Watching Your Free Light Chain Ratio to Determine Smoldering Myeloma Progression to Active Myeloma

“You have multiple myeloma” are the four most devastating and life-altering words I have ever heard, but what prompted this diagnosis? 

Doctors have a set of agreed upon diagnostic criteria for every condition. This is what is used to confirm a diagnosis. However, it is important to know that diagnostic criteria are not set in stone. They can evolve and change when new evidence is learned. The same is true for new findings in smoldering myeloma to determine how likely patients will be to progress to active myeloma.

When I was diagnosed in 2008 the agreed upon criteria for active myeloma was having more than 10% plasma cells in the bone marrow or biopsy-proven bony or extramedullary plasmacytoma, and any one or more of the following CRAB features and myeloma-defining events:

• C - High calcium with blood calcium over 0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
• R - Renal insufficiency with a creatinine clearance <40 mL per minute or serum creatinine >177mol/L (>2mg/dL)
• A - Low hemoglobin of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
• B - One or more bone lesions on skeletal radiography, CT, or PET/CT
• If the bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement

An Update in 2014

In 2014, the International Myeloma Working Group updated the diagnostic criteria for active myeloma to include three new biomarkers entitled myeloma defining events. The three new criteria are:

• 60% 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 light chain is at least 100mg/L (a patient's involved free light chain either kappa or lambda is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range)
• More than one focal lesion on MRI that is at least 5mm or greater in size.

So how important is this free light chain ratio over 100 when it comes to determining if smoldering myeloma will progress to active myeloma?

Using the Free Light Chain Ratio as a Progression Marker in Smoldering Myeloma

At the recent European Hematology Association (EHA) conference, Dr. Theresia Akhlaghi (@TAAkhlaghi for my fellow Twitter followers) from Memorial Sloan Kettering Cancer Center (MSKCC) presented a session entitled Evaluating Serum Free Light Chain Ratio as a Biomarker for Multiple Myeloma.

The free light chain ratio is a measurement that divides your involved light chain (kappa or lambda number) by your uninvolved light chain (kappa or lambda number). For example, if you had IgG kappa myeloma, you would divide your kappa number by your lambda number, giving you a ratio. A normal ratio between these two numbers is 0.26 - 1.65. 

In her presentation she showed evidence that not everyone with a free light chain ratio greater than 100 was imminent to progress from smoldering myeloma to active myeloma. It should be noted that patients diagnosed with high risk smoldering myeloma were excluded from this research. In her presentation, Dr. Akhlaghi concluded that:

• Patients with a free light chain ratio over 100 are a mixed group with varying risk
• Those with a free light chain ratio over 100 and both bone marrow plasma cells over 20% and an M-spike over 2g/dL progressed within 2 years (median time to progression was 18 months, 2-year progression rate 89%)
• Those with a free light chain ratio over 100 and no other Mayo-2018 risk factors were monitored for a median time of 5 years, and some up to a decade without progressing
• While a free light chain ratio over 100 is a marker of high risk of progression from SMM to active myeloma, a subset of patients can be monitored for many years without progressing
• Considering additional markers of high-risk disease such as Mayo-2018 risk factors and urine monoclonal protein levels can help identify patients with imminent risk of progression

So the free light chain ratio is not alwasy an end-all, be-all measurement when it comes to smoldering myeloma progression.

Will there be an update to the active myeloma diagnostic criteria?  This research will be discussed and validated before any changes are made by the IMWG, but this is important information to have if you are a smoldering myeloma patient deciding when treatment should be started.