German researchers recently reported that certain chromo­som­al ab­nor­mal­i­ties in patients' myeloma cells are associated with more rapid pro­gression from smol­der­ing myeloma to active, or symptomatic, mul­ti­ple myeloma.

Specifically, patients in the study who had the chromo­som­al ab­nor­mal­i­ties del(17p), t(4;14), and 1q gain, as well as patients with more chromo­somes than normal (hy­per­dip­loi­dy), experienced shorter times until pro­gression to sympto­matic myeloma.

Previous studies have shown that hy­per­dip­loi­dy positively affects out­comes for patients with symptomatic myeloma. In this study, however, the investigators found that hy­per­dip­loi­dy negatively affects outcomes for smol­der­ing myeloma patients.

The researchers also confirmed previous research linking measures of tumor load, such as the share of abnormal plasma cells in the bone marrow, to a smoldering myeloma patient's risk of pro­gres­sion.

In the conclusion to their study, the investigators write that chromo­som­al ab­nor­mal­i­ties “help identify pa­tients with faster pro­gres­sion to symptomatic myeloma and should be assessed in all patients with smol­der­ing multiple myeloma.”

Background

Chromosomal ab­nor­mal­i­ties ^[1] are the result of structural changes in the chromosomes of a patient’s mye­lo­ma cells.

These changes may occur through deletions, insertions, duplications, or movement of chromo­som­al re­gions.  Some patients also have missing or extra copies of entire chromosomes.

When a patient has more than the normal number of chromosomes (23 pairs of chromosomes) in their myeloma cells, they have hy­per­dip­loi­dy.

Researchers have extensively studied the effects that chromo­som­al ab­nor­mal­i­ties have on the course of symptomatic multiple myeloma and the survival of patients with this disease.

Previous studies have shown that certain chromo­som­al ab­nor­mal­i­ties – particularly ones called del(17p), t(4;14), and 1q gain – negatively affect the survival of symptomatic myeloma patients (see related Beacon news articles 1 ^[2] and 2 ^[3]).

On the other hand, hy­per­dip­loi­dy has been shown to positively affect the survival of treated symptomatic myeloma patients.

According to the investigators of the current study, chromo­som­al ab­nor­mal­i­ties have not been as extensively studied in smol­der­ing myeloma patients.  One of the few previous studies on the subject was published earlier this year (see related Beacon ^[4] news).

Smoldering myeloma ^[5] is a precursor to multiple myeloma in which the patient does not display any of the typical myeloma-related symptoms, such as elevated calcium levels, kidney damage, anemia, or bone lesions. Compared to the general population, smol­der­ing myeloma patients are at a higher risk of devel­op­ing symptomatic myeloma.

Results from recent studies indicate that the risk of pro­gres­sion from smol­der­ing to symptomatic myeloma is 10 percent per year for the first five years after a smol­der­ing myeloma patient’s diagnosis. This risk re­duces to 3 percent per year for the next five years, and to 1 percent per year thereafter. The median time to pro­gres­sion is about five years.

However, the risk of pro­gres­sion varies significantly among patients.

The current standard of care for smol­der­ing myeloma is a ‘watch and wait’ approach, which involves mon­itor­ing the patient regularly and beginning treatment only once the disease progresses to symptomatic myeloma.  This approach is based on previous evidence that treatment during the smoldering stage of the disease does not have an impact on overall survival, yet exposes patients to chemotherapy – and therefore side effects – for a longer period of time.

Recent studies, however, have begun to show that treatment may delay disease pro­gres­sion and even extend overall survival for certain smol­der­ing myeloma patients at high risk of progressing to myeloma (see related Beacon news articles 1 ^[6] and 2 ^[7]).

It is therefore important to find reliable ways of determining which smol­der­ing myeloma patients are at high risk for disease pro­gres­sion.

In the current study, the investigators sought to assess whether chromo­som­al ab­nor­mal­i­ties play a role in the pro­gres­sion of smol­der­ing myeloma to symptomatic myeloma.

Study Design

Researchers from the University Hospital of Heidelberg and the German Cancer Research Center in Heidelberg retrospectively analyzed data from 248 patients who were diagnosed with smol­der­ing multiple myeloma between November 2003 and September 2012 at one of their institutions.

The median patient age was 60 years.

None of the patients included in the analysis received treatment before pro­gres­sion to symptomatic multiple myeloma or amyloidosis, a myeloma-related disease in which proteins accumulate in organs such as the heart or kidneys, leading to organ damage.

The study investigators used a technique called interphase fluorescent in situ hybridization (iFISH) to detect and identify chromo­som­al ab­nor­mal­i­ties.

The median follow-up time was 3.5 years.

Results

During the course of the study, 33 percent of patients progressed from smol­der­ing myeloma to symptomatic myeloma, 2 percent progressed to amyloidosis, and 2 percent died of causes unrelated to myeloma.  The median time to pro­gres­sion was 5.6 years.

The investigators detected chromo­som­al ab­nor­mal­i­ties in 91 percent of patients. The most common ab­nor­mal­i­ties included hy­per­dip­loi­dy (43 percent of patients), 1q gain (29 percent), t(11;14) (23 percent), del(13q) (20 percent), t(4;14) (9 percent), and del(17p) (6 percent).

The presence of del(17p), t(4;14), gain 1q, and hy­per­dip­loi­dy had significant negative impacts on time to pro­gres­sion. Patients with hy­per­dip­loi­dy had a decreased median time to pro­gres­sion of 3.9 years, and time to pro­gres­sion was 3.9 years for patients with gain 1q, 2.9 years for patients with t(4;14), and 2.0 years for patients with del(17p).

In contrast, the chromo­som­al ab­nor­mal­i­ties del(13q) and t(11;14) did not have a statistically significant effect on time to pro­gres­sion.

A fifth (20 percent) of patients had high tumor mass, which the investigators defined as having both 10 per­cent or more of total bone marrow plasma cells and a monoclonal (M) protein level of at least 3 g/dL. All other patients included in the study were defined as having low tumor mass.

Patients with low tumor mass had significantly longer time to pro­gres­sion (9.0 years) than patients with high tumor mass (1.2 years).

A fifth of patients also had a high proportion of cancerous plasma cells in their bone marrow, defined as hav­ing greater than 95 percent cancerous bone marrow plasma cells. Time to pro­gres­sion for these pa­tients was also 1.2 years, which was significantly shorter than the 9.0 years for patients with a lower proportion of cancerous bone marrow plasma cells.

Overall, the investigators found that four factors -- a high proportion of cancerous bone marrow plasma cells, high tumor mass, hy­per­dip­loi­dy, and having one or more high-risk chromo­som­al ab­nor­mal­i­ties (del(17p), t(4;14), and gain 1q) -- were independently associated with an increased risk of pro­gres­sion from smol­der­ing to symptomatic myeloma.

For more information, please refer to the study in Journal of Clinical Oncology ^[8] (abstract).