Table 4.

Vitamin D deficiency (VDD) and MM prognosis, clinical outcomes, and disease sequelae.

Reference	Association with Survival	Association with Staging	Association with Relevant Hematological Markers	Association with Clinical Outcomes/Symptoms
Ng et al. (2009) [14]	N/A	VDD associated with higher ISS staging (p = 0.03); Unadjusted OR for being VDD was 3.56 for ISS stage III compared to stage I	VDD associated with higher mean CRP level (p = 0.02) and lower albumin levels (p = 0.003)	No association found for VDD and skeletal morbidity (fractures and lytic lesions)
Clement et al. (2011) [15]	N/A	N/A	N/A	Four months of supplementation with vitamin D (3000 IU) resulted in one individual (case report) reporting reduced generalized musculoskeletal pain
Lauter and Schmidt-Wolf (2015) [17]	Of seven participants who died of progressive disease, five were vitamin D insufficient, one was deficient, and one was sufficient (p = 0.932)	N/A	MM patients with VDD had higher plasma cells in bone marrow (44.8%) compared to those classified as sufficient (13.3%)	No association found for vitamin D status and lytic bone lesions or disease activity. MM patients found to be without renal insufficiency were also found to have significant increases in vitamin D levels after supplementation
Maier et al. (2015) [18]	N/A	N/A	N/A	Among MM patients with bone lesions, the mean vitamin D level was reported to be deficient (14.8 ng/mL)
Wang et al. (2016) [19]	N/A	N/A	N/A	No association found between VDD and the occurrence of either motor PN or sensory PN. VDD was associated with the severity of PN (>grade 2) for both motor PN (p = 0.042) and sensory PN (p = 0.009). No association was observed for pain
Eicher et al. (2020) [20]	MM patients who underwent chemotherapy treatment and ASCT who had VDD had significantly shorter PFS (median 16.0 months) compared to those with normal levels (median 19.5 months) (p = 0.0412) OS was shorter among VDD patients (20.4 months) compared to those with normal levels (21.4 months) (p = 0.049)	N/A	N/A	N/A
Graklanov and Popov (2020) (Publication 1 [21] and 2 [22])		No association found between vitamin D status and ISS stage	No association found between vitamin D status and hemoglobin levels	No association found between vitamin D levels and response to treatment. No association found between vitamin D levels and bone disease
Kumar et al. (2020) [23]	N/A	VDD associated with higher stage of disease (p < 0.001)	N/A	N/A
Nath et al. (2020) [24]		No association found between vitamin D status and ISS stage	No association between vitamin D status and creatinine or albumin	Lower vitamin D levels were significantly associated with lower performance status (ECOG ≥ 2) (p = 0.003). The rate of peripheral neuropathy was significantly higher among patients with VDD (73%) compared to those who were not deficient (33%) (p = 0.03). A non-significant association was noted for VDD and self-reported peripheral neuropathy symptom severity (p = 0.08). No significant association between VDD and skeletal morbidity or 5-year fracture history was observed
Yellapragada et al. (2020) [26]	VDD was significantly associated with worse OS (median 3.10 years, 95% CI: 2.73 to 3.52) compared to patients with normal levels (median 3.91 years, 95% CI: 3.59 to 4.38) (p = 0.002). The estimated mortality risk for VDD was a 24% increase (HR: 1.24; p = 0.02). Log-transformed vitamin D level was reported to be a significant predictor of survival in White patients in univariate (HR: 0.77, p = 0.002) and multi-variate (HR: 0.74, p = 0.009) analysis, but not in African American patients for either analysis	N/A	N/A	N/A
Sincan and Erdem (2021) [27]		Lower levels of vitamin D were associated with increased ISS stage (p = 0.01)	No association was observed between vitamin D levels and hemoglobin, albumin, or creatinine. Lower levels of vitamin D were significantly associated with a higher mean % of plasma cells in bone marrow (p = 0.02)	Lower vitamin D levels were significantly associated with bone fracture (p = 0.007) and the presence of lytic bone lesions (p = 0.01)
Oortgiesen et al. (2022) [28]	N/A	N/A	N/A	Vitamin D levels were significantly and inversely associated with the occurrence of PN (p = 0.035)

VDD: Vitamin D deficiency (as defined but for each individual study), CRP: C-reactive protein, ISS: International Staging System, OR: odds ratio, N/A: not applicable, PN: peripheral neuropathy, ASCT: autologous stem cell transplantation, PFS: progression free survival, OS: overall survival, ECOG: Eastern Cooperative Oncology Group, CI: confidence interval, and HR: hazard ratio.