To the best of our knowledge, this is the first study in Japan to assess the distribution of serum vitamin D levels in MM patients. This study made three important clinical observations.
First, Japanese patients with MM showed a high incidence of vitamin D deficiency. In our cohort, the majority of patients (84%) had less-than-sufficient levels of serum vitamin D (25(OH)D < 30 ng/ml), with one-third (32%) deficient in vitamin D (25(OH)D < 20 ng/ml) and an additional 52% with insufficient levels of vitamin D (25(OH)D 20–29 ng/ml). Median serum 25(OH)D level for the whole cohort was 22 ng/ml (IQR, 18.8–26.3 ng/ml). In a large cohort study of Japanese women over 50 years old (the JPOS study, N = 1211), only 10% of participants had sufficient levels of vitamin D (25(OH)D ≥30 ng/ml), while 52% and 38% had vitamin D deficiency (25(OH)D < 20 ng/ml) and insufficiency (25(OH)D 20–29 ng/ml), respectively . Another Japanese general population-based cohort study (the ROAD study, N = 1683) showed that only 19% of the Japanese population had sufficient vitamin D levels (25(OH)D ≥30 ng/ml) and mean serum 25(OH)D level was 23.4 ng/ml . On the other hand, several studies from Western countries have reported on serum vitamin D status in MM patients [22–27]. In those studies, although the criteria for vitamin D deficiency and insufficiency differed between studies, 25(OH)D levels < 20 ng/ml and < 30 ng/ml were reported in 24–31% and 72–87% of MM patients, respectively. Given such results, the distribution of serum 25(OH)D levels in Japanese MM patients seems similar to those in the general Japanese population and MM patients in Western countries.
Second, the present study found that serum vitamin D levels were not significantly associated with skeletal morbidity or bone turnover markers such as TRACP-5b or total P1NP. The relationship between vitamin D levels and bone complications in MM patients remains controversial. For example, Ng et al. reported that the prevalence of vitamin D deficiency increased in parallel with higher ISS stage among newly diagnosed MM patients, whereas no significant correlation was identified between vitamin D status and bone disease . Badros et al. also reported that vitamin D deficiency was independent of bone disease in patients with newly diagnosed or relapsed MM . However, in that study, serum bone alkaline phosphatase (bALP), as a marker of bone formation, and intact PTH levels were higher in vitamin D-deficient patients than in vitamin D-sufficient patients. Furthermore, Diamond et al. demonstrated a significantly higher urinary deoxypyridinoline excretion rate and lower dual-energy X-ray absorptiometry T-score were observed in vitamin D-deficient MM patients . The exact reasons for the discrepancies in results between the present study and previous investigations is unclear. However, one possible explanation may be that our study mainly included relapsed and/or refractory MM patients with different disease status and treatment schedules. In fact, many patients in our cohort had recently been treated with bortezomib and/or bone-targeted drugs such as bisphosphonates and denosumab.
In addition, we found that MM patients with suboptimal 25(OH)D levels who received vitamin D nutritional guidance, including cholecalciferol supplementation (1000 IU/day), subsequently showed elevated serum 25(OH)D levels with decreased serum levels of intact PTH. Notably, in patients who achieved complete remission of MM, serum levels of total P1NP, a marker of bone formation, increased significantly after vitamin D restitution, whereas TRACP-5b, a marker of bone resorption, decreased or remained unchanged. Lipe et al. have also demonstrated that, in patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM, oral calciferol supplementation (6000 IU/day for 8 weeks, followed by 2000 IU/day) improved bone metabolism markers such as receptor activator of nuclear factor-kappa B ligand/osteoprotegerin, while reducing disease activity markers . Meanwhile, in MM patients, several reports have indicated that serum bALP increased during bortezomib treatment and that the degree of increase was related to treatment response [29–31]. Importantly, Kaiser et al. revealed upregulation of VDR signaling as a mechanism for bortezomib-induced stimulation of osteoblastic differentiation . In addition, serum 25(OH)D levels are reportedly associated with a sustained appropriate response to bisphosphonate treatment in postmenopausal osteoporotic women [33–35]. Taking these findings together, vitamin D supplementation could help achieve optimal bone formation in patients with plasma cell neoplasms. Further research is needed to clarify whether appropriate vitamin D replacement can reduce the residual risk of bone complications in MM patients.
The third important finding of this study was that in our Japanese MM cohort, patients with vitamin D deficiency (25(OH)D < 20 ng/ml) exhibited significantly worse OS compared to patients with insufficient/sufficient vitamin D levels (25(OH)D ≥20 ng/ml). Several retrospective studies in Western countries have shown associations between vitamin D status and prognosis in MM patients. For example, Rakhee et al. showed that low pre-transplant serum 25(OH)D levels (< 23 ng/ml) were related to inferior OS in MM patients undergoing high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) . Eicher et al. also reported that MM patients with lower serum 25(OH)D levels (< 25 ng/ml) had inferior progression-free survival and OS in the HDC with ASCT setting . More recently, Yellapragada et al. evaluated a large number of MM patients (N = 1889) in the Veterans Affair’s nationwide database and revealed that patients with lower serum 25(OH)D levels (< 20 ng/ml) experienced significantly worse OS than patients with normal levels . Interestingly, such a survival effect of vitamin D levels was observed only in Caucasian Americans, not in African Americans. Although several in vitro studies have shown direct or indirect anti-myeloma effects of vitamin D [32, 38–40], the exact reasons for these survival differences according to serum vitamin D concentrations and ethnic backgrounds remain unclear. On the other hand, no reports to date (including the present study) have shown that vitamin D supplementation actually improves the prognosis of MM patients. Serum vitamin D levels are primarily affected by exposure to both ultraviolet radiation and dietary sources. As a result, low serum levels of vitamin D may simply reflect reduced outdoor activity and malnutrition, which are likely surrogate markers associated with “frailty” in MM patients. Indeed, in our cohort, some vitamin D-deficient MM patients had lower HR-QOL scores on questionnaires, although the difference was not statistically significant. Whether vitamin D supplementation can overcome the poor survival and frailty of MM patients with vitamin D deficiency should be investigated in further prospective studies.
Some limitations of this study need to be recognized. First, our study was limited by the relatively small cohort from a single-center referral population (Gunma Prefecture, located in the northern part of the Kanto region in Japan). The hours of sunshine in Gunma prefecture are relatively long in Japan (approximately 2,400 h/year). Therefore, the results of this study may not be fully generalizable to the entire Japanese population. Second, serum 25(OH)D levels in this study were measured only once in each patient during the winter season, so whether seasonal changes in vitamin D levels were associated with bone disease or prognosis remains unclear. Third, the present data were collected from patients with relapsed and/or refractory MM, and serum 25(OH)D levels were measured during or after MM treatment. The clinical setting thus differed from those of previous studies described above [23, 36, 37]. Meanwhile, our results indicate that serum vitamin D levels are associated with the prognosis of MM patients, regardless of the time of measurement. Additional studies with a larger number of uniformly treated patients are warranted to confirm and expand on these preliminary findings.