Serum CD147 Levels Are Increased in Multiple Myeloma Patients and Elevated Levels Are Associated with Refractory Disease and Shortened Progression Free Survival

Introduction: CD147 is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. CD147 gene expression levels are elevated in several types of human cancer. Recent studies show that expression of CD147 is increased in multiple myeloma (MM) patients (pts)' tumor cells and higher levels are associated with progressive disease (PD) and resistance to immunomodulatory agents through its binding to cereblon. CD147 forms a complex with MCT1, a proton monocarboxylate and lactate transporter, and this complex is a regulator of glycolysis and cellular metabolic pathways promoting the survival and proliferation of MM cells. However, no data exists on levels of serum CD147 among pts with MM or other hematological malignancies. Plasma levels of CD147 are elevated in pts with acute kidney injury (AKI). We analyzed the relationship between serum (s) CD147 levels and renal function and response to treatment among MM pts and its relationship to their progression free survival (PFS).

Methods: We collected serum samples from 152 MM pts who were treated at a single clinic. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. To determine levels of sCD147, we used an enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN). Mann-Whitney analysis was used to analyze the relationship between sCD147 and clinical status. A subset of pts (n=62) had their sCD147 levels measured immediately prior to starting a new treatment regimen. Using Kaplan-Meier analysis, PFS was compared between pts with sCD147 levels above or below 5.00 ng/mL. Levels of sCD147 were measured from pts at the start of treatment who achieved a complete response (CR) and among those with PD without achieving any response (refractory disease [RD]). In addition, sCD147 levels were also assessed among pts in CR and those with PD at the time of their sample blood draw. The Spearman correlation coefficient was used to correlate levels of serum creatinine with sCD147.

Results: Previous studies show median sCD147 levels in healthy donors is 2.5 ng/mL and invariably below 4.5 ng/mL consistent with our healthy donors (all < 4.50 ng/mL). At the time of sampling, the median level of sCD147 among pts with MM who were in CR (n=49, median=3.69 ng/mL) was not different compared with the median level of among pts with PD (n=74, median=3.86 ng/mL; P=0.3525). Overall, pts' sCD147 levels assessed prior to the initiation of treatment were not different among those achieving CR (n=16, median=3.79 ng/mL) compared with those showing RD (n=46, median=4.06 ng/mL; P=0.3895). Consistent with data obtained on pts with AKI from other causes, levels of sCD147 were directly correlated with serum creatinine levels in MM pts (n=136, Spearman correlation coefficient < 0.0001). Among pts without renal failure, only 1/52 (2%) of pts in CR at the time of blood draw showed a sCD147 level > 6.00 ng/mL (6.39 ng/mL) whereas 21/97 (22%) of pts with RD showed a level above this threshold (range, 6.01-17.20 ng/mL). Notably, pts with sCD147 levels drawn prior to the start of treatment that were above the maximum value for all normal donors (sCD147 levels > 5.00 ng/mL; n=34) showed a much shorter PFS (median=2.11 months) compared with those with levels below this level (n=81; median=4.64 months; P=.0204). When PFS was determined among MM pts without renal failure, there remained a difference among those with levels > 5.00 ng/mL compared with those with levels below this threshold (2.11 vs 5.27 months; P=0.04).

Conclusions: This is the first study to evaluate serum CD147 levels in hematologic malignancies. Our results in MM pts show these levels correlate with renal function as previously shown among pts with AKI. Notably, sCD147 levels > 6.00 ng/mL predict for RD, and baseline levels elevated above the threshold of healthy donors (> 5.00 ng/mL) also predict for a markedly shorter PFS among all MM pts or those without renal failure. This demonstrates that sCD147 levels > 5.00 ng/mL at baseline may predict poor outcome for MM pts and may be a new prognostic factor for MM pts and those with other hematologic malignancies. Current work is focusing on the relationship of sCD147 levels to outcomes among MM pts receiving specific drug treatments especially immunomodulatory agents given recent studies suggesting that increased intratumoral expression of CD147 is associated with poor outcome for MM pts receiving these drugs.