The line between benign and malignant is becoming harder to define, said Joseph R. Mikhael, MD, FACP, a professor at the Translational Genomics Research Institute in Phoenix and chief medical officer of the International Myeloma Foundation.
The internal medicine specialist “is really critical in helping determine that … to make sure that we don't overcall nor undercall cancers,” he said during his session at Internal Medicine Meeting 2023, held in San Diego. “The idea is to catch early, and maybe not too early.”
One example is prostate cancer. “If I went and biopsied the prostate of every man in San Diego over the age of 75 today, chances are a quarter or a third of them will have some evidence of prostate cancer,” Dr. Mikhael said. “But for the overwhelming majority of them, it'll be a tiny schmutz of a few cells that, chances are, wouldn't grow to significance until they turn 120.”
Similarly, with blood cancers, there is often a tiny amount of malignancy that may never grow to significance, he noted. “I describe it to patients as finding a little dust in the corner: It's so small, it doesn't affect the room, we don't need to get a vacuum cleaner and get rid of it,” Dr. Mikhael said. “So where do you draw the line between that tiny little bit of dust and enough dirt in the room that we have to do something about it? That's the essence of this talk today.”
He reviewed practical approaches to two premalignant conditions, monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis (MBL).
MGUS and multiple myeloma
MGUS is an asymptomatic condition that affects about 5% of patients over age 40 years, Dr. Mikhael noted, adding that it is twice as common in those of African American descent. MGUS precedes multiple myeloma, with an annual risk of transformation of about 1%, he added.
Multiple myeloma used to be defined by the CRAB criteria alone (calcium elevation, renal complications, anemia, and bone disease). In 2014, the International Myeloma Working Group updated the diagnostic criteria with three more features: 60% plasma cells in the bone marrow, a serum free light-chain ratio greater than 100, and an MRI with one or more focal lesions in the marrow, said Dr. Mikhael, who called the new criteria SLiM CRAB.
But often, by the time patients present with these criteria, the diagnosis has been delayed, he said. Patients with multiple myeloma may see their primary care clinician three times with signs and symptoms before they're referred to hematology and diagnosed, according to results of a study published in November 2021 by Blood. “We need your help,” Dr. Mikhael said. “If I'm the one diagnosing myeloma, it's late.”
These delays are more pronounced in certain populations, he added. “Typically, in African American and Hispanic populations, we've seen this prolonged for lots of reasons. Part of it is because of diabetes.”
Diabetes can mimic symptoms of myeloma, including anemia, proteinuria, renal insufficiency, and neuropathy, Dr. Mikhael said. “It can unfortunately hamper the accurate diagnosis of myeloma,” he said. “So it is really important that we capture those signs and symptoms that point us in that direction, because we're not at a stage yet where we're recommending screening for plasma cell disorders.”
Internal medicine and primary care physicians represent the “gatekeepers to myeloma” because for most patients, the initial presenting symptoms are fatigue and back pain, and the most common sign is anemia, Dr. Mikhael noted. “How many times are you going to see those three things in a clinic?”
While there's no complete consensus about how to approach such common manifestations, clinical judgment is key, he said. Patients with symptoms like persistent bone or back pain, unexplained fracture, renal insufficiency without a clear cause, and osteopenia or osteoporosis that is not compatible with age and gender may raise suspicion for myeloma, Dr. Mikhael said. “This is not a perfect list, but these are the essential areas that should launch you into testing.”
Laboratory workup includes a complete blood count (CBC) with differential and platelet count, kidney function tests (chemistry panel, estimated glomerular filtration rate, and electrolytes), and serum proteins (albumin, beta-2 microglobulin, lactate dehydrogenase, and C-reactive protein), he noted.
“But then, perhaps most importantly, are the monoclonal proteins,” with testing including serum and urine protein electrophoresis, immunofixation electrophoresis, quantitative immunoglobulins, and a serum free light-chain assay, Dr. Mikhael said. “That really should be the standard of what we do. And not only is it helpful ultimately in the diagnosis, but we can use it, of course, in monitoring.”
Based on those results, MGUS risk scores can provide guidance using three factors: M-spike greater than 1.5 g/dL, non-IgG type, and abnormal free light-chain ratio, he added. “You either get a score of 0, you've got none of those, or you get 1, 2, or 3. If your score is 0, your 20-year risk of developing myeloma is only 5%,” Dr. Mikhael said. “But if you have all three, your risk is nearly 60%, so there is a difference in the way we approach it,” although not all patients will require a bone marrow evaluation.
In general, patients with MGUS should be followed up about once a year, he said. “I typically follow MGUS patients twice annually the first year and then go to annually, just in case we caught them in a more proliferative phase,” Dr. Mikhael said.
He added that early detection isn't just better patient care; it's cost-saving care. “Detecting things earlier, even though there's some upfront testing, can save a lot of organ damage and complications later,” said Dr. Mikhael, who was lead author of a multiple myeloma review for primary care clinicians that promoted earlier diagnosis among diverse populations, published in the January American Journal of Medicine.
MBL and chronic lymphocytic leukemia (CLL)
In many ways, MBL is “the MGUS of CLL,” Dr. Mikhael said. “It's where there is monoclonality, there is a low level of the disease, but we want to be careful not to overcall it, and we also don't want to undercall it because it is actually quite prevalent.”
MBL refers to a monoclonal population of B lymphocytes less than 5,000 cells/µL (<5 × 109/L) in peripheral blood that has been present for three or more months, without other key features that define a B-cell lymphoproliferative disorder (e.g., lymphadenopathy, organomegaly, cytopenias, or extramedullary involvement).
The incidence of about 3% to 5% is also similar to that of MGUS, he noted. “And sure enough, much like MGUS precedes myeloma, MBL seems to precede CLL, so it does seem that most patients go through that phase.”
Risk factors for MBL onset include a family history of CLL, certain genetic polymorphisms, age, and recurrent infections, Dr. Mikhael noted. Risk factors for MBL progression to CLL include CD38 positivity, unmutated immunoglobulin heavy-chain variable region gene, 17p deletion, and elevated B-cell count, he said.
While MBL is an asymptomatic precondition of CLL, these individuals are at greater risk of developing infections, Dr. Mikhael said. “So there is some inherent immune effect already, and also, there is a greater risk of developing malignancy in general.”
Sending a patient with MBL for diagnostic evaluation by a hematologist would entail a history and physical, immunophenotype of lymphocytes, a CBC with differential, and fluorescence in situ hybridization testing, he noted. “But they're probably not going to do a CT, not going to do a marrow [biopsy], and not going to do some of the other more sophisticated prognostic testing.”
As for patient counseling and monitoring, reducing use of the term “leukemia” is generally a good idea, Dr. Mikhael said. “There is a consensus that maybe calling it MBL instead of ‘preleukemia’ sounds a little better because, of course, the word leukemia just comes with such a stigma and such a concern,” he said. “But at the same time, these people do have to be followed … on an annual basis.”
Follow-up should include a physical exam and a CBC that looks specifically for the white blood cell count, Dr. Mikhael said. “There are some recommendations that vitamin D levels be checked and vitamin D be given because of vitamin D deficiency's connection to lymphoproliferative diseases in general, and obviously making sure that they are well vaccinated because of that [infection] risk,” he said.