NEW YORK CITY—Atypical, or smoldering myeloma is usually a case for watchful waiting, but a Mayo Clinic hematologist says some cases should be treated as multiple myeloma even when there are no “CRAB” features.
A diagnosis of malignant myeloma is commonly based on CRAB criteria—elevated calcium, renal failure, anemia, and bone lesions.
Speaking here at the Lymphoma & Myeloma International Congress on Hematologic Malignancies, S. Vincent Rajkumar, MD, Professor of Medicine at the Mayo Clinic, said there is a subset of patients with smoldering myeloma, perhaps 20 percent, who are at very high risk of progression to multiple myeloma but who do not have end-organ damage.
“The current definition of multiple myeloma that requires end-organ damage is outdated,” he said. “We are now saying there are other factors besides end organ damage that can be used to identify patients who need therapy.”
This would change practice, he said in an interview after his presentation. Rajkumar described some of the highly specific markers already determined to be prognostic, including high levels of circulating plasma cells, bone marrow involvement of 60 percent or more, a free light chain ratio (involved/uninvolved) of 100 or more, and, especially, an involved free light chain level of 100 or more.
“And a rapid increase in M protein and bone marrow plasmacytosis with MRI or PET changes, that might be enough for me to treat,” he said.
Details of other biomarkers of high predictive value are in a recent article he coauthored in Nature Reviews Clinical Oncology (2012;9:494-496).
Not a Common Diagnosis
Smoldering myeloma is not a common diagnosis in the clinic, Rajkumar said. Of the 1,700 multiple myeloma patients seen in 2011 at the Mayo Clinic, for example, only 81 had smoldering myeloma. And only 16 of those then developed bone lesions, fractures, and renal failure in the first two years.
He encouraged hematologists to enroll patients in the randomized Phase III ECOG 3A06 trial of lenalidomide vs. observation in patients with asymptomatic high-risk smoldering myeloma, to answer the question of best management for these cases.
“Eight out of 10 patients identified with these specific biomarkers actually will progress within the first couple of years and will get into serious trouble,” he said. “Ignoring that means you will be willing to be wrong eight out of 10 times.”
The Chairman of the meeting, Morton Coleman, MD, Clinical Professor of Medicine and Director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital-Weill Cornell Medical Center, said that Rajkumar “may be on the right track” in establishing criteria to select patient at very high risk: “If it is true that we can tease out that subset of patients who are apt to go into full-blown multiple myeloma and treat them early, Dr. Rajkumar suggested there might even be a survival advantage,” Coleman said in an interview.
“That remains to be seen, and there are studies ongoing to more particularly define this question.
“But before there could be any wide application of early treatment, you have to show not only enhanced progression-free survival, which I have no doubt they will show, but you have to enhance survival.”
Progression of Paraprotein
Another speaker at the meeting, David S. Siegel, MD, PhD, Chief of the Division of Multiple Myeloma at John Theurer Cancer Center at Hackensack University Medical Center, said the progression of paraprotein should be criterion enough to establish the diagnosis of myeloma.
“The staging systems we have now don't allow the fact that paraprotein is rising to be included in our consideration of whether or not the patient has myeloma,” he told OT. “But the reality is that the patients who are progressing are the ones who are ultimately going to need therapy.
“The first time you see them, they have 500 mg of light chain in their urine, the second time they have 1,500 mg, and while according to the diagnostic criteria that person still doesn't have multiple myeloma, the next time you see them they have renal failure. So what are you supposed to do, sit there and wait for the patient to show up with renal failure? That's not in anybody's best interest, including the people who pay for the drugs and pay for the care. And yet that's what they expect us to do—not treat that patient until they become symptomatic, and that's reprehensible.”
Siegel said free light chain ratios greater than 100 percent or 60 percent bone involvement only identify a very small subset of patients. “If it's progressing it should be called myeloma and there should not be any debate from insurers or clinical trials as to those patients being defined as symptomatic myeloma patients, whether they have a CRAB criteria or not.” he said.
This presents a significant technical problem with insurers and clinical trial organizers, he added. “If they look at the charts and ask if these patients have symptomatic myeloma, well, they don't. And if you try to include that patient in a clinical trial at a later date, [they'll say] that patient got started on treatment without justification and they're not eligible for a transplant or clinical trial—and that's just wrong.”
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