Cliff, Edward R. Scheffer

Abstract Purpose: Polatuzumab vedotin (polatuzumab) was approved for up-front treatment of diffuse large B-cell lymphoma in combination with chemoimmunotherapy (Pola-R-CHP) based on the POLARIX trial. However, when stratified by cell of origin (COO), polatuzumab seems to have greater efficacy in activated B-cell than germinal center B-cell (GCB) subtype disease. Most studies of polatuzumab used RNA expression to assess COO, whereas in routine clinical practice, the immunohistochemistry-based Hans algorithm is used. Experimental Design: To assess the impact of COO by immunohistochemistry on polatuzumab efficacy, we conducted a multicenter real-world study of adults with large B-cell lymphoma (LBCL) receiving polatuzumab from 2015 to 2024, split by receipt of polatuzumab in first-line versus relapsed/refractory settings. The primary endpoint was overall response rate (ORR) to polatuzumab-based treatment in GCB versus non-GCB relapsed/refractory LBCL. Results: Of 740 patients, 305 received polatuzumab in the first-line setting and 435 in the relapsed/refractory setting. In the relapsed/refractory cohort, the ORR in non-GCB versus GCB LBCL was 59.7% versus 36.3% [OR, 2.6; 95% confidence interval (CI), 1.77–3.84; P < 0.0001], with a complete response rate of 35.7% versus 17.7% (OR, 2.6; 95% CI, 1.66–4.02; P < 0.0001). Progression-free survival was longer for patients with non-GCB versus GCB COO (HR, 0.64; 95% CI, 0.5–0.83; P = 0.0006). In the first-line cohort, ORR, complete response rate, and progression-free survival were similar in non-GCB versus GCB LBCL, as hypothesized based on outcomes in the Pola-R-CHP arm of POLARIX, suggesting that the addition of polatuzumab overcomes the adverse risk of non-GCB COO in patients receiving R-CHOP. Conclusions: Based on these data, COO classification by the Hans algorithm is a strong predictor of polatuzumab efficacy in LBCL, informing real-world treatment decisions.

Introduction: Although not formally approved for the treatment of multiple myeloma (MM), the BCL2 inhibitor venetoclax (ven) has shown promising activity in patients (pts) with MM whose disease harbors t(11;14). The randomized BELLINI trial (VenVd vs Vd in unselected MM pts, Kumar Lancet Oncol 2020) demonstrated improved PFS, especially in the 35 patients with t(11;14) [HR 0.11], although worse OS in the intention to treat population due to increased treatment related mortality. The subsequent CANOVA trial (Vendex vs Pomdex in MM pts with t(11;14), Mateos IMS 2023) failed to show a PFS benefit (median PFS 9.9 mo vs 5.8 mo, p=0.237), leaving an uncertain future for ven in myeloma, despite the biological rationale and clinical activity. We therefore analyzed real world physician practice patterns using off-label ven for MM in the US. Methods: This retrospective observational study used data from the US nationwide Flatiron Health electronic health record (EHR)-derived de-identified longitudinal database. The Flatiron Health database contains structured and unstructured data curated via technology-enabled abstraction from approx. 280 cancer clinics and 800 unique sites of care. We included all patients in the Flatiron Health database with multiple myeloma (ICD-9 203.0x or ICD-10 C90.0x, confirmed with clinical review) who had received ven as part of any line of MM treatment. This included patients who commenced ven between 2016-2024. The primary endpoint was time to next treatment or death (TTNT) from ven initiation, with overall survival (OS) from ven initiation as the key secondary endpoint, both of which were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model, using R v 4.3.0. Results: We included 208 patients who received ven for MM. They had a median of three prior lines of therapy (range 0-12), a median age of 67 years (Range 34-85 yrs), and 59% were male. Race/ethnicity breakdown was: Non-Hispanic White: 136 pts (72.7%), Black 36 (19.3%), Hispanic 10 (5.3%), Asian 5 (2.7%), other/unknown 21 (10.1%). Most had commercial insurance (188 pts, 91.3%) and 108 pts (52%) were cared for in academic settings while 100 (48%) were in community settings. ECOG performance status was 0 in 50 pts (24%), 1 in 80 pts (38.5%), ≥2 in 31 pts (14.9%) and unknown in 47 (22.6%). ISS Stage was I in 42 pts (20.2%), II in 43 pts (20.7%), III in 52 pts (25.0%) and unknown in 71 (34.1%). 148 pts had t(11;14) (71.2%), while 25 pts did not (12%) and 35 pts had unknown t(11;14) status (16.8%). Most pts received ven as part of a triplet combination (106 pts, 51%), followed by doublets (39, 18.8%; 21 ven+dex and 18 ven+non-dex doublet), quads (38, 18.3%), as a single agent (17, 8.2%) or in other combinations such as with multi-agent cytotoxic chemotherapy or in addition to quadruplet therapy (8, 3.9%). Most common first ven-containing regimens used were VenDd (34 pts), VenKd (31), VenVd (25), Vendex (21), VenDVd (13), VenDKd (7). Ven was used as part of ≥2 different regimens in 20 patients, in 10 of whom those regimens were non-consecutive. Median TTNT was 10.2 months (mo) in all comers, 12 mo in pts with t(11;14), 3.4 mo in pts without t(11;14) and 7.6 mo in pts with unknown t(11;14) status. Median OS was 27.6 mo in all comers, 30.5 mo in pts with t(11;14), 8.1 mo in pts without t(11;14) and 27.9 mo in pts with unknown t(11;14) status. Pts with t(11;14) receiving ven had a significantly longer TTNT than those without t(11;14) [median 12 mo vs 3.4 mo, HR 0.59, 95%CI 0.42-0.84, p=0.003]. and a significantly longer OS [median 30.5 mo vs 8.1 mo, HR 0.58, 95% CI 0.38 - 0.89, p=0.012]. Discussion: We evaluated US ven prescribing patterns in 208 pts with MM in the largest real world study of ven in MM to date. While it was mostly used in pts with t(11;14) (71%), there was occasional use in pts without t(11;14), and it was used in a wide variety of combination regimens. Ven achieved meaningful TTNT in some patients and both TTNT and OS were greater in pts with t(11;14) than those without. This suggest that despite mixed data from clinical trials, clinicians are using ven for MM patients in practice and further data is required to optimize its use and understand its best combination treatment partners in MM.

Background: Polatuzumab vedotin (Pola) is an antibody drug conjugate targeting CD79b that incorporates the microtubule disrupting monomethyl auristatin E payload. Pola was approved in 2023 for the upfront treatment of diffuse large B cell lymphoma (DLBCL) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (polaRCHP) based on the POLARIX trial. However, the activity of pola appears to vary based on DLBCL cell of origin (COO) subtype, with greater efficacy in activated B cell (ABC) DLBCL compared to germinal center B cell (GCB) DLBCL (Russler-Germain Blood 2023). When outcomes in POLARIX are stratified by COO, polaRCHP demonstrated progression free survival (PFS) and overall survival (OS) benefits over RCHOP in patients with ABC but not GCB subtype DLBCL (PFS HR 0.34 ABC vs 1.03 GCB, OS HR 0.27 ABC vs 1.64 GCB; Morschhauser ASH 2023 and FDA data). Most prospective studies of pola used gene expression to assess COO, which is not readily clinically available. This study aims to examine if COO subtype by Hans algorithm (based on CD10, BCL6, and MUM1 expression by immunohistochemistry) is predictive of pola responses and outcomes in patients with large B cell lymphoma (LBCL). Methods: We conducted a retrospective, multicenter observational study of adults with LBCL who received pola (monotherapy or in combination) from 2015-2024 with Hans algorithm COO data and response assessment available. Patients were stratified by receipt of pola in the frontline vs relapsed/refractory (R/R) setting. The primary endpoint was overall response rate (ORR) to pola-based treatment in GCB vs non-GCB subtypes. Secondary endpoints included complete response rate (CRR), PFS, and OS. For time to event endpoints, patients responding to pola who received CAR T or stem cell transplantation prior to progression were censored at time of cellular therapy. Demographics were summarized by descriptive statistics. Comparative and survival analyses used Chi squared/Fischer exact tests and Kaplan Meier analysis. Data cutoff was July 1, 2024. Results: 718 patients were included. Median follow-up was 15 months (interquartile range [IQR] 8-32). Median age at LBCL diagnosis was 66 years (IQR 56-74); 62% were men; 69 (10%) had double hit lymphoma (DHL); 129 (18%) had underlying low grade lymphoma. Pola was used in the frontline setting in 293 (41%) patients, of whom 139 (47%) had GCB vs 154 (53%) non-GCB COO. Of the 426 patients receiving pola for R/R LBCL (including one patient receiving pola retreatment), 224 (53%) had GCB vs 202 (47%) non-GCB COO. Among patients receiving pola-based regimens in the R/R setting (GCB vs non-GCB: pola monotherapy = 7% vs 4%, pola + R = 26% vs 26%, pola + BR = 55% vs 61%, pola + other = 12% vs 9%; p = 0.44), the ORR in GCB vs non-GCB LBCL was 36% vs 61% (p < 0.001), while CRR in GCB vs non-GCB was 17% vs 36% (p < 0.001). COO remained a significant component of logistic multivariate regression models of ORR (p < 0.001) and CRR (p < 0.001) when incorporating IPI at original LBCL diagnosis, histology, DHL status, and refractory status to frontline therapy. Despite this, no significant PFS or OS differences by COO were seen, potentially due to approximately 1/4 patients being censored due to receiving subsequent cellular therapy (e.g. CAR T) prior to progression. In patients receiving frontline pola-based regimens (of which 275 [94%] included an anthracycline), ORR and CRR were similar in GCB vs non-GCB (ORR 89% vs 88% p > 0.5; CRR 76% vs 77% p > 0.5). While PFS and OS were similar between COO groups in the frontline cohort, follow-up and cohort size were limited. Conclusion: Based on this real-world evidence, COO classification by Hans algorithm is a strong predictor of the activity of pola-containing therapy in R/R LBCL, with significantly higher ORR and CRR in patients with non-GCB compared to GCB COO LBCL. This aligns with the cumulative existing evidence. ORR and CRR to pola-containing therapy in the frontline setting did not differ significantly by COO subtype, but longer follow-up of larger cohorts is needed to clarify the predictive role of COO by Hans algorithm in this setting, especially considering the PFS advantage with polaRCHP in POLARIX was not associated with significant differences in ORR or CRR. Overall, clinicians should consider factoring COO subtype into treatment decisions regarding pola-containing regimens, and studies of pola-based therapies should stratify patients and report outcomes by COO subtype.

Abstract Background Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM. Methods All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life. Results Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively). Conclusion In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM.

AbstractIn the POLARIX trial, pola‐R‐CHP demonstrated improved progression‐free survival (PFS) compared to R‐CHOP in untreated intermediate‐ to high‐risk DLBCL. We surveyed practicing clinicians regarding their interpretation of POLARIX, including impressions of efficacy, safety, and cost. Of 174 respondents, most from academic centers (82%) in the United States (57%), 70% stated they would not replace R‐CHOP with pola‐R‐CHP due to insufficient PFS difference, lack of overall survival benefit, and excessive cost. Respondents not recommending pola‐R‐CHP expressed concerns about financial implications for both society and patients. We observed considerable heterogeneity in both study interpretation and plans for real‐world implementation of pola‐R‐CHP.