Multiple myeloma and cancer: Is there a D‐lightful connection?

Vitamin D deficiency is now recognized as the most common nutritional deficiency world-wide [1]. Vitamin D deficiency has been associated not only with skeletal abnormalities but also with a large number of chronic diseases, including deadly cancers, autoimmune diseases, infectious diseases, heart disease, and type II diabetes [2–6]. It has been estimated that more than 2,000 genes are either directly or indirectly regulated by vitamin D [7]. Once vitamin D is made in the skin or ingested in the diet, it requires two obligate hydroxylations; first, in the liver to form 25-hydroxyvitamin D [25(OH)D]. This is the major circulating form that is measured for determining a patient’s vitamin D status [1]. However, 25(OH)D is biologically inert and requires a hydroxylation in the kidneys to produce the active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D interacts with its vitamin D receptor (VDR) in the small intestine to enhance intestinal calcium absorption, and in osteoblasts to increase the expression of receptor activator of NFjB ligand (RANKL) [1]. The RANKL interacts with the preosteoclast RANK, inducing its maturation. Thus, the primary function of vitamin D is to maintain calcium homeostasis by enhancing intestinal calcium absorption and mobilizing calcium from the skeleton [1,8]. It is also recognized that many tissues and cells in the body have the enzymatic machinery to convert 25(OH)D to 1,25(OH)2D. The colon, prostate, breast, and brain are among the organs capable of making 1,25(OH)2D [9–12]. Activated monocytes and macrophages also produce 1,25(OH)2D, which is thought to be important in regulating the innate immunity response to infectious diseases [13]. It has also been suggested that the production of 1,25(OH)2D by macrophages locally regulates both activated Tand B-lymphocyte activities [1]. There has long been an association with living at higher latitudes and being at higher risk of vitamin D deficiency, with increased risk of dying of deadly cancers. As early as 1941, it was observed that people in the south who were at higher risk of nonmelanoma skin cancer, which was considered easy to detect and treat, somehow imparted an immunity from the deadly cancers [14]. In the 1980s and 1990s, several studies surfaced, relating living at higher latitudes with increased risk of developing and dying from colorectal, prostate, breast, and ovarian cancer [15,16]. Most of the studies, however, were association studies, and there remained skepticism as to the relationship between vitamin D and risk of cancer. The Women’s Health Initiative reported that calcium (1,000 mg/d) and vitamin D (400 IU/ d) had no benefit for reducing colorectal cancer [17]. However, women who had a blood level of <12 ng/mL at the initiation of the study, and were followed for 8 years in a presumably vitamin D-deficient state had a 253% increased risk of developing colorectal cancer within 8 years [18]. Women in Canada, who had the most sun exposure as teenagers and young adults, reduced their risk of developing breast cancer by >50% [19]. These observations are consistent with the report by Lappe et al. [20] who observed that postmenopausal women taking 1,100 IU of vitamin D3/d and 1,500 mg of calcium reduced their overall risk of developing cancer by more than 60% in 4 years. 1,25(OH)2D regulates many genes that are in control of cell growth and could potentially decrease risk of malignant cell development, growth, and metastases [1,7,21]. 1,25(OH)2D is one of the most potent inhibitors of cell growth. It induces cellular maturation [1,2,21], inhibits angiogenesis, and induces apoptosis, for the purpose of keeping cell growth in check and preventing malignancy [1,2,21]. It is believed that the local production of 1,25(OH)2D within most cells in the body acts in an autocrine fashion to help keep cell growth in check, which may be the explanation for why vitamin D deficiency has been associated with increased risk of many deadly cancers [6,15,16,22]. In this issue of the American Journal of Hematology, Ng et al. [22] report on the effects of vitamin D deficiency on the clinical presentation and prognosis of patients newly diagnosed with multiple myeloma (MM). They hypothesized that vitamin D deficiency would be associated with greater skeletal disease at the time of diagnosis and that there would be a poorer prognosis. The authors used a blood level of 25(OH)D < 50 nmol/L (20 ng/mL) as the definition for vitamin D deficiency. It is known that there is an inverse relationship with 25(OH)D and parathyroid hormone (PTH) levels, and the PTH levels begin to plateau at 75–100 nmol/L (30–40 ng/mL) [23–25]. In addition, the efficiency of intestinal calcium absorption is maximized above 80 nmol/L (32 ng/mL) [26]. Because the authors reported the percent of patients with <50 nmol/L, it is unknown whether any of the patients had a blood level above what is now considered to be vitamin D-sufficient, that is, >75 nmol/L. There was an association with vitamin D deficiency and increased levels of C-reactive peptide (CRP), a measure of inflammatory activity that confirmed previous observations [27]. The consequence of vitamin D deficiency on the skeleton is two-fold. The secondary hyperparathyroidism induced by vitamin D deficiency will increase the number of osteoclasts, causing the removal of mineral and matrix from the skeleton, which can result in osteopenia and osteoporosis [1]. The secondary hyperparathyroidism also causes phosphaturia, resulting in an inadequate calcium-phosphate product in the circulation, leading to a defect in the mineralization of newly laid down osteoid, causing osteomalacia [1]. The authors neither report on the bone mineral density of their patients nor do they provide physical examination evidence for periosteal discomfort associated with osteomalacia [28,29].