Patients with smoldering myeloma, on the other hand,
have no CRAB features. That changed in 2014, when the
International Myeloma Working Group (IMWG) updated
the diagnostic criteria for MM, adding additional specific
biomarkers to patient evaluation criteria for those who
did not display CRAB features. These included level
of serum or urine monoclonal protein (serum ≥3 g/dL
or urinary monoclonal protein of ≥500 mg/24 hours),
percentage of clonal bone marrow plasma cells (≥10%),
and serum free light chain ratio (involved to unin-
volved ratio of > 100). 1 In addition, the IMWG, including
clinicians at the Mayo Clinic in Rochester, Minnesota,
and the Centro de Investigacion Medica Aplicada in
Pamplona, Spain, recommended the use of MRI imaging
to detect the presence or absence of focal lesions. These
updated criteria, known as “SLiM CRAB,” identify a new
group of patients whose disease features now warrant
treatment, rather than the traditional “watch and wait”
approach. “SLiM” refers to three factors: ≥60% (S) plasma
cells by flow cytometry on clonal bone marrow plasma
cells, kappa-to-lambda or lambda-to-kappa light chain (Li)
ratio of >100, and ≥1 focal lesion on MRI (M).
“These criteria expanded our definition of multiple
myeloma to include patients who were previously diag-
nosed with smoldering myeloma but now are considered
to have symptomatic myeloma,” said Sagar Lonial, MD,
myeloma expert and Professor and Chair of Hematology
and Medical Oncology at the Emory University School
of Medicine and Winship Cancer Institute in Atlanta. Dr.
Lonial also served on the IMWG committee that published
the updated diagnostic criteria. “These biomarker-
driven criteria have been widely adopted around the world,”
said Dr. Lonial. “This system allows us to identify those
patients who have an 80% risk of progression to symptom-
atic myeloma within 1 year, and to intervene early with
treatment.”
According to Shaji K. Kumar, MD, who treats patients
and conducts research at the Mayo Clinic in Rochester,
Minnesota, about 7% and 10% of patients who were
previously labeled as having smoldering myeloma are
now classified as having MM based on these criteria.
Despite the acceptance of these new criteria, Dr. Richter
highlighted some caveats in the data from the IMWG. For
example, the research supporting the changes used data
from patient aspirate samples to estimate the percentage
of clonal plasma cells.
Risk-Stratifying Smoldering Myeloma
The reshuffling of patients from “smoldering” to “symp-
tomatic” based on the 2014 update resulted in the need to
redefine “high-risk” smoldering myeloma with the highest
risk of progression to MM. “There was a prior risk stratifi-
cation tool from 2008, but we found that we had to go back
to the drawing board and figure out a new risk stratification
model with different risk cutoffs,” Dr. Kumar recounted.
Addressing this issue, in 2018, Dr. Kumar and colleagues
published a revised risk stratification strategy that clini-
cians have dubbed the ”20/2/20” criteria. 2 Analyzing 421
patients with smoldering myeloma, the researchers were
able to categorize patients as having low, intermedi-
ate, or high risk of progression based on three features:
presence of >20% bone marrow plasma cells, a serum M
protein spike of >2 g/dL, and a free light chain ratio of
>20. Each factor is an independent predictor of a short-
er time to progression. The low-risk group, with none
of the features, had a 5% risk of disease progression at
2 years. Intermediate-risk patients had at least one of
these features and a 17% risk of progression, while high-
risk patients had at least two features and a 46% risk of
progression.
“For patients who have a risk of progression of 50%
at 2 years, as a community, I think we are comfortable
about discussing the potential for early interventions
with those patients,” Dr. Kumar explained.
“This tool is a way for us to provide a prognosis of
which patients fits into the highest-risk smoldering cat-
egory, but who do not meet the criteria for symptomatic
myeloma,” Dr. Lonial commented.
“It’s a great bedside tool through which clinicians
count the number of risk factors present to identify
those at higher risk for developing symptomatic dis-
ease,” added Dr. Richter.
How to Prevent Progression
Equipped with criteria to help answer the question of who
to treat, the next question becomes what to treat them
with. Researchers have two basic hypotheses about early
treatment for those with high-risk smoldering myeloma,
Dr. Kumar said: “The first is whether treatment can im-
prove overall survival and the second is whether an early
intervention could potentially cure some patients.”
Thus far, two phase III studies have demonstrat-
ed that early treatment can delay the development to
symptomatic myeloma. The first, published in 2013 by
the Spanish Myeloma Group, randomized 119 patients
with high-risk smoldering myeloma to observation
or early induction treatment with lenalidomide plus
dexamethasone. Compared with observation, treatment
delayed progression to active disease (not reached vs.
21 months), increased overall survival (94% vs. 80%),
and did not compromise the efficacy of subsequent
therapies. 3
However, the regimen has not been adopted widely
because of several issues with the trial. First, the patients
were risk-stratified using a flow cytometry technique
that is not easily executed at all treatment centers. The
second, according to Dr. Kumar, is that patients were not
diagnosed using modern imaging techniques such as MRI
and PET. In retrospect, using the 2014 staging criteria,
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