NCCN Broadens Myeloma Diagnostic Criteria, Recommends Novel Agents

The updated NCCN myeloma guideline broadens the diagnostic criteria for active disease and integrates novel therapies into the treatment paradigm.

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.

Transplant candidates

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

Nontransplant candidates

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.

Relapsed/Refractory MM

The reason for incorporating continuous lenalidomide/dexamethasone to melphalan/prednisone in newly diagnosed nontransplant candidates with MM is a significant extension of PFS with a favorable safety profile,6 establishing this regimen as a new standard of care, said Anderson.Eight new options for the treatment of previously treated MM appear in the most recent update to the guideline. Carfilzomib/lenalidomide/dexamethasone is a category 1, the monoclonal antibody daratumumab, ixazomib/lenalidomide/dexamethasone, and the monoclonal antibody elotuzumab with lenalidomide/dexamethasone are among the preferred regimens. Pomalidomide/low-dose dexamethasone was elevated to category 1 for patients with relapsed/refractory MM.

Carfilzomib/lenalidomide/dexamethasone in relapsed MM enhanced PFS by about 6 months whether patients had high-risk or standard cytogenetics compared with a doublet of lenalidomide and dexamethasone.7 Carfilzomib/dexamethasone without lenalidomide is another addition in this setting, having proved superior to bortezomib/dexamethasone on the endpoint of PFS with equivalent tolerability and little neuropathy.8

The combination of pomalidomide and carfilzomib has also been added as an option in patients with relapsed/refractory disease.

“For the very first time, we have a histone deacetylase inhibitor included in the armamentarium of [relapsed/refractory] myeloma,” said Anderson. Panobinostat added to bortezomib and dexamethasone improved median PFS by 4 months and increased rates of CR and near CR compared with bortezomib/dexamethasone.9

The monoclonal antibodies daratumumab and elotuzumab also appear for the first time as options for MM patients who have received prior therapy or have refractory disease.


  1. Anderson KC. Updates on diagnostic criteria and management of multiple myeloma. Presented at: 21st NCCN Annual Conference, March 30-April 2, 2016; Hollywood, FL.
  2. Durie B, Hoering A, Rajkumar SV, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): Results of the randomized phase III Trial SWOG S0777. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 25.
  3. Cerrato C, Gay F, Petrucci MT, et al. Significant survival improvement with maintenance in patients achieving a complete response: pooled analysis of 4 Italian phase III trials in newly diagnosed multiple myeloma patients. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 1974.
  4. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012; 120:1801-1809.
  5. Kumar S, Berdeja JG, Niesviky R, et al. Long-term ixazomib maintenance is tolerable and improves depth of response following iIxazomib-lenalidomide-dexamethasone induction in patients (pts) with previously untreated multiple myeloma (MM): Phase 2 study results. Presented at 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 82.
  6. Benhoubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;271:906-917.
  7. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.
  8. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): Results from the phase III study ENDEAVOR. Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 8509.
  9. San Miguel J, Wesiel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055-1066.


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