The International Myeloma Working Group (IMWG) has issued updated criteria for the diagnosis of multiple myeloma.

The criteria have been published in The Lancet Oncology ^[1] and are ac­com­panied by recommendations for monitoring and updated criteria for other related plasma cell disorders.

The new diagnostic criteria represent a paradigm shift in the approach to multiple myeloma and will have considerable impact on the management of the disease.

For decades, the diagnosis of multiple myeloma required the presence of “end-organ” damage that could be attributed to the underlying plasma cell disorder. Thus, in order to be diagnosed with multiple myeloma and start treatment, patients needed to have one or more of the following “CRAB” features: increased calcium level, kidney (renal) failure, anemia, and destructive bone lesions.

One of the problems with this requirement – especially in the case of smoldering multiple myeloma – was that therapy could be started for patients only after damage to the body had already been done. In many cases, such damage can be serious and potentially irreversible. While a ”watch-and-wait” approach is appropriate and reasonable for low-risk smoldering myeloma patients, some patients diagnosed with smoldering multiple myeloma are at such a high risk of progressing to symptomatic myeloma that it did not make sense to wait for the near-inevitable to happen.

With the availability of several new treatment options for multiple myeloma, we needed to urgently identify patients who can benefit from therapy before serious organ damage occurred. There is also the potential that early therapy can prolong life. The new IMWG criteria allow the use of early indicators to diagnose myeloma before CRAB symptoms happen, and also allow the use of modern imaging methods to make an early diagnosis.

The most important changes to the diagnostic criteria for myeloma, as well as other major changes, are listed below.

Updated Definition of Multiple Myeloma

The revised IMWG criteria will allow, in addition to the classic CRAB features, the following three markers as “myeloma defining events” (MDEs).

• Sixty percent or greater clonal plasma cells on bone marrow examination
• Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L (a patient’s “involved” free light chain – either kappa or lambda – is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range)
• More than one focal lesion on MRI that is at least 5 mm or greater in size.

The presence of at least one of these markers will be considered sufficient for a diagnosis of multiple myeloma, regardless of the presence or absence of symptoms or CRAB features. Each of these markers has been shown in two or more independent studies to be associated with an approximately 80 percent or higher risk of developing myeloma-related organ damage within two years.

In addition, the IMWG criteria allow the use of CT and PET-CT for detecting osteolytic bone lesions in order to make the diagnosis of myeloma. In patients with equivocal findings on MRI, CT, and/or PET-CT, the IMWG recommends follow-up imaging. The use of modern imaging methods at diagnosis and follow-up will enable the diagnosis of myeloma to be made before serious bone damage, such as pathologic fractures, can develop.

Updated Definition of Smoldering Multiple Myeloma

The revised criteria for multiple myeloma automatically affect what we call “smoldering multiple myeloma.” Thus, the diagnosis of smoldering myeloma will now have an upper limit of 60 percent for the percentage of clonal plasma cells in the marrow. Patients considered to have smoldering myeloma should not have any myeloma defining events or amyloidosis.

A new kind of smoldering multiple myeloma, termed light chain smoldering multiple myeloma, has been recently described in a study conducted at the Mayo Clinic, and the specific monoclonal protein level required for this diagnosis has also been added.

Updated Definition and Classification of Plasmacytoma

Sometimes patients present with just a single plasma cell tumor in their body. This is called a solitary plasma­cytoma.  When the tumor presents as a single bone lesion, it is called a solitary bone plasma­cytoma. When it occurs as a single tumor outside the bone, it is a solitary extramedullary plasma­cytoma.

True solitary plasma­cytoma without any clonal plasma cells in the bone marrow has an excellent chance of cure, and needs to be differentiated from more advanced stages of the disease as well as myeloma.

The IMWG recommends the term “solitary plasma­cytoma with minimal marrow involvement” if bone marrow clonal cells are present but less than 10 percent. Patients with a single bone lesion or extramedullary plasma­cytoma who have 10 percent or more clonal bone marrow plasma cells, on the other hand, will be considered as having multiple myeloma.

Imaging recommendations

MRI, CT, or PET-CT of the whole body or spine/pelvis are needed to make a diagnosis of smoldering multiple myeloma, solitary plasma­cytoma, or solitary plasma­cytoma with minimal marrow involvement. If imaging studies show changes that are not clear cut, a repeat examination in three to six months is recommended.

Monoclonal Gammopathy of Undetermined Significance (MGUS)

The definition of MGUS has not changed. However, a new entity termed light chain MGUS has been defined.

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The IMWG effort to update the diagnostic criteria was a major undertaking that took years of work, including the research and publication of key papers to support the major changes. Researchers from around the world worked hard on this project and provided detailed input. These criteria will evolve as new data emerge, and many groups are continuing to investigate new biomarkers.

However, the biggest hurdle – which is a philosophical shift in what is called a malignancy – has been cleared, and this will make future changes that help patients easier to accomplish.

Finally, no written criteria can substitute clinical judgment. In many cases, physicians will need to continue to use judgment in making decisions on which patients need immediate therapy, and in deciding when con­tinued observation will be in the patients’ best interests.

Dr. S. Vincent Rajkumar is a professor of medicine and chair of the Myeloma Amyloidosis Dysproteinemia Group at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.