Results from a recent retrospective study indicate that chromosomal ab­nor­mal­ities may be useful for predicting which smoldering myeloma patients have a higher risk of progressing to active, or symptomatic, multiple myeloma.

Specifically, researchers from the Mayo Clinic found that patients with a chromo­somal abnormality known as t(4;14) progressed to myeloma faster, and had shorter survival compared to patients with other chromo­somal abnormalities.

“This study shows that risk of progression from smoldering multiple myeloma to symptomatic multiple myeloma is affected by the underlying cytogenetic type of the disease, with t(4;14) having the highest risk,” said the Mayo Clinic's Dr. Vincent Rajkumar, lead investigator of the study.

Patients with a chromosomal abnormality known as del(17p) also appeared to progress more rapidly than those with other chromosomal abnormalities.  However, the number of patients with del(17p) was small, making it difficult for the researchers to draw any definitive conclusions about this patient group.

Based on their findings, the investigators recommend that follow-up care for smoldering myeloma patients be adjusted according to their genetic profile.

“Patients with t(4;14) and del(17p) need to be followed more closely,” Dr. Rajkumar told The Beacon. “Clearly, not every patient with these abnormalities will progress early, but the risk of progression is higher,” he added.

Dr. Rajkumar and his colleagues also state that the different chromosomal abnormalities should be con­sidered in future trials investigating the effect of treatment in smoldering myeloma patients.

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.

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 t(4;14), del(17p), and 1q gain – negatively affect the survival of myeloma patients who have these abnormalities (see related Beacon news 1 ^[2] and 2 ^[3]).

However, chromosomal abnormalities have not been as extensively studied in smoldering myeloma patients.

Smoldering myeloma ^[4] 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 (active) 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.

However, the risk of progression varies significantly among patients.

The Mayo researchers note, though, that there is currently no data available on the effect that chromosomal abnormalities have on the risk of smoldering myeloma progressing to multiple myeloma.

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 at this 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 active myeloma (see related Beacon ^[5] news and related interview ^[6]).

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

Study Design

The researchers retrospectively analyzed the genetic profiles of 351 patients with smoldering multiple myeloma who had been seen at the Mayo Clinic between January 1991 and June 2010. The patients had a median age of 63 years at the time of their smoldering myeloma diagnosis, and patients were followed for a median of 6.8 years after their diagnosis.

Among the patients included in the analysis, 44 percent had trisomies (an extra copy of one or more chromosomes), 36 percent had chromosome 14 translocations (rearrangement of a part of chromosome 14 with part of another chromosome, such as t(4;14) or t(11;14)), 4 percent had both, and 15 percent had no chromosomal abnormalities.

The researchers divided the patients into four groups based on the chromosomal abnormalities they had: High-risk patients had t(4;14) or del(17p) (a deletion of a region of chromosome 17), intermediate-risk patients had trisomies, standard-risk patients had t(11;14) or other chromosome 14 translocations, and low-risk patients had no abnormalities.

Results

Overall, 62 percent of the patients included in the analysis progressed to myeloma. The median time to progression was four years.

Among the four risk groups, the researchers found that the high-risk patients had the fastest time to progression (median of 2.0 years), compared to the intermediate and standard-risk patients (2.8 years and 4.6 years, respectively). The median time to progression in the low-risk group had not been reached yet.

The median overall survival of all patients from the time of smoldering myeloma diagnosis was 11.3 years.

The high-risk patients had the shortest median overall survival from smoldering myeloma diagnosis com­pared to the other three groups (8.8 years for high-risk, 11.3 years for intermediate-risk, 12.3 years for standard-risk, and 11.3 years for low-risk).

The median overall survival of all patients from the time of active myeloma diagnosis was 6.4 years.

Once again, the high-risk patients had the shortest median overall survival from active myeloma diagnosis compared to the other three groups (5.0 years for high-risk, 6.4 years for intermediate-risk, 7.2 years for standard-risk, and 9.3 years for low-risk).

“I think that with t(4;14) and del(17p), there is biologically a more aggressive clone with greater risk of pro­gression, as well as increased risk after diagnosis of symptomatic myeloma,” explained Dr. Rajkumar.

“With the use of cytogenetics [information about a patient's chromosomal abnormalities] and other prom­is­ing biomarkers, I hope that in the near future we will be able to identify patients who are candidates for early intervention in clinical practice,” Dr. Rajkumar told The Beacon.

For more information, please refer to the study in Leukemia ^[7] (abstract).