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New Myeloma Guideline Expands Diagnostic Criteria, Adds Novel Agents

Published Online: Jul 06,2016
Substantial changes were made to the latest version of the NCCN guideline for multiple myeloma to address the multitude of newly approved agents for patients with this disease, according to a presentation by Kenneth Anderson, MD, at the 2016 NCCN Annual Conference.

In the relapsed/refractory setting, 8 new options appear in the most recent update to the guideline. In newly diagnosed patients, primary therapy now includes lenalidomide plus dexamethasone in combination with bortezomib (preferred) or the ixazomib. Additionally, the “active” myeloma category was expanded through an adjustment in the diagnostic criteria, to make more patients eligible for therapy.

“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 multiple myeloma 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 multiple myeloma guidelines includes a revised International Staging System that incorporates cytogenetics for the first time, in order to define prognosis following treatment. Moreover, more stringent measures of complete response (CR) were included, with a molecular CR now defined as <1 myeloma cell per 1 million normal cells by sequencing or immunophenotypic CR by multicolor flow cytometry, the most sensitive of which can detect <1 myeloma per 1 million normal cells.


In bone marrow transplant candidates, primary treatment options in the most recent guideline include a proteasome inhibitor plus lenalidomide and dexamethasone. The recommendation for the use of triplet combination therapy in newly diagnosed multiple myeloma is based on synergies in activity in preclinical models and in the clinic, said Anderson. The 3 primary proteasome inhibitors available include bortezomib, carfilzomib, and the oral agent ixazomib, which was most recently introduced. These agents have shown varying levels of evidence in the frontline setting.

In the phase III SWOG S0777 trial, the triplet of bortezomib plus lenalidomide and dexamethasone demonstrated improvements in CR rates (including molecular CR), progression-free survival (PFS), and overall survival (OS) compared with lenalidomide/dexamethasone alone.2

The complete response rates were 15.7% and 8.4%, with bortezomib and without. Median PFS with bortezomib was 43 versus 30 months with lenalidomide and dexamethasone alone (HR, 0.712; 96% CI, 0.560-0.906; one-sided P = .0018). The median OS was 75 months in the bortezomib arm compared with 64 months for the doublet (HR, 0.709; one-sided P = .0125).

Ixazomib and carfilzomib were not listed under the preferred regimens, but were identified as other options. Carfilzomib plus lenalidomide and dexamethasone was included in the new guideline as a category 2A therapy in the frontline setting, based on a phase I/II study showing a response rate of 100%, with a near CR rate of 87% and a stringent CR rate of 65%. The 3-year PFS rate was 79.6%.3

Ixazomib, which is approved in the relapsed/refractory setting, has also been explored as an upfront therapy, with a phase III currently ongoing. In a phase II study,4 induction therapy with the all-oral regimen of ixazomib plus lenalidomide/dexamethasone produced a 90% response rate, including a 59% very good partial response or better.

Following induction, ixazomib was continued as single agent maintenance therapy. In the maintenance arm, 11 patients experienced a CR with continuous ixazomib (52%), 4 of which were stringent CRs (19%). Overall, 33% of patients had an improvement in their response during maintenance treatment.

The recommendation to use triplet therapy upfront applies to transplant candidates and very fit nontransplant candidates. Following induction regardless of transplant, maintenance therapy “is a standard of practice in multiple myeloma,” Anderson said.

Preferred maintenance regimens in the new guideline are bortezomib, lenalidomide, and thalidomide. PFS is approximately doubled with the use of lenalidomide maintenance post-transplant. 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.5

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New Myeloma Guideline Expands Diagnostic Criteria, Adds Novel Agents
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