Addition of Monoclonal Protein to MALT-IPI Improved Identification of MALT Patients at High Risk of Progression with Current First-Line Therapies

Introduction
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL or MALT lymphoma) is the most common subtype of MZL. MALT international prognostic index (IPI) was derived from the IELSG-19 trial wherein patients (pts) were randomized to rituximab (R), chlorambucil, or their combination. It identified age ≥70 years, stage 3/4, and an elevated lactate dehydrogenase (LDH) level as prognostic factors (Thieblemont C, Blood 2017). However, chlorambucil +/-R is rarely used in the first-line MZL treatment in USA, so the utility of MALT-IPI in pts receiving current standard immunochemotherapy is unclear. Furthermore, MALT-IPI did not include monoclonal protein (M-protein), which is an independent prognostic variable (Epperla N, Blood Adv 2023). Hence, we evaluated the outcomes of pts with MALT lymphoma treated in the contemporary era, using stratification by MALT-IPI with addition of M-protein.

Methods
This multicenter, retrospective cohort study included adult pts with MALT lymphoma diagnosed from 2010-2020, who had information on MALT-IPI at diagnosis, and who were treated at 10 US medical centers using first-line R monotherapy, R+bendamustine, RCHOP, or RCVP. Main endpoints were progression-free survival (PFS) and overall survival (OS) measured from the start of first-line therapy. Survival was estimated from flexible parametric models, reporting hazard ratios (HR) with 95% confidence intervals (CI). Missing data were accounted for using multiple imputation.

Results
The study included 468 pts (72% aged ≤70 years; 56% women; 42% stage 3/4), whose EMZL was treated with first-line R monotherapy (62%), R-bendamustine (29%), or RCHOP/RCVP (9%). MALT-IPI was low in 40%, intermediate (int) in 37%, and high in 23%.

The 5-year PFS for MALT-IPI low, int and high groups were 72%, 64%, and 48%, respectively. The difference between low and int groups was not statistically significant (HR=1.38; 95%CI 0.93-2.04; P=0.11). Based on observed outcomes for all subgroups, presence of M-protein provided additional prognostication for the high MALT-IPI group, but not for the groups with low/int MALT-IPI. Therefore, we defined a dichotomous EMZL-MPI defining “high risk” (15% of pts) as the group with MALT-IPI high and M-protein present, and EMZL-MPI “low risk” for all other combinations. The 5-year PFS was 39% and 67% for the two groups, respectively (HR=2.41; 95%CI, 1.61-3.61; P<0.0001). Thus, combining M-protein with MALT-IPI identified a subset of EMZL pts at risk for shorter PFS after current first-line therapies.

EMZL-MPI reclassified 35% of high MALT-IPI pts as low risk, and the 5-year PFS for the reclassified group did not significantly differ from the low/int MALT-IPI (65% vs 67%, HR=1.07, 95%CI 0.51-2.25; P=0.85).

The 5-year estimates for OS for MALT-IPI groups were 97% for low, 91% for int (HR=2.28; 95%CI 0.98-5.59; P=0.07), and 81% for high (HR=4.87; 95%CI, 2.00-11.8; P<.001). The estimates for low- and high-risk EMZL-MPI groups were 93% and 79%, respectively (HR=3.17; 95%CI, 1.50-6.70; P=0.002). Similar to PFS, we found that the 86% 5-year OS for the high MALT-IPI reclassified as low-risk EMZL-MPI was not statistically significantly different from the OS in the low/int MALT-IPI groups (P=0.23).

We further investigated whether the prognostic significance of the high-risk EMZL-MPI differs according to first-line therapy. High-risk EMZL-MPI was prognostic for shorter PFS after R monotherapy (HR=2.94; 95%CI 1.67-5.19; P=0.0002), whereas high MALT-IPI without M-protein was not (HR=1.07; 95%CI 0.39-2.96; P=0.89). Similar results were obtained for OS. In contrast, for pts treated with combination immunochemotherapy, neither high-risk EMZL-MPI (HR=1.00; 95%CI 0.40-2.53; P=0.99) nor high MALT-IPI (HR=0.88; 95%CI=0.31-2.55; P=0.82) were prognostic.

Discussion
In this multicenter study, the addition of M-protein to high MALT-IPI helped identify a truly high-risk subgroup (MALT-IPI high/M-protein present) of pts with EMZL, particularly those treated with anti-CD20 antibody alone. Measuring the presence of M-protein at diagnosis in all newly diagnosed pts may improve prognostication and influence the choice of therapy. Neither MALT-IPI nor EMZL-MPI provide sufficient prognostication for pts receiving combination immunochemotherapy, and novel prognostic biomarkers are needed for stratification in this setting.