[therapist]

Light chain MGUS - risk of progression

by therapist on Thu Jan 15, 2015 7:59 pm

It was mentioned in a earlier posting that:

the Mayo Clinic identified 3 factors that will influence progression from MGUS to multiple myeloma:

1. Non-IgG isotype
2. Serum M protein greater than 1.5 g/dL
3. Kappa / lambda or lambda/kappa ratio being skewed, or out of normal range.

For patients with 0 of these major risk factors, the risk of progression at 20 years is 5%. For patients with 1, the risk factor is 21%. For those having 2 of these conditions, it's 37%, and for those meeting all three of those criteria, it's 58%."

My question here is about the risk factors for progression in a kappa free light chain case (no heavy chain involvement). In that case, does the non-IgG isotype refer to IgA and IgM cases, or does it include light chain cases as well?

Also, does the skewed free light chain risk factor include those who are light chain only, because naturally their ratio is off because that is all they have?

[Ian]

Re: Light chain MGUS - risk of progression

by Ian on Fri Jan 16, 2015 4:10 am

Hi therapist,

I don't think the risk factors for progression in MGUS, generally, are applicable to light chain MGUS.

As best I can tell, the key study that's been done so far on light chain MGUS is one that was done by Dr. Dispenzieri and her colleagues at the Mayo Clinic. It was published in 2010:

A Dispenzieri et al, "Prevalence and Risk of Progression of Light-Chain Monoclonal Gammopathy of Undetermined Significance (LC-MGUS): A newly defined entity," The Lancet, May 15, 2010 (full text at PubMed)

The study shows that people with light chain MGUS have a risk of progression that is similar to low-risk (regular) MGUS. Based on a quick read of the study, it looks like it doesn't develop any risk factors for higher or lower rates of progression in light chain MGUS, and I haven't found any other study that does (but I also didn't do an exhaustive search).

One thing that struck me as I was reading the Dispenzieri study, which I hadn't noticed when reading other studies on MGUS and smoldering multiple myeloma by the Mayo group, is that the study is based almost completely on data from people of European descent. I think this is an issue with all the Mayo studies in regard to MGUS, due to the data they use, and it also somewhat affects the studies they've done about smoldering myeloma.

Hope this helps a bit. Good luck!

[Multibilly]

Re: Light chain MGUS - risk of progression

by Multibilly on Fri Jan 16, 2015 8:23 am

I also don't think that the free light chain ratio values for light chain restricted multiple myeloma are different ("off") than those found in "regular" multiple myeloma patients that also present with a heavy chain istoype. The standard Freelite assay simply measures only the free light chains, and not the heavy/light chain pairs. I've never seen any different normal free light chain reference ranges called out for light chain restricted multiple myeloma. .

But I may indeed be wrong about this assumption for light-chain restricted multiple myeloma, so it's a good question to ask your doc ... or maybe somebody with experience with light chain restricted multiple myeloma could comment on this.

[Dr. Prashant Kapoor]

Re: Light chain MGUS - risk of progression

by Dr. Prashant Kapoor on Sat Jan 17, 2015 10:22 pm

Hello Therapist,

The three Mayo risk factors for progression from MGUS to a plasma cell proliferative disorder (for example myeloma) or a lymphoproliferative disorder, which you have nicely stated above, are applicable to non-light chain MGUS – for example IgG MGUS, or non-IgG MGUS such as IgA, IgM or IgD MGUS.

Light chain MGUS was defined later, and is diagnosed upon fulfillment of certain criteria that are stated below:

1. The presence of an abnormal free light-chain (FLC) ratio (ie, ratio of kappa to lambda free light chains <0.26 or >1.65)
2. Increased level of the appropriate involved light chain (e.g., increased kappa FLC in patients with a ratio >1.65 and increased lambda FLC in patients with a ratio <0.26)
3. No monoclonal immunoglobulin heavy chain (IgG, IgA, IgD, or IgM)
4. Less than 10 percent clonal lymphoplasmacytic cells in the bone marrow
5. Absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the plasma cell disorder.

Please note that the mere presence of an abnormal FLC ratio alone, without an increase in the involved light chain, is not considered light chain MGUS.

Light chain MGUS may progress through idiopathic Bence Jones proteinuria to light chain multiple myeloma or AL amyloidosis, or light chain deposition disease. The estimated risk of progression is much lower, at 0.3 percent per year.

[Alex M]

Re: Light chain MGUS - risk of progression

by Alex M on Tue Jan 20, 2015 6:02 pm

Isn't urinary monoclonal protein less than 500 mg / 24 hours also one of the criteria?

[Dr. Prashant Kapoor]

Re: Light chain MGUS - risk of progression

by Dr. Prashant Kapoor on Wed Jan 21, 2015 8:15 pm

Hi Alex,

Thank you for pointing this out. This criterion was indeed recently added to the previous definition of light chain MGUS, based on a new study of nearly 100 patients with ‘idiopathic Bence Jones proteinuria’ that was published in October 2014. This study involved patients with urinary monoclonal light chain of ≥ 0.2 g / 24 hours in the absence of serum monoclonal immunoglobulin (M protein) or active myeloma or a related disorder.

In this study, with a very mature follow up, the patients with urinary M-protein of at least 0.5 g / 24 hours had a risk of progression very similar to that seen in patients with smoldering multiple myeloma.

Due to the high probability of progression of patients with this degree of protein in the urine to active myeloma, a threshold of 0.5 g (or 500 mg) per 24 hours was selected to define a new entity of "light chain smoldering multiple myeloma." The entity also included anyone with isolated monoclonal proteinuria with at least 10% bone marrow plasma cells or both these features in the absence of end organ damage.

This new entity was developed to fill the gap between light chain MGUS and light chain multiple myeloma, but a limitation of the study was that the serum free light chain was not measured on all the study patients, and, as such, a serum free light chain threshold could not be established for the definition of light chain smoldering multiple myeloma.

An important fallout of these findings was the establishment of an upper limit of urinary monoclonal protein for the precursor entity of light chain MGUS, which you have correctly highlighted.

Prashant

[Ruben_1980]

Re: Light chain MGUS - risk of progression

by Ruben_1980 on Wed May 23, 2018 4:21 am

Dear all,

I encountered an interesting publication written by German researchers, entitled "Light chain monoclonal gammopathy of undetermined significance is characterized by a high disappearance rate and low risk of progression on longitudinal analysis".

I just noted that the Beacon has a helpful summary of this publication:

"Researchers Find No Disease Progression, And Frequent Disease Disappearance, In Study Of Light Chain MGUS," The Myeloma Beacon, May 15, 2018 (also: German translation of article)

For me the key takeaways are:

• Light chain MGUS may go into full remission (particularly if the involved levels are on the lower end); and
• Results from earlier studies are confirmed that light chain MGUS has a relatively low risk of progression.

Best wishes,
R