Results from a recent Italian study confirm that smoldering myeloma patients with at least 60 percent of the cells in their bone marrow being plasma cells are 5.6 times more likely than others to progress to symptomatic multiple myeloma.

In addition, the findings indicate that bone marrow aspiration may be a better tool than bone marrow biopsy for predicting rapid progression from smoldering to active myeloma.

The study investigators suggest that smoldering myeloma patients with at least 60 percent plasma cells should be treated soon after diagnosis.

However, Dr. Ola Landgren from the National Cancer Institute and who was not involved with the study cautioned that the results are “based on a small number of patients.”

“In my opinion, both procedures [biopsies and aspirations] are needed,” said Dr. Landgren.

“Aspirations allow for more sophisticated analyses of the bone marrow in the lab,” Dr. Landgren explained. “Core biopsies are important because they give information about growth patterns of the cancerous cells.”

Smoldering multiple myeloma, also called inactive or asymptomatic myeloma, is an early stage of myeloma in which the person does not yet show any symptoms such as bone or kidney damage.

The current standard of care is to regularly monitor smoldering myeloma patients and only begin treatment once the disease progresses to symptomatic myeloma. It is thought that this ‘watch and wait’ strategy reduces side effects by shortening the period of exposure to chemotherapeutic drugs without negatively affecting overall survival.

Some smoldering myeloma patients, however, progress rapidly to symptomatic disease. Previous studies have indicated that such high-risk patients may benefit from treatment soon after diagnosis (see related Beacon news), but attempts to identify clinical parameters that distinguish patients who are at a higher risk of progression have had mixed findings.

“Current clinical models to predict progression from smoldering to symptomatic myeloma are unreliable,” said Dr. Landgren. When researchers from his group used two different methods, one developed by the Mayo Clinic and another by a Spanish group, to identify risk of progression among smoldering myeloma patients, they found the two methods identified different patients as being high risk. “There is no doubt that we need better markers,” noted Dr. Landgren.

He also cautioned that ‘blind’ procedures, such as biopsy and aspiration, that sample only a small portion of the bone marrow might not be truly representative of the patient’s disease state.

“A blind biopsy, which is still standard of care, may not be representative of the actual disease burden. This is an inherent problem with blind procedures. In my opinion, we need more ‘global’ markers (that do not depend on a few millimeters of biopsy done in a blind fashion) that can capture disease burden and activity,” said Dr. Landgren.

“The plasma cell percentage can vary greatly throughout the bone marrow in a given patient. There is emerging MRI-based evidence that some patients have diffuse disease, others have focal disease, others have a mix, and others have limited bone marrow disease but yet active disease with symptoms,” he explained.

A recent study conducted at the Mayo Clinic showed that smoldering myeloma patients with at least 60 percent plasma cells in the bone marrow progress to symptomatic disease within two years after their diagnosis.

In the current study, the Italian researchers sought to confirm the Mayo Clinic findings and to identify additional clinical and biological characteristics that may distinguish high-risk smoldering myeloma patients from others.

Therefore, the researchers retrospectively analyzed data from 397 patients diagnosed with smoldering myeloma between January 1980 and December 2010.

The median patient age was 63 years.

All patients underwent bone marrow aspiration to determine the percentage of plasma cells in their bone marrow; the median was 19 percent. More specifically, 39 percent of patients had less than 15 percent plasma cells, 59 percent of patients had 15 percent to 59 percent plasma cells, and 2.5 percent of patients had more than 60 percent plasma cells.

Nearly 36 percent of patients also underwent bone marrow biopsy.  Using this technique, the median percentage of plasma cells in the bone marrow was 25 percent.

After a median follow up time of 11.25 years, 37.5 percent of patients had progressed to symptomatic myeloma. The researchers estimated that 45 percent of patients would progress to symptomatic myeloma within 10 years, 55 percent within 15 years, and 75 percent within 20 years.

Results from the analysis confirmed that a bone marrow plasma cell percentage of at least 60 percent significantly increased the risk of progression (5.6-fold) within two years of being diagnosed with smoldering myeloma.

The researchers found that by 10 years, 50 percent of patients with less than 15 percent plasma cells had progressed, 60 percent of patients with 15 percent to 59 percent plasma cells progressed, but all patients with more than 60 percent plasma cells progressed during that time.

In addition, patients with more than 60 percent plasma cells also had more severe symptoms at progression.

Hemoglobin levels less than 12.5 g/dL and monoclonal (M) protein levels greater than 2.5 g/dL were also associated with increased risk of progression (1.8-fold and 2-fold, respectively).

Having more than 60 percent plasma cells did not, however, affect overall survival.  Across all patients included in the study, the overall survival rate was 43 percent at 10 years after diagnosis, 38 percent at 15 years, and 24 percent at 20 years.

The researchers used data from the 144 patients who underwent both bone marrow aspiration and biopsy to investigate which procedure more accurately predicted high risk of progression.

While aspiration showed a median plasma cell percentage of 19 percent in these patients, biopsy showed a median of 25 percent.

Only one patient (0.7 percent) had more than 60 percent plasma cells according to bone marrow aspiration.  This patient also had more than 60 percent plasma cells according to biopsy and progressed within a year of their diagnosis.

In comparison, an additional 6 patients (5 percent in total) had more than 60 percent plasma cells according to biopsy results, but these patients did not progress as rapidly (four progressed in two to eight years, and two had not yet progressed).

These results led the researchers to conclude that bone marrow aspiration more accurately predicts smoldering myeloma patients at high risk of rapidly progressing to symptomatic myeloma.

For more information, please see the study in Cancer (abstract).