Characterization of B12 Deficiency in Patients with Plasma Cell Disorders

Abstract Background: Although vitamin B12 deficiency has been reported in patients with plasma cell dyscrasias (PCDs), no mechanism has been identified. Excess free light chains (FLCs), readily measurable by the serum FLC assay since 2001, could disrupt the renal proximal tubule receptors megalin and cubulin where B12 is reabsorbed. We sought to identify risk factors for B12 deficiency in PCD patients to elucidate a possible mechanism. In particular, we hypothesized that rates of B12 deficiency would be higher in PCD patients with higher FLC burdens. Methods: Of 1482 patients with ICD9 codes for PCDs, 530 met the inclusion criteria of having both serum B12 and FLC values. We reviewed the electronic medical records to obtain clinical data collected in the time preceding the patient's lowest B12 level. Patients were excluded if the lowest B12 was elevated in the setting of known concurrent vitamin B12 replacement therapy. Data from eligible patients were analyzed using chi-square, Student's independent t test, and Spearman's rank-order correlation to identify associations between B12 insufficiency (defined as <250 pg/ml or <350pg/ml and B12 treatment history) and PCD characteristics. This retrospective study was approved by the Mount Sinai IRB. Results: Overall, 26.6% patients were found have vitamin B12 insufficiency. Other than an IgG isotype PCD (P=0.025) there were no significant differences in age, gender, or PCD diagnosis between patients with and without B12 insufficiency (see Table 1). As expected, there was a strong negative correlation between eGFR and involved FLC, r(248) = -0.277, p < 0.001. However, unexpectedly, there was also a significant negative correlation between B12 level and eGFR, rs(487) = -0.106, p = 0.019 such that insufficient B12 was associated with normal eGFR (p = 0.001). There was no correlation between B12 level and involved FLC (p = 0.948) nor B12 level and Bence Jones proteinuria (p = 0.302). Discussion: While our data do not appear to support the proposed mechanism of FLC disruption of renal receptors, B12 deficiency was more common in our sample (26.6%) than the previously reported 13.6% prevalence among PCD patients (Baz et al Cancer 2004). While B12 deficiency and PCDs are both associated with higher age, the prevalence of B12 deficiency among older adults is only 10-15% (Baik et al Annu Rev Nutr 1999). Therefore, prospective studies are needed to explore other characteristics of PCD patients, such as chemotherapy treatment (Tandon et al Indian Pediatr 2015) or aspirin use (van Oijen et al Am J Cardiol 2004), contributing to a high prevalence of B12 deficiency in this population. Detection and treatment of B12 deficiency among PCD patients remains clinically important to reduce ensuing sequelae of neurologic dysfunction and cytopenias, which are complications of PCDs and their treatments. Table 1. Demographics and disease characteristics by B12 status. Vitamin B12 Status Insufficient B12 Normal B12 Total p Gender N %a N %a N %b Male 78 30.2 180 69.8 258 48.7 0.066 Female 63 23.2 209 76.8 272 51.3 Total 141 26.6 389 73.4 530 Age at PCD Diagnosis (median) 61 62 0.857 PCD N %a N %a N %b Multiple myeloma 60 35.9 107 64.1 167 78.4 0.488 Non-multiple myeloma 14 30.4 32 69.6 46 21.6 Total 74 34.7 139 65.3 213 Isotype N %a N %a N %b IgG 50 44.2 63 55.8 113 53.3 0.025 IgA 9 22.5 31 77.5 40 18.9 IgM 3 30.0 7 70.0 10 4.7 Kappa only 4 16.0 21 84.0 25 11.8 Lambda only 8 33.3 16 66.7 24 11.3 Total 74 34.9 138 65.1 212 Renal Function (KDOQI stages) N %a N %a N %b Stage 1-2 52 36.9 89 63.1 141 29.0 0.001 Stage 3 67 29.1 163 70.9 230 47.2 Stage 4 12 16.7 60 83.3 72 14.8 Stage 5 8 18.2 36 81.8 44 9.0 Total 139 28.5 348 71.5 487 a row percent, b column percent Table 2. Light chain burden and relevant labs by B12 status. Vitamin B12 Status Insufficient B12 Normal B12 Total p FLC Burden* N %a N %a N %b Normal FLC 12 34.3 23 65.7 35 16.4 0.354 Not measurable FLC, abnl ratio 23 40.4 34 59.6 57 26.8 Measureable FLC, nl BJP 18 26.1 51 73.9 69 32.4 Measurable FLC, elevated BJP 15 44.1 19 55.9 34 16.0 Massive BJP (>3g/24hr) 6 33.3 12 66.7 18 8.5 Total 74 34.7 139 65.3 213 Labs (medians) Folate, serum 14.0 14.6 0.919 MCV 91.3 92.4 0.055 Hemoglobin 10.9 10.6 0.940 LDH 186 199 0.145 Albumin 3.8 3.9 0.958 *normal = (sFLC<100mg/l), k/l ratio 0.26-1.85; measureable = sFLC ³100mg/l; abnl ratio = k/l ratio<0.26 or >1.85; elevated bence jones protein (BJP) = M-spike or BJP>200mg/24hr arow percent, b column percent Disclosures Chari: Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Biotest: Other: Institutional Research Funding; Millennium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.