderson, MD
The updated NCCN guideline on the diagnostic criteria for and management of multiple myeloma (MM)—Version 3.2016—broadens the population of patients eligible for therapy by expanding the active myeloma category and also integrates novel therapies at all stages of disease.
Speaking at the 2016 NCCN Annual Conference, Kenneth Anderson, MD, noted 7 new drug approvals with indications in MM in 2015 alone.1
“In the guidelines this year, the criteria for treatment of multiple myeloma have changed,” said Anderson, director of the Multiple Myeloma Center at Dana-Farber Cancer Institute. “Previously, treatment has demanded abnormalities in calcium, renal function, anemia, and bone disease [the so-called CRAB features]. However, that is no longer true.”
Even without CRAB features, the following are sufficient to define active MM in asymptomatic patients, and qualify such patients for treatment, according to the NCCN:
• Bone marrow plasmacytosis ≥60%
• Abnormal free light chain ratio ≥100 (involved kappa) or <0.01 (involved lambda)
• Focal bone marrow lesions detected by functional imaging
The new iteration of the MM guideline includes a revised International Staging System that incorporates cytogenetics for the first time to define prognosis following treatment. In addition, more stringent measures of complete response (CR) are a part of Version 3.2016. A molecular CR is defined as <1 myeloma cell of 1 million normal cells by sequencing, or immunophenotypic CR by multicolor flow cytometry, the most sensitive of which can detect <1 myeloma of 1 million normal cells.
In bone marrow transplant candidates, primary treatment options in the most recent guideline include bortezomib/lenalidomide/dexamethasone (category 1) and ixazomib (a new oral proteasome inhibitor)/lenalidomide/dexamethasone.
A recommendation for the use of combination therapy in newly diagnosed MM is based on synergies in activity in preclinical models and in the clinic, said Anderson. The triplet of bortezomib/lenalidomide/dexamethasone improves CR rates (including molecular CR), progression-free survival (PFS), and overall survival (OS) compared with lenalidomide/dexamethasone.2
The recommendation to use triplet therapy up front applies to transplant candidates and very fit nontransplant candidates.
Whether the patient proceeds to transplant or not, maintenance therapy following induction therapy “is a standard of practice in MM,” he said. Preferred maintenance regimens in the new guideline are bortezomib, lenalidomide, and thalidomide. PFS is approximately doubled with the use of lenalidomide maintenance posttransplant. In North America, maintenance until progression is recommended. Subcutaneous bortezomib every other week as maintenance has also conferred a PFS and 5-year OS advantage versus no maintenance, whether or not the patient undergoes transplant.3
Carfilzomib/lenalidomide, and dexamethasone was included in the new guideline as a category 2A (other) therapy based on a phase 1/2 study showing a 100% CR and 85% stringent or near CR.4
Ixazomib has a half-life of 3 to 4 days, requiring only once weekly administration. An all-oral regimen of ixazomib/lenalidomide/dexamethasone for the initial treatment of MM produced a 100% response rate. Ixazomib used as single agent for maintenance upgraded these responses.5
Attempts to improve upon the responses with triplet therapy include the addition of panobinostat, a broad-acting histone deacetylase inhibitor, as a fourth agent, or a monoclonal antibody.
In newly diagnosed nontransplant candidates, primary therapy in Version 3.2016 now includes lenalidomide/bortezomib/dexamethasone (category 1) and ixazomib/lenalidomide/dexamethasone as an “other” regimen. Adding novel agents to melphalan and prednisone in this setting has translated into improvement in PFS and OS.