A New Prognostic Score Using Lymphocyte to Monocyte Ratio and Immunoglobulin Levels to Predict Progression in Multiple Myeloma Patients Undergoing Autologous Transplant
Authors: Sweiss Karen , Calip Gregory Sampang , Lee Jonathan , Mahmud Nadim , Rondelli Damiano , Patel Pritesh 
Published: October 2019

Abstract
High dose chemotherapy followed by autologous stem cell transplant (ASCT) prolongs progression-free survival (PFS) of patients with multiple myeloma (MM). However, there is wide variability in response and survival after ASCT and therefore prediction of prognosis remains a challenge. Biomarkers of immunologic and inflammatory changes, such as the peripheral blood monocyte and lymphocyte counts have been shown to impact clinical outcomes in other cancers and may have prognostic value in MM. We hypothesized that clinically available surrogates for immune suppression and systemic inflammation occurring in MM including the lymphocyte to monocyte ratio (LMR) and immunoglobulin (Ig) levels tested pre-transplant and at day 90 after ASCT may predict treatment-free survival (TFS). We also determined whether a composite immune score predicts disease progression.
One hundred and thirty patients who received melphalan 200 mg/m2 and ASCT between 2002 and 2016 were included in the final analysis. The median age was 59 (range: 34-77) years and most patients were male (n=71, 55%), IgG subtype (n=65, 50%), and ISS stage 3 at diagnosis (n=55, 57%). Sixteen (12%) patients were diagnosed with high risk FISH/karyotype. Median number of prior treatments was 2 (range: 1-5), with the majority being IMiD- (n=82, 63%) or PI-(n=72, 55%) based. The median time to transplant was 8 months (range: 3-144), and approximately half of patients received post-ASCT maintenance treatment (n=60, 46%). Treatment response was at least a very good partial response or better in 28 (27%) patients pre-transplant and 59 (59%) patients post-transplant (p=0.0001).
We collected the following values at baseline (Day -2) and Day +90 post-ASCT: absolute lymphocyte count (ALC); absolute monocyte count (AMC); lymphocyte to monocyte ratio (LMR); and the number of Ig levels suppressed. Values were separated into upper and lower quartiles for analysis. For the entire cohort, the median PFS was 25 months. At Day 90 post-ASCT, a high ALC (18 versus 23 months, p=0.04) and low AMC (13 versus. 25 months, p=0.02) predicted for superior TFS. When combined into a lymphocyte-monocyte ratio, we were able to demonstrate that a lower LMR (defined as <2.4) strongly predicted for worse TFS (16 versus 52 months, p=0.004). Finally, we evaluated the impact of low Ig levels on TFS and observed that when compared to patients with normal Ig levels, patients with 2 to 3 suppressed Ig levels had significantly worse TFS (17 versus. 51 months, p=0.04). In a multivariate Cox proportional hazards model, we calculated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for protein subtype, ISS stage, number of prior treatments, novel agent induction, and use of maintenance treatment. A low LMR (95% CI 0.01-0.15, HR 0.01; p=0.001) and suppressed Ig levels (95% CI 1.45-39.71, HR 7.58; p=0.017) were strongly associated with poor TFS.
We then developed an immune score by combining the LMR and Ig values. Patients were divided into either poor (low LMR and 2-3 suppressed Ig levels), good (high LMR and normal Ig levels) and intermediate (all other patients) risk groups. The median TFS for poor, intermediate and good risk groups was 7.5 versus 27 versus 79 months respectively (p=0.0004).
In order to examine whether autograft composition impacted lymphocyte and monocyte counts at day 90, we compared total infused cell numbers by automated differential counts and CD3 and CD14 expression between the poor and good risk groups. Total infused lymphocyte (1.74x108 versus 2.46x108, p=0.72), monocyte (3.18 x108 versus 3.39 x108, p=0.86), CD3 (1.52 x108 versus 1.37 x108, p=0.92), and CD14 (2.7 x108 versus 1.9 x108, p=0.44) cell numbers were similar between the 2 groups, suggesting that LMR at Day +90 was independent of the infused graft lymphocyte and monocyte numbers.
With long-term follow-up, we demonstrate the importance of two readily available biomarkers, the lymphocyte to monocyte ratio and immunoglobulin levels, in determining risk of progression in MM patients after ASCT. We observed that independent of the infused autograft cell composition, at day +90 a combination of the LMR and Ig levels could identify patients who will either have a long duration of remission or patients with very poor prognosis who may thus benefit from more intensified post-ASCT consolidation/maintenance or use of immunotherapy.

Disclosures
Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.