Episode 041: Myeloma Series, Pt.2 - Intro to MGUS and Smoldering Myeloma
In today’s episode, we continue our myeloma series, this time we’ll delve deeper into the spectrum of plasma cell dyscrasias, including defining MGUS, discussing surveillance of MGUS, defining smoldering myeloma (SM). We are slowly inching our discussion towards the diagnosis of Multiple myeloma (MM)!
This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.
We highly recommend you go back and listen to episode 040 to review fundamentals of testing!
Monocloncal gammopathy of undetermined significance (MGUS)
What is a monoclonal gammopathy of undetermined significance (MGUS)?
As discussed in prior episode, MGUS is defined by:
Monoclonal protein quantity (M-spike) <3 g/dL
<10% plasma cells in bone marrow
No “myeloma defining events” (more below)
If one or more of the criteria above are met, then you do a bone marrow biopsy and either whole body PET/CT or MRI to evaluate for lytic lesions
This is done so that we can identify patients who may already have myeloma or have a very high risk of developing myeloma
Affects surveillance strategies
What is the risk of progression of MGUS to overt Multiple Myeloma (MM)?
Study performed at Mayo Clinic (Rajkumar et. al. Blood. 2005.) evaluating the 20-year risk of progression to MM in patients with MGUS
If patients have all three of the risk factors, 20-year risk of progression to MM is 58%.
If only 1 risk factor, 20-year risk of progression to MM is 21%
If no risk factors are present, 20-year risk of progression to MM is 2%
This is why our guidelines are the way that they are – if someone is very low risk, spare them the bone marrow biopsy and imaging, as risk of progression is very low!
How do we interpret serum free light chains in renal failure?
As discussed in episode 040, recall the antibody structure: Y-shaped. 2 heavy chains, 2 light chains
Normally, your body produces more kappa light chains than lambda light chains.
Both of these are renally cleared
Lambda forms dimers and has a higher molecular weight, which decreases its renal clearance. Therefore, in normal situations, the kappa:lambda ratio is <1 (0.26-1.65)
In renal dysfunction, the reticuloendothelial system clears the light chains (this is not dependent on molecular weight) so the lambda dimers don’t affect clearance. Therefore, there is kappa predominance
Patients on dialysis can have kappa lambda light chains >13mg/dl and normal FLC ratio range is elevated (3.1 is normal)
How do we monitor MGUS patients?
Repeat labs at 6 months. If all lab markers are low risk, and no new red flag symptoms (bone pain, hypercalcemia, unexplained anemia, weight etc), no need to repeat labs further in the absence of symptoms
If not low risk, then repeat labs annually (CBC, CMP (renal function), SPEP and free light chains).
Studies show that most of the highest risk of progression from MGUS or Smoldering myeloma to overt MM occurs in the first year (so surveillance in the first year is very important)
After 5 years, there is a significant decrease in risk of progression
When should we proceed with bone marrow biopsy and imaging in patients undergoing surveillance?
Biggest predictor for progression to MM is M-spike rise by 0.5 and decreasing Hb of 0.5 over a course of 1 year (Atrash et al. Blood Cancer Journal 2017). These patients require further evaluation with bone marrow biopsy and/or imaging.
Smoldering Myeloma
How do we define Smoldering Myeloma (SM)?
M protein >3 g/dL (serum) or ≥ 500mg monoclonal protein/24h (urine) or Clonal plasma cells in BM ≥ 10%-60%
AND no myeloma defining events
What are “myeloma defining events”?
SLiMCRAB Criteria
S: ≥60% clonal plasma cells in BM
Li: Light chain ratio>100 or <0.1
Should also have corresponding urine monoclonal protein >200 mg/24 hours (Visram et al. Leukemia 2022)
Study showed that free light chain difference > 100 and urine < 200 was same risk as free light chain < 100 → another reason why a 24 hour UPEP is so important
M: MRI showing >1 focal lesion (>5mm in size)
C: HyperCalcemia: >11mg/dl
R: Renal insufficiency: CrCl<40 or Serum Cr>2
A: Anemia: <10 g/dl or 2g/dl below normal for that patient
B: Bone lesions: ≥1 bone lesions on CT, PET CT or bone radiographs.
Smoldering myeloma is a heterogenous disease!
A very impactful retrospective study showed (Kyle et al. 2007) that the 20-year risk of progression of SMM to MM is 80%
Smoldering myeloma has a progression risk that decreases over time like in MGUS with a 10% per year risk of progression in the first 5 years
This means that some patients with smoldering myeloma have biologically pre-malignant disease and some have more close to overt malignant disease with rapid progression in the first few years
We use risk scores to identify those who are more likely to be closer to the overt malignant disease
How do we risk stratify smoldering myeloma patients?
One scoring system is the Mayo Criteria: 20/2/20 Criteria (Calculator)
FLC ratio of >20 FLC
M-spike >2g/dL
BM plasma cells >20%
If 2 or more of these criteria are present, patients are at very high risk of progression
50% risk of progression in the first 2 years (Mateos et al. Blood Cancer Journal 2020).
How to monitor patients with low risk Smoldering Myeloma?
Monitor labs every 3-4 months for the first 5 years, then every 6 months thereafter
Closer monitoring if patients develop high risk features during this time.
What are other risk factors not encompassed in the 20/2/20 score that we should pay attention to in our SM patients?
If there is M-spike increase by 0.5 and concurrently Hb decrease by 0.5 in 12 months, this portends about 90% risk of progression to MM
Decreasing uninvolved quantitative immunoglobulins (suggests patient is preferentially producing clonal immunoglobulin)
If PET CT showed diffuse uptake OR if MRI showed 1 focal lesion (recall that you need >1, per SLiM CRAB), these patients should have repeat imaging in 6 months and then can adjust based on the patient’s scenario
High risk FISH or cytogenetic abnormalities - more to come on this in a future episode
We highly recommend you listen to our first 4 episodes in our hemepath series in preparation!
References:
https://pubmed.ncbi.nlm.nih.gov/15855274/: 2005 article from Rajkumar et al. with 20-year progression of MGUS to myeloma.
https://www.nejm.org/doi/full/10.1056/NEJMoa1709974 : 2018 article from Kyle et al. discussing long term progression of disease in MGUS patients
https://www.nejm.org/doi/full/10.1056/NEJMoa070389 : 2007 article from Kyle et al. discussing risk of progression of SM to MM
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224422/ : 2018 article from Atrash et. al discussing how changes in M-protein and hemoglobin as predictors of progression of SM.
https://www.nature.com/articles/s41375-022-01529-w : 2022 article from Visram et. al showing how corresponding urine monoclonal protein >200 mg/24 hours is just as important as FLC ratio in SLiMCRAB
https://www.nature.com/articles/s41408-020-00366-3 : The International Myeloma Working Group guidelines on risk stratifying smoldering myeloma patients by Mateos et. al 2020
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Vivek Patel
Shownotes: Maria Khan, Ronak Mistry
Graphics, social media management: Ronak Mistry
This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.
