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‘Missing Piece of Myeloma Puzzle’ Defined

Kim, Meeri PHD

doi: 10.1097/


A new retrospective cohort study has for the first time defined the clinical course of light-chain smoldering multiple myeloma—i.e., the disease stage preceding light-chain multiple myeloma.

A subset of patients with idiopathic Bence Jones proteinuria were found to have an increased risk of disease progression to light-chain multiple myeloma, which accounts for approximately 15 to 20 percent of all myeloma patients. The subset is identified by monoclonal light-chain excretion of 0.5 g in 24 hours or higher, at least 10 percent bone marrow plasma cells, or both, in the absence of end-organ damage. These parameters define the new entity, called light-chain smoldering multiple myeloma (LC-SMM).

In the study (Lancet Haematology 2014;1:e28-e36), led by Robert A. Kyle, MD, MACP, Professor of Medicine in the Department of Medicine, Laboratory Medicine & Pathology at the Mayo Clinic, after the diagnosis of idiopathic Bence Jones proteinuria, patients with LC-SMM went on to develop multiple myeloma or light-chain amyloidosis at a rate of approximately four percent a year for the first five years, and then decreased to three to four percent per year for the next five years. However, patients as far out as 15 years after diagnosis remained at risk of progression.

For patients, the cumulative probability of progression was found to be high: about 28 percent at five years, 45 percent at 10 years, and 56.5 percent at 15 years.

These patients with light-chain smoldering multiple myeloma represent the missing link between the premalignant phase, termed light-chain monoclonal gammopathy of undetermined significance (LC-MGUS), and symptomatic light-chain multiple myeloma, the researchers explained. Because the risk and rate of disease progression have now been outlined in detail, this particular subset of patients can be observed with greater vigilance and may even benefit from early intervention if the risk of disease progression is high.

“When we describe new entities like this, they become recognized in practice,” Kyle said in an interview. “The hope is that light-chain smoldering multiple myeloma will be recognized much more often.”

More than 30 years ago, Kyle and his colleagues first described seven cases of idiopathic Bence Jones proteinuria with a urinary excretion of greater than 1.0 g in 24 hours. None of the patients had evidence of symptomatic disease initially, but as the researchers continued to follow the cohort over the years, the majority of patients developed myeloma or amyloid light-chain (AL) amyloidosis. So even though idiopathic Bence Jones proteinuria could remain stable for long periods of time, the study showed a high risk of progression.

For the new study, the team collected records from the Mayo Clinic database of Bence Jones proteinuria patients with measurable monoclonal light chain in the urine of 0.2 g or greater in 24 hours diagnosed between 1960 and 2004. Individuals with intact monoclonal immunoglobulins in the serum or any evidence of multiple myeloma, AL amyloidosis, or other related plasma-cell proliferative disorders were excluded.

“When we described those cases in 1982, three or four had progressed to multiple myeloma or amyloidosis,” said Kyle. “But we had only seven cases then, and now we have 101.”

For each of the 101 patients with idiopathic Bence Jones proteinuria, data for risk factors of progression (such as serum and urine monoclonal protein concentrations and proportion of plasma cells in the bone marrow) were entered into an electronic database for analysis. The primary endpoint was progression to symptomatic multiple myeloma or light-chain amyloidosis.

There were a total of 901 person-years of follow-up in the 59 patients with LC-SMM, during which 27 patients developed multiple myeloma and seven developed AL amyloidosis. The cumulative probability of progression for the 101 patients with idiopathic Bence Jones proteinuria was 19.9 percent at five years, 36.6 percent at 10 years, and 47.2 percent at 15 years. The median time to progression was 15.4 years.

However, certain factors were associated with a significantly increased relative risk, the researchers found. For instance, patients who had monoclonal light-chain excretion of 0.5 g per 24 hours or higher at diagnosis had nearly twice the risk of progression at 10 years compared with those with a lower excretion rate.

“If you have less than 500 mg, then you call that light-chain monoclonal gammopathy of undetermined significance which is asymptomatic,” said Kyle. “If you have more than 500 mg of protein in your urine, then you've moved up a notch to a situation called light-chain smoldering multiple myeloma.”

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Paul Richardson: ‘Results of Great Interest’

When asked his opinion on the study, Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and the R. J. Corman Professor of Medicine at Harvard Medical School, said he found the results of great interest. In particular, he noted the impact on better defining future treatment opportunities and said he is looking forward to randomized clinical trials comparing patient outcomes with and without earlier intervention in these patients.

“There are subgroups of patients who have smoldering myeloma and live with their disease for 20 years, before it becomes more active,” said Richardson. “This study defines a group of patients where the disease is much less forgiving and at a significantly higher risk of earlier progression, and thus may benefit from earlier intervention.”

In general, patients with LC-SMM are not treated unless they develop symptomatic multiple myeloma. Recently, the criteria have been modified in an attempt to intervene earlier for those at higher risk and to thus receive earlier treatment.



“If they had certain features, such as a very high plasma cell level in the bone marrow or renal insufficiency or if they have changes in the bone that are seen with MRI or CT scans—those are all patients that we now treat because they have about an 80 percent chance of developing symptomatic multiple myeloma in the next two years,” Kyle said.

He added that although clinicians should not treat patients with asymptomatic Bence Jones proteinuria, he hopes that the condition will be tested for and recognized in greater numbers as a precursor to light-chain symptomatic multiple myeloma.

“Although we've been able to detect monoclonal light-chains in the laboratory for more than 100 years, hopefully now it will be in the consciousness of the hematologists and oncologists who care for these patients,” he said. In the past decade, the free light-chains can be recognized in the blood and thus increases the recognition of light-chain multiple myeloma.

In general, most physicians don't collect a 24-hour urine specimen and fail to identify the presence of the Bence Jones protein before myeloma actually develops, Kyle said. Later, the patient may have already progressed to multiple myeloma, manifested by anemia, kidney failure, and bone pain. Only then, a physician will typically collect the 24-hour urine specimen, find the protein, and make the diagnosis of light-chain multiple myeloma.

“In the past, we would usually only observe smoldering patients without treatment,” Richardson said. “With the advent of novel therapies, and in particular those that target immunological aspects of the disease, the opportunities for intervening are much better, and we can do so sooner, largely because we now have much more effective, convenient, and less toxic treatments available.”

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Accompanying Editorial

In an accompanying editorial (Lancet Haematology; 2014:1:4-5), Xavier Leleu, MD, PhD, Assistant Professor in the Department of Haematology at Hôpital Claude Huriez, applauds Kyle et al for finally “completing the puzzle” of multiple myeloma by defining light-chain smoldering multiple myeloma.



“If we diagnose the light-chain variant, now we know how these patients are going to evolve,” Leleu said. “We know what follow-up and future we are going to expect.”

Although the ability to identify the minority of patients who are rapidly progressing to symptomatic myeloma is becoming closer to reality, he describes the fine line between treating at-risk patients early and leaving well enough alone, since sometimes interventions may make the patient's condition worse. For instance, the treatment may destroy part of the cancer that is sensitive, allowing the resistant, surviving portion to take over.

“If the body is able to control the tumor bulk, by treating you never know how you can unbalance this equilibrium,” he said. “You may just make things worse, whereas the disease may not have developed for 10 to 15 years.”

© 2014 by Lippincott Williams & Wilkins, Inc.
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