Results of a recent retrospective study conducted at the Mayo Clinic in­di­cate that the survival of patients with non­se­cre­tory multiple myeloma has improved over the last decade.

Nonse­cre­tory multiple myeloma is a rare form of myeloma in which a patient’s disease cannot be diagnosed or tracked by the presence of monoclonal protein in the blood or urine.  This is not the case for most myeloma patients, who have “se­cre­tory” disease which can be tracked using lab results such as a patient’s “M-spike” or free light chain levels.

The authors of the new study found that, among multiple myeloma patients diagnosed between 1973 and 2001, the median overall survival was sim­i­lar for patients with non­se­cre­tory myeloma (3.6 years) and se­cre­tory mye­loma (3.5 years).

Overall survival improved in both se­cre­tory and non­se­cre­tory myeloma patients diagnosed between 2001 and 2012 compared to the earlier period. However, the improvement in survival was greater in patients with non­se­cre­tory multiple myeloma. The median overall survival for non­se­cre­tory patients diagnosed between 2001 and 2012 was 8.3 years compared to 5.4 years for se­cre­tory patients diagnosed in the same time period.

The researchers note that the improvement in survival in the later period occurred during the time when the newer, “novel” therapies for multiple myeloma began to see widespread use.  It is not clear, however, why the introduction of these newer therapies had a greater impact on the survival of non­se­cre­tory myeloma patients than se­cre­tory patients.

Background

Multiple myeloma is a cancer in which the body overproduces plasma cells. In healthy people as well as people with myeloma, plasma cells produce antibodies – also known as immunoglobulins – that help the body fight infection.

Each plasma cell produces one type of immunoglobulin, and the body produces many types of plasma cells. Together, the different types of plasma cells produce the range of different kinds of immunoglobulin needed by the body.

The excess plasma cells in myeloma patients, however, typically overproduce a single type of plasma cell. When this happens, it leads to overproduction of the immunoglobulin associated with that type of plasma cell. The accumulation of this immunoglobulin is what is detected in lab tests that track, for example, a patient’s M-spike.

In patient with non­se­cre­tory multiple myeloma, on the other hand, the plasma cells do not produce (“secrete”) excess immunoglobulins.  As a result, the disease cannot be diagnosed or tracked using standard blood and urine tests.

Nonse­cre­tory myeloma can be detected, however, through bone marrow biopsies, PET scans, and through its impact on a patient’s bones, hemoglobin levels, and other signs of the disease (for more information on non­se­cre­tory myeloma, please see this physician column ^[1] by Dr. Bijay Nair).

According to the authors of the new study, there is currently limited information available about the clinical course and prognosis of patients with non­se­cre­tory multiple myeloma. To shed more light on the topic, the researchers conducted a retrospective analysis of data collected at their institution.

Study Design

The authors searched the Mayo Clinic multiple myeloma database to identify non­se­cre­tory myeloma patients diagnosed between January 1973 and June 2012.  Patients were identified as having non­se­cre­tory myeloma if their serum and urine immunofixation did not show any monoclonal protein at diagnosis and at all subsequent check-ups.

A total of 124 non­se­cre­tory patients were identified. The median age of the patients was 62, and 71 percent of the patients were diagnosed before 2001.

Data on initial therapy was available for 121 patients, and 116 of them received drug-based therapy as part of their initial treatment. Of those, 77 percent received conventional che­mo­ther­apy and 23 percent received treatment with one or more novel agents, such as thalidomide ^[2] (Thalomid), Velcade ^[3] (bortezomib), and Rev­limid ^[4] (lenalidomide). Also, 27 percent of the patients who were initially treated with either conventional che­mo­ther­apy or novel agents went on to have an autologous stem cell transplant following their initial therapy.

Results of bone marrow biopsies from the time of diagnosis were available for 119 patients; 70 percent of these patients had a bone marrow plasma cell percentage of 10 percent or greater.

Serum free light chain testing was performed in 29 patients at the time of diagnosis. The free light chain ratio was abnormal in 65 percent of these patients.

The median follow-up time was 102 months.

Survival results for the non­se­cre­tory patients were compared to those for 7075 se­cre­tory myeloma patients in the Mayo Clinic database who were diagnosed during the time period covered by the study. The study au­thors note that the number of non­se­cre­tory and se­cre­tory patients in the database indicates that non­se­cre­tory myeloma accounted for 1.7% of all multiple myeloma diagnoses in their center's database for the study period.

Study Results

The researchers looked first at how non­se­cre­tory patients responded to treatment and changes in their sur­vival over time.

They found that the overall response rate to initial treatment did not differ significantly between the non­se­cre­tory patients who received conventional che­mo­therapy (88 percent) and those who received novel agents (84 percent) as initial treatment.

The median progression-free survival after initial therapy was 28.6 months during the entire period covered by the study, and the median overall survival was 49.3 months.

The median overall survival of the non­se­cre­tory patients improved significantly over time. It was 43.8 months for patients diagnosed prior to 2001, increasing to 99.2 months for patients diagnosed between 2001 and 2012.

The median overall survival also was significantly longer for the non­se­cre­tory patients who received novel agents as part of their initial therapy (not yet reached), compared to those who received conventional che­mo­ther­apy (46.1 months).

The authors do not report, however, if there was any difference in progression-free survival between patients treated with conventional che­mo­ther­apy and those treated with novel agents, nor do they report whether there was any change in progression-free survival over time.

Overall survival was higher in non­se­cre­tory patients who had a normal free light chain ratio at diagnosis than in those who had an abnormal ratio. This result also has been found in previous studies that have looked at the impact of the free light chain ratio on the prognosis of myeloma patients in general (not just non­se­cre­tory patients).

The researchers turned next to a comparison of overall survival trends in non­se­cre­tory and se­cre­tory mye­loma patients.

They found that, among patients diagnosed before 2001, the median overall survival was similar in patients with non­se­cre­tory myeloma (3.6 years) and patients with se­cre­tory myeloma (3.5 years).

Overall survival also increased for both non­se­cre­tory and se­cre­tory patients in the 2001-2012 time period compared to the earlier period. The improvement in survival that occurred during the later period, however, was greater for non­se­cre­tory patients.

The median overall survival for non­se­cre­tory patients diagnosed between 2001 and 2012 was 8.3 years, compared to 5.4 years for se­cre­tory patients diagnosed in the same time period.

The researchers considered several potential explanations for the observed divergence in overall survival, but were not able to develop a satisfactory explanation.

Differences in disease stage at diagnosis, for example, could not account for the divergence.  There also was not enough data to determine if differences in chromo­somal ab­nor­mal­i­ties at the time of diagnosis could be the cause of the divergence in survival.  Only nine of the non­se­cre­tory patients had their chromo­somal ab­nor­mal­i­ties checked at the time of diagnosis.

The authors did note, however, that among the nine non­se­cre­tory patients for whom chromo­somal ab­nor­mal­i­ty information was available for the time of diagnosis, the types of ab­nor­mal­i­ties that were present did not seem different from those normally found in newly diagnosed se­cre­tory myeloma patients.

For more information, please refer to the study by Chawla, S. et al., “Clinical Course and Prognosis of Non-Secretory Multiple Myeloma,” in the European Journal of Haematology, February, 2015 (abstract ^[5]).