NCCN Makes Major Changes to Multiple Myeloma Guidelines

Changes Reflect Rapid Progress in the Management of MM

Fran Lowry

April 04, 2016

HOLLYWOOD, Florida — In the latest version of the multiple myeloma guidelines issued by the National Comprehensive Cancer Network (NCCN), three major changes reflect the rapid advances in the diagnosis and treatment of this disease.

The population of patients now eligible to start therapy has been broadened, use of the Revised International Staging System for Multiple Myeloma (J Clin Oncol. 2015;33:2863-2869) is now recommended, and newer agents for the treatment of multiple myeloma are included.

The updated guidelines were presented here at the NCCN 21st Annual Conference by Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute in Boston, and chair of the NCCN Multiple Myeloma/Systemic Light Chain Amyloidosis/Waldenström's Macroglobulinemia Panel.

Dr Kenneth Anderson

"We have expanded our guidelines to include more patients who can benefit from our novel treatments," Dr Anderson told Medscape Medical News.

For the first time, asymptomatic patients are now eligible for treatment, even if they are devoid of the spectrum of features abbreviated as CRAB (calcium elevation, renal insufficiency, anemia, or bone abnormalities).

Previously we've waited for those complications to develop, but now we...can start to treat those patients sooner.

"Now, patients who have bone marrow plasmacytosis of 60% or greater, or who have a free light-chain ratio abnormality greater than 100 or bone lesions detected on sensitive imaging, such as MRI or PET–CT scan, are eligible for treatment, even if they do not have the so-called CRAB features. Previously, we've waited for those complications to develop, but now we do not have to wait and can start to treat those patients sooner. That is a very important difference," he said.

To stratify patients with newly diagnosed multiple myeloma, "traditionally, we have used the International Staging System, which is predicated on serum albumin and beta-2 microglobulin," Dr Anderson continued. "We have now the revised staging system, which utilizes the beta-2 microglobulin and albumin that incorporates the FISH [fluorescent in situ hybridization] evidence of high-risk cytogenetics."

For newly diagnosed patients, whether or not they are transplant candidates, the most important changes are the incorporation of lenalidomide/bortezomib/dexamethasone as a category 1 preferred regimen. Dr Anderson noted that this recommendation is based on a phase 3 randomized trial showing superiority of the triplet therapy over a doublet, as highlighted at last year's annual meeting of the American Society of Hematology.

Another triplet included in the guidelines for the first time is lenalidomide/ixazomib/dexamethasone.

Ixazomib (Ninlaro, Millennium/Takeda), an oral proteasome inhibitor, was approved in the United States in November 2015.

"For the first time, we have a triplet consisting entirely of oral medications included as initial treatment. It is a very major advance for caregivers and especially for patients," Dr Anderson said.

New Options for Relapsed Myeloma

In the area of previously treated multiple myeloma, there were several changes to the updated guidelines, including agents in new drug classes.

The preferred regimens for previously treated multiple myeloma now are as follows, all with category 1 evidence:

  • bortezomib

  • bortezomib/liposomal doxorubicin

  • carfilzomib/lenalidomide/dexamethasone

  • elotuzumab/lenalidomide/dexamethasone

  • ixazomib/lenalidomide/dexamethasone

  • lenalidomide/dexamethasone

  • panobinostat/bortezomib/dexamethasone

  • pomalidomide/dexamethasone

Panobinostat (Farydak, Novartis), approved in the United States in February 2015, is a histone deacetylase inhibitor, a class of agent that is mentioned for the first time in the guidelines, Dr Anderson noted.

Panobinostat used in combination with bortezomib in relapsed multiple myeloma was shown to be superior to bortezomib alone, he explained.

Monoclonal Antibodies Make an Appearance

Two monoclonal antibodies — options for use in relapsed multiple myeloma — are also new in the updated guidelines.

Elotuzumab (Empliciti, Bristol-Myers Squibb) was approved in the United States in November 2015, as was daratumumab (Darzalex, Janssen).

"We have, for the first time, not one but two monoclonal antibodies. The first one is elotuzumab, targeting the antigen SLAMF7. It is approved not alone but together with lenalidomide and dexamethasone on the basis of a randomized trial showing that elotuzumab with lenalidomide/dexamethasone prolonged progression-free survival compared with lenalidomide/dex alone," Dr Anderson said.

The second is daratumumab, a monoclonal antibody targeting CD38. "This was approved as a single agent because it achieved about a 30% response rate even in patients whose myeloma was resistant to bortezomib and lenalidomide," he said.

An Exciting Time

"We have a new definition of the disease, we don't wait for CRAB features to develop, we treat if we have 60% plasma cells or a free light-chain ratio greater than 100 or bone lesions on sensitive imaging techniques. Once we have found patients eligible for treatment, we have a new way of staging them," Dr Anderson reported.

"New options for transplant or nontransplant candidates with newly diagnosed disease include lenalidomide/bortezomib/dexamethasone and ixazomib/lenalidomide/dexamethasone," he said.

"In terms of options for relapsed myeloma, we have the immunomodulatory drug combination of pomalidomide/dexamethasone. For the proteasome inhibitors, we have carfilzomib alone, carfilzomib with dex, and carfilzomib with lenalidomide/dex, and we also have ixazomib alone, ixazomib with dex, and ixazomib/lenalidomide/dex. For the histone deacetylase inhibitor, we have panobinostat with bortezomib. And for the monoclonal antibodies, we have daratumumab alone and elotuzumab combined with lenalidomide/dex. So it's been remarkable progress, but the best is yet to come," Dr Anderson said.

Dr Steven Treon

"It was a pleasure to be able to moderate the session where Ken Anderson spoke," said Steven P. Treon, MD, PhD, director of the Bing Center for Waldenström's Macroglobulinemia at the Dana-Farber Cancer Institute, who was not part of the guidelines panel.

"This is really a very exciting time, thinking about all the new drugs that have come to be approved now for the treatment of multiple myeloma," he told Medscape Medical News.

"Truly, this is of historical proportion because we have gone from a time when we were desperate and trying therapies that had very little laboratory or preclinical support, to now really being able to see how we can rationally develop medicines and get them to patients in fast time. Of course you can never say that we are doing things as fast as we could because we always want to be faster, but these are, in fact, close to record breaking times in getting these therapeutics off the ground through the FDA," he said.

"It says a lot about the preclinical work that's been done. It says a lot about the hard work that many clinical teams put in, but it also says a lot about the FDA and the fact that they are paying attention to myeloma and helping to improve patient lives," Dr Treon said.

The rapid evolvement of new treatments for multiple myeloma reflects the investment scientists have made in understanding the basic science and pathogenesis behind the disease, he added.

"We can only expect more, especially as we are unraveling the genome and understanding the genetics that are behind multiple myeloma," he said.

"We have to recognize that there are probably many diseases that are buried under the name 'multiple myeloma.' As time goes on, I think we are going to be able to exploit the weaknesses of each of these subtypes that exist within multiple myeloma," Dr Treon said.

The new medications have increased overall survival in multiple myeloma patients by two- to threefold, which is remarkable, he added.

"A lot of good things are happening, but one challenge is how we integrate all these great ideas so that we have a logical longitudinal pathway forward. The one area where I sense that we still have some questions is the role of transplant, especially in this era of novel therapies. The period of lenalidomide maintenance may have made an impact here. Newer molecules like daratumumab and some of the novel proteasome inhibitors also will probably be impactful, and as we integrate those into the front-line strategy, we may have to do another rethink about transplant," he said.

Dr Anderson reports financial relationships with Acetylon Pharmaceuticals, C4 Therapeutics, Celgene Corporation, Gilead Sciences, Millennium Pharmaceuticals, OncoPep, and Takeda Pharmaceuticals North America. Dr Treon has disclosed no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 21st Annual Conference. Presented April 1, 2016.


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