Results of a large analysis conducted in Sweden show that multiple myeloma patients are more likely than the general population to develop certain cancers, including acute myeloid leukemia, myelodysplastic syndromes, and non-melanoma skin cancer.

Furthermore, the researchers found that patients with the myeloma precursor disease monoclonal gammopathy of undetermined significance (MGUS) also have a greater risk of developing these cancers than the general population.

Like myeloma patients, MGUS patients have abnormal proteins in the blood as a result of defective plasma cells in the bone marrow. However, unlike myeloma patients, MGUS patients typically do not have any symptoms and do not receive any form of treatment unless their condition worsens.

According to the researchers, the increased frequency of certain cancers among previously untreated MGUS patients suggests that factors unrelated to treatment may contribute to the development of secondary cancers in patients with plasma cell disorders such as multiple myeloma.

“Based on this study, I think we now have evidence to suggest that non-treatment-related factors may also play a role [in the development of secondary cancers],” said Dr. Ola Landgren of the U.S. National Cancer Institute and one of the study authors.

Traditionally, myeloma specialists have speculated that the increased risk of secondary cancers in myeloma patients was due to prior treatment with certain drugs.

Past studies, for instance, have shown that melphalan ^[1] (Alkeran), chemotherapy used as preparative treatment prior to stem cell transplantation, may be the main cause of this increased risk in myeloma patients.

In addition, concerns arose over the use of Revlimid ^[2] (lenalidomide) when several clinical trials last December showed that patients who received Revlimid maintenance therapy had an elevated risk of developing secondary cancers (see related Beacon ^[3] news).

Dr. Landgren acknowledged these concerns but affirmed that the cause of secondary cancers in myeloma patients is still unclear.

“At this time, nobody knows the exact underlying mechanisms of the development of [secondary cancers] following myeloma,” Dr. Landgren told the Myeloma Beacon.

To shed more light on the development of secondary cancers in multiple myeloma patients, the researchers retrospectively analyzed data from 8,740 myeloma patients and 5,652 MGUS patients diagnosed between 1986 and 2005 in Sweden. The median patient age at diagnosis was 72 years and 73 years, respectively.

Among the myeloma patients, 0.8 percent developed a blood-related secondary cancer and 5.8 percent developed a non-blood-related secondary cancer.

The researchers found that compared to the general population, myeloma patients had a 1.26-fold increased risk of developing a secondary cancer.

Specifically, these patients had an 11.51-fold increased risk of developing acute myeloid leukemia or myelodysplastic syndromes ^[4], a group of blood disorders characterized by the accumulation of abnormal stem cells in the bone marrow.

They also had a 1.19-fold increased risk of developing a non-blood-related cancer, most commonly stomach cancer and non-melanoma skin cancer.

The researchers observed that these risks were not significantly different between myeloma patients diagnosed before 1995, when the standard of care in Sweden was an extended regimen of melphalan plus prednisone ^[5], and after 1995, when short courses of high-dose melphalan followed by autologous stem cell transplantation became the standard of care.

Based on this observation, they speculated that lower doses of melphalan therapy administered over a longer period of time may impact the risk of developing secondary cancers as much as short courses of high-dose melphalan before stem cell transplantation.

The researchers also observed that the risk of developing a secondary cancer was not significantly different for myeloma patients diagnosed before and after the introduction of Revlimid and thalidomide ^[6] (Thalomid) in Sweden in 2000.

However, they acknowledged the need for additional data to analyze these results because usage of Revlimid and thalidomide was low during the study period.

Among the MGUS patients, 14 percent developed a blood-related cancer, most commonly multiple myeloma, and 13 percent developed a non-blood-related cancer.

Compared to the general population, MGUS patients had an 8.01-fold increased risk of developing acute myeloid leukemia or myelodysplastic syndromes. None of the patients who developed either of these two diseases, however, later developed multiple myeloma.

The researchers found that MGUS patients who had a monoclonal (M) protein level greater than 1.5 g/dL had a higher risk of developing either of these two cancers than patients with an M protein level less than 1.5 g/dL.

Additionally, they found that only MGUS patients whose blood contained the M protein IgG or IgA, but not IgM, developed either of these two cancers.

MGUS patients also had a 1.56-fold increased risk of developing a non-blood-related cancer compared to the general population, most commonly non-melanoma skin, endocrine, and breast cancer.

According to the researchers, these findings indicate that non-treatment-related factors may contribute to the development of secondary cancers in myeloma patients.

However, since myeloma patients had a higher risk of developing either acute myeloid leukemia or myelodysplastic syndromes than MGUS patients, the researchers speculated that treatment-related factors may still increase the risk for secondary cancers.

“In the future, it is possible that research will define biological mechanisms that are associated with [secondary cancers] following myeloma. Ultimately, such insights would be useful [in helping] clinicians choose therapies that do not increase the risk of [secondary cancers],” said Dr. Landgren.

For more information, please see the study in the journal Blood ^[7] (abstract).