Associations between multiple myeloma and other malignancies

In this issue of Leukemia and Lymphoma, Dr. Hasskarl and colleagues report on associations between myeloma and other malignancies [1]. More specifically, among almost 600 patients with myeloma, the authors found 10% to have another malignancy (8% solid tumors and 2% hematologic neoplasms). In about a third of the reported patients with myeloma diagnosed with another cancer, the other malignancy was detected subsequent to myeloma diagnosis (median 35 months; range 12–66 months) [1]. Overall, 12 patients with myeloma developed a solid tumor and six developed a hematologic malignancy. The most common subsequent type of malignancy was acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (five cases). This observation is particularly interesting given that AML/MDS is a well-recognized complication of cancer therapy, especially hematopoietic stem cell-toxic therapies such as ionizing radiation and alkylating agent-based chemotherapy (melphalan, nitrosoureas), occurring a median of 4–5 years after treatment [2–4]. In this respect, this phenomenon has become even more relevant as growing awareness of therapy-related myelodysplasia and leukemia has recently also been reported in association with purine nucleoside treatments, particularly when these are combined with DNA-damaging agents in patients with indolent lymphoproliferative disorders [5–7]. Unfortunately, due to the restricted number of cases, the present study was unable to dissect out the role of myeloma therapy, tumor biology, and host-related factors in relation to the risk of second malignancies occurring subsequent to the diagnosis of myeloma. Future studies are needed to follow up on these associations.

In about two-thirds of the reported patients with myeloma diagnosed with another malignancy, the other cancer was detected before/around myeloma diagnosis (41 cases); the time between the first malignancy and subsequent myeloma diagnosis ranged between 0 months and 12 years, with a median of 42 months [1]. The most frequent types of solid tumors detected before/around myeloma diagnosis were: colorectal (seven cases), gynecological (seven cases), skin (six cases), urothelial (six cases), and prostate (four cases) cancer. Lymphoma (n = 6) was the most common type of hematologic malignancy detected before/around myeloma diagnosis. In the present study, although a larger number of malignancies were detected before/around as opposed to subsequent to myeloma diagnosis (43 cases vs. 18 cases), the study design did not enable the investigators to evaluate whether the tumors detected before/around myeloma diagnosis were significantly more prevalent than in the general population. In order to further establish these types of associations, one has to assess whether patients with colorectal cancer, for example, are at higher risk of developing myeloma than are the general population. Indeed, in a recent population-based study from the USA, Curtis and colleagues used the large National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database to evaluate the risk of second malignancies subsequent to any type of cancer among more than two million cancer patients who survived at least 2 months [8]. Overall, they found cancer survivors to have a 14% increased risk of developing a new malignancy than expected in the general population [8]. Regarding the tumor sites that were detected before/around myeloma diagnosis in the present study, Curtis and colleagues [8] assessed a large number of patients and found no statistically increased risk of developing myeloma among patients diagnosed with a primary cancer in the following sites (versus the risk of developing myeloma in the general population, i.e. observed/expected; O/E): colon (n = 179 370; O/E = 0.92; not significant), rectum (n = 21 900; O/E = 0.99; not significant), cervix/uterus (n = 37 757; O/E = 0.74; not significant), ovary (n = 41 869; O/E = 0.84; not significant), melanoma (n = 66 059; O/E = 0.86; not significant), urothelial (n = 137 571; O/E = 0.89; not significant), and prostate (n = 292 029; O/E = 1.00; not significant) [8]. Thus, at the present time, there is no evidence to suggest that the risk of developing myeloma is increased among patients diagnosed with a primary cancer in any of the above listed sites.

Without doubt, the present investigation by Dr. Hasskarl and colleagues serves as a good indicator of clinical progress in myeloma [1]. Only a few years ago, the average survival for a patient with newly diagnosed myeloma was 3–4 years. Clearly, at the beginning of the 21st century, due to several novel therapies, we have started to see patterns of improved survival in myeloma [9]. Consequently, an increased fraction of patients with myeloma are living longer, and, in turn, they will receive more types of myeloma therapies during the natural course of their disease. Because of these facts, clinicians who treat and follow patients with myeloma are now starting to encounter long-term complications as the next coming challenge in clinical myeloma management.

Future studies are needed to better describe patterns of second malignancies subsequent to myeloma, and to uncover underlying mechanisms (treatment-, tumor-, and host-related factors) of these associations. In this context, the study reported here by Hasskarl and colleagues is important in making physicians treating patients with myeloma more aware of the need to include more data regarding the incidence of second neoplasms in their myeloma registries. Ultimately, such insights will be used to tailor therapy, improve survival, and reduce the risk of second malignancies. It is likely that this topic will become increasingly important in the future, given the good news that patients with myeloma are now living longer and longer [9].