New Myeloma Guideline Expands Diagnostic Criteria And Adds New Agents to the Mix

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The National Comprehensive Cancer Network (NCCN) establishes guidelines for myeloma treatments. Doctors use these guidelines to understand the various treatment options that are available and approved for patients. Eight new options were updated in the guidelines for 2016. To help make sense of it all, here are key take-aways according to a recently published article in Targeted Oncology:

Newly Diagnosed Multiple Myeloma

Up-Front Treatment

In newly diagnosed patients, primary therapy now includes lenalidomide plus dexamethasone in combination with bortezomib (preferred) or the oral proteasome inhibitor,  ixazomib.  Here’s more information on the newly-approved drug ixazomib:

Defining Active Myeloma At Earlier Stages

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 Kenneth 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, if patients have the following, they can be diagnosed with “active myeloma” and qualify for treatment:

  • 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 guidelines have a revised International Staging System (ISS) that incorporates cytogenetics for the first time in order to define prognosis following treatment. Stringent measures of complete response (CR) were included, with a molecular complete response 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.

Upfront Therapy for Transplant Candidates

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 three primary proteasome inhibitors available include bortezomib, carfilzomib, and the oral agent ixazomib, which was most recently introduced. These agents have shown varying levels of success in the frontline setting but based on results from the Phase III SWOG S0777 trial, a triplet (bortezmib, len, dex) was clearly better than the doublet of len/dex alone.

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Upfront Therapy for Non-Transplant Candidates

  • In newly diagnosed non-transplant candidates with multiple myeloma, primary therapy now includes the triplet of lenalidomide plus bortezomib and dexamethasone or ixazomib plus lenalidomide and dexamethasone, which is listed as an “other” regimen.
  • Adding a proteasome inhibitor or immunomodulatory agent to melphalan and prednisone in this setting has translated into improvement in progression free survival and overall survival.

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  • Continuous lenalidomide plus dexamethasone was incorporated into the guideline and was superior to melphalan, prednisone, and thalidomide in newly diagnosed transplant-ineligible patients with multiple myeloma.
  • Findings from this study established the lenalidomide regimen as a new standard of care, said Anderson. In the study, median PFS with continuous lenalidomide/dexamethasone was 25.5 months compared with 21.2 months with melphalan, prednisone, and thalidomide. Additionally, continuous lenalidomide/dexamethasone was superior to the melphalan-containing regimen for OS. The 4-year OS rate was 59% with lenalidomide versus 51% for the melphalan group.

Relapsed/Refractory Multiple Myeloma

Ixazomib as Upfront Treatment and as Maintenance Therapy

Ixazomib has also been explored as an upfront therapy, with a phase III currently ongoing. In a phase II study, 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 complete response with continuous ixazomib (52%), 4 of which were stringent complete responses (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 non-transplant 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. Progression free survival 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 progression free and 5-year overall survival advantage versus no maintenance, whether or not the patient undergoes transplant.

Triple Combinations

A number of the preferred regimens listed in the new guideline for pretreated patients included triplet combinations, specifically those that build upon lenalidomide and dexamethasone, which are recommended alone or in combination with carfilzomib, elotuzuumab, ixazomib, cyclophosphamide, or panobinostat. Additionally, the latest guideline elevated the combination of pomalidomide and low-dose dexamethasone to category 1 regimen for patients with relapsed/refractory multiple myeloma.

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  • The triplet of carfilzomib, lenalidomide and dexamethasone was found to be superior to lenalidomide and dex alone (phase III ASPIRE trial).
  • Adding elotuzumab to lenalidomide and dexamethsone was better than lenalidomide and dexamethasone alone. The addition of the antibody reduced the risk of progression or death by 27% and improved OS by 4.1 months. The agent received a category 1 listing as a preferred regimen in the pretreated setting.

Other Additions

  • Daratumumab is currently recommended following 3 prior treatment regimens. Alone it showed a 65% one-year overall survival rate and a 29.2% response rate (phase II MMY2002 study). In another study (phase I/II GEN501 study) the response rate was 36%, median progression free survival was 5.6 months, and the 1-year overall survival rate was 77%.
  • The first HDAC inhibitor, panobinostat, showed sustained improvements in progression free survival and is suggested for patients who have received at least two prior regimens. It extended progression free survival by 3.9 months (phase III PANORAMA-1 trial) compared to bortezomib and dexamethasone alone. In a group of 147 patients, adding panobinostat to bortezomib and dex improved progression free survival by 7.8 months for patients who had received two prior treatments (including bortezomib and an iMiD).

“It’s been a truly remarkable year in multiple myeloma, we’ve had 16 new FDA approved treatments in the last 12 years and last year alone we had 7 new FDA approved treatments, so the 2016 version of the NCCN guidelines is completely revised,” concluded Anderson.

To read the article in its entirety, click here.

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About Author

Lizzy Smith was diagnosed with myeloma in 2012 at age 44. Within days, she left her job, ended her marriage, moved, and entered treatment. "To the extent I'm able, I want to prove that despite life's biggest challenges, it is possible to survive and come out stronger than ever," she says.

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