Serum Soluble Syndecan-1 (ssCD138) Can Contribute to the Discrimination of Lenalidomide Resistant Multiple Myeloma (MM) Patients

Background Lenalidomide resistance is one of the main emerging therapeutical concerns in MM. SsCD138 levels were shown of prognostic significance in MM at diagnosis while their contribution during disease course has not been evaluated.

Aims To evaluate ssCD138 possible prognostic contribution in MM patients treated with Lenalidomide.

Patients and methods :

Sixty-nine patients treated with Lenalidomide were included in the study. All received dexamethasone (RD) but one maintenance. Medical records were reviewed and frozen sera samples were tested after patient's informed consent. SsCD138 levels were determined by ELISA (Diaclone Research) according to the manufacturer's instructions. Median age of patients was 67 years with 50% women. Immunoglobulin type was IgG in 67% patients, IgA in 22%, Light-Chain in 10% and IgD in 1%. ISS 1, 2 and 3 were 37%, 24% and 39% respectively. ssCD138 were measured at RD initiation, best response and relapse. Median value was used as cut off and any concentrations above median were defined as "High". Median PostLenOS was 27mo, median time to next treatment (TNT) was 12,5mo. Time from RD initiation to the second relapse after RD (LenPFS2) was 24,5mo. Median number of previous treatment lines was 3. Forty healthy individuals were also tested. Statistical analysis was performed using SPSS software v.25.

Results:

Median ssCD138 was 234 ng/ml (15-841) at RD initiation, 97 ng/ml(12-1500) at plateau and 247(51-395) at relapse while it was 52 ng/ml (21-1070) in Healthy Individuals. Patients achieving VgPR and better had more than 50% reduction in ssynd-1 levels from treatment initiation to plateau (r=0,344, p=0,05). Patients with High ssynd-1 levels at RD initiation presented shorter LenPFS 2 (p=0,011) and TNT (p=0,018). Factors measured at RD initiation impacting on LenPFS2 were ssCD138 levels (HR:2 .p=0,025), abnormal LDH (HR:4,47 ,p=0,0001), ISS (HR=1,54, p=0,008) and b2-microglobulin>5.5mg/L(HR: 2,23, p=0,009), Bone Marrow Infiltration (BMINF)>60% (HR : 2,39, p=0,048), albumin<3.5g/dl (HR: 2,72, p=0,12). In univariate analysis for TNT predictors, ssCD138 levels (HR:2,32, p=0,009), ISS (HR:1,46, p=0,001), b2-microglobulin>5.55mg/L (HR:1,76, p=0,008) and Free Light Chain Ratio(FLCR)>100 (HR:2,08, p=0,000), albumin<3.5 g/dl (HR: 1,75, p=0,031) BMINF>60% (HR : 2,18, p=0,01), Hb<10 g/dl (ΗR:3,3, p=0,001) were significant. Variables of importance for PostLenOS were ISS (HR:1,4 , p=0,004) b2-microglobulin>5.5mg/L (HR:1.61 ,p= 0,031), FLCR>100 (HR:2,8 , p=0,0001) levels, albumin<3.5 g/dl (HR: 2,45, p=0,001), BMINF>60% (HR : 2,8, p=0,002). Based on the independent variables patients were assigned a score of 1 with both FLCR>100 and elevated ssCD138 levels and 0 with both these values normal. Patients with 1 point presented an estimated TNT of 4 Vs 14 months (p=0,001) and shorter LenPFS of 11 Vs 28 months (p=0,001). The estimated PostLenOS was 15 Vs 33 months in patients with 1 and 0 point respectively (p=0,005).

Conclusion

SsCD138 levels in MM patients treated with RD were significantly associated with LenPFS2 and TNT. A Prognostic score based on ssCD138 and FLCR>100 was shown effective for the prediction of PostLenOS, LenPFS2 and TNT. These results suggest that soluble syndecan-1 levels can discriminate patients at risk to the lenalidomide resistant early. Indeed validation in larger cohort is necessary.