Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12–31 months and ongoing).

Multiple myeloma is a heterogeneous condition characterized by the proliferation of monoclonal B-cells, for which there is currently no curative treatment available. Relapses are, unfortunately, common after first-line treatment. While the prognosis for relapsed refractory multiple myeloma is generally poor, advances in the treatment of relapsed or refractory multiple myeloma offer hope. However, the expansion of effective options in targeted treatment offers renewed optimism and hope that patients who fail on older therapies may respond to newer modalities, which are often used in combination. We review currently approved and novel investigational agents classified by mechanisms of action, efficacy, approved setting, and adverse events. We delve into future directions of treatment for relapsed/refractory multiple myeloma, reviewing novel agents and therapeutic targets for the future.

Extranodal (EN) diffuse large B-cell lymphoma (DLBCL) has been historically associated with inferior survival outcomes compared to nodal DLBCL. However, outcomes of patients with EN DLBCL following chimeric antigen receptor T-cell (CAR-T) therapy are not well established. In this multi-center retrospective cohort study, we evaluated the outcomes of patients with EN DLBCL who underwent CAR-T in the relapsed/refractory (R/R) setting. The primary objective was overall survival (OS), while secondary objectives included progression-free survival (PFS), response rates, and toxicity rates. A total of 218 patients were included in the analysis. The most common sites of EN involvement were skin/soft tissue (25%), bone (22%), and lung (17%). Overall response rate (ORR) and complete response rate (CRR) at first post-treatment evaluation were 62% (n = 127) and 40% (n = 82), respectively. Median follow-up was 3.5 years. Median PFS and OS were 4.0 months (95% CI = 3.1–7.2) and 25.7 months (95% CI = 16.1–51.6), respectively. Cytokine release syndrome (CRS) of any grade occurred in 73% (n = 159) of patients, and 6% (n = 12) had grade ≥ 3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade occurred in 37% (n = 81) of patients, and 19% (n = 41) developed grade ≥ 3 ICANS. In the multivariable analysis, factors that were independently prognostic of inferior OS were 3 or more lines of therapy prior to CAR-T, bulky disease at the time of CAR-T, hepatobiliary, and pancreas involvement, while refractory disease to the most recent therapy prior to CAR-T was associated with inferior PFS. Future studies should further evaluate outcomes of CAR-T in patients with specific EN sites of involvement that appear to be associated with inferior survival such as the liver and pancreas.

Background:Mosunetuzumab (Mosun) is a bispecific CD20xCD3 antibody approved for the treatment of follicular lymphoma (FL) after ≥2 lines of therapy. In that setting, Mosun provides 60% complete response (CR) rate despite prior immunosuppressive therapy [Budde et al., Lancet Oncol 2022]. BrUOG-401 (NCT04792502) is an investigator-initiated, multicenter, single arm, phase 2 clinical trial testing the hypothesis that administering Mosun for previously untreated FL or marginal zone lymphoma (MZL) will result in a higher CR rate than standard chemoimmunotherapy. Additionally, selective immune augmentation using low-dose lenalidomide (Len) may improve response for patients who do not attain CR on interim assessment. Here, we present the pre-planned interim efficacy analysis of this trial. Methods:Patients with previously untreated, high-burden or symptomatic FL or MZL received subcutaneous Mosun for 8 planned cycles (C) with step-up dosing in C1 (day 1: 5mg, day 8 & 15: 45 mg; then 45mg on day 1 of C2-C8). Patients who attained only partial response [PR] or stable disease at interim assessment after C4 received the addition of Len augmentation (10mg daily, continuously) during C5-C8, with an optional extension up to C12. The primary endpoint is the CR rate at the end of therapy, assessed using PET-CT-based Lugano criteria [Cheson et al., JCO 2014]. However, for the primary hypothesis evaluation, we used CT-based criteria to test the superiority of the CR rate over the historical 53% CR rate reported (using CT criteria only) with bendamustine/rituximab chemotherapy in the RELEVANCE trial (Morschhauser et al., NEJM 2018). This pre-planned interim analysis occurred after 25 patients were evaluable for response, with futility stopping rule if ≤13 CR's were observed. Secondary objectives include safety, overall response rate (ORR), progression-free and overall survival (OS), as well as the rate of conversion from PR to CR on Mosun+Len augmentation. Adverse events (AE) were graded using CTCAE v5 criteria, and cytokine release syndrome (CRS) using the 2019 ASTCT criteria. Results:As of July 2024, 37 patients (median age 65, range 30-89; 58% women; 86% white non-Hispanic) were enrolled, including 22 (59%) with FL and 15 (41%) with MZL. The lymphoma stage was 2 in 14%, 3 in 22%, and 4 in 64%. Among the FL patients, FLIPI was low in 6, intermediate in 7, and high in 9. Two patients discontinued treatment (1 for AE, 1 for progression) before completing C8. The most common AE on treatment included injection site reaction (n=18 [49%]; grade [G]1 in 17, G2 in 1), fatigue (43%; G1/2 in 15, G3 in 1), and rash (38%; G1/2 in 11, G3 in 3). Other G3/4 AE's (in ≥2 patients) included Pneumocystis jirovecii pneumonias (PJP, occurred during C2 and C3), hypertension, weakness, pain, and neutropenia (each in n=2). There were 6 (16%) CRS events, all G1 and during C1, and all resolved. One patient received tocilizumab. No G3/4 toxicities attributed to Len were observed. At the data cutoff, 25 patients were evaluable for response. Using Lugano criteria, the CR rate was 82% (95% confidence interval [CI], 60-95%), and the ORR was 86% (95%CI, 65-97%). The CR rate was 80% for FL and 86% for MZL. Six patients received Len augmentation and 3 of the evaluable 4 converted to CR, whereas one had (after initial PR) progressive disease with biopsy-proven histologic transformation. With short follow up (median 5.8 months), no recurrence was observed among patients with CR; OS is 100%. The 14 observed CR's (using CT-based criteria) satisfied the interim analysis criterion for the pre-planned two-stage design. Flow cytometry demonstrated, apart from a rapid B-cell depletion, a temporary decrease in circulating TEMRA CD8+ T-cells and a significant increase in LAG3 and PD-1 expression at C2. At the end of C4, patients not attaining early CR showed significantly lower counts of NK cells (P=0.009) and no effector memory T-cell expansion. These differences resolved after 4 cycles of Mosun+Len augmentation. Conclusions:Fixed-duration subcutaneous Mosun resulted in a high CR rate during first-line treatment of FL and MZL with limited toxicity, including only 16% rate of G1 CRS, and similar CR rates in FL and MZL on this initial assessment. Selective immune augmentation using low-dose continuous Len was safe and may facilitate conversion to CR for slow early responders. Study enrollment continues and both safety and efficacy analyses with longer follow-up will be presented.

Light chain amyloidosis is a plasma–cell disorder with a poor prognosis. It is a progressive condition, causing worsening pain, disability, and life-limiting complications involving multiple organ systems. The medical regimen can be complex, including chemotherapy or immunotherapy for the disease itself, as well as treatment for pain, gastrointestinal and cardiorespiratory symptoms, and various secondary symptoms. Patients and their families must have a realistic awareness of the illness and of the goals and limitations of treatments in making informed decisions about medical therapy, supportive management, and end-of-life planning. Palliative care services can thus improve patients’ quality of life and may even reduce overall treatment costs. Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by the excessive secretion of light chains by an indolent plasma cell clone that gradually accumulates in vital organs as amyloid fibrils and leads to end-organ damage. With progressive disease, most patients develop diverse clinical symptoms and complications that negatively impact quality of life and increase mortality. Complications include cardiac problems including heart failure, hypotension, pleural effusions, renal involvement including nephrotic syndrome with peripheral edema, gastrointestinal symptoms leading to anorexia and cachexia, complex pain syndromes, and mood disorders. The prognosis of patients with advanced AL amyloidosis is dismal. With such a complex presentation, and high morbidity and mortality rates, there is a critical need for the establishment of a palliative care program in clinical management. This paper provides an evidence-based overview of the integration of palliative care in the clinical management of AL amyloidosis as a means of reducing ER visits, rehospitalizations, and in-hospital mortality. We also discuss potential future collaborative directions in various aspects of clinical care related to AL amyloidosis.

Background/Objectives: Teclistamab is a bispecific antibody targeting BCMA and CD3, approved for relapsed/refractory multiple myeloma. It is administered continuously until progression or intolerance; however, prolonged use may increase infections and treatment burden. This study compares continuous versus fixed-duration teclistamab to determine whether treatment discontinuation after response is feasible without compromising outcomes. Methods: A multicenter retrospective study was conducted on adults with relapsed/refractory multiple myeloma treated with teclistamab between August 2022 and May 2024. Patients received step-up dosing followed by weekly administration. Those who achieved ≥VGPR and discontinued therapy due to deep response, toxicity, or preference were assigned to the fixed-duration group. Outcomes included response rates, progression-free survival (PFS), overall survival (OS), and adverse events. Results: Eighty-eight patients were included (continuous: n = 72; fixed: n = 16). The fixed group had higher complete response rates (69% vs. 44%) and shorter median time to best response (1 vs. 2 months). Median PFS was 16 months for continuous dosing versus 13 months for fixed-duration. Twelve-month PFS was similar (65% vs. 66%). Twelve-month OS was 83% vs. 81% in the continuous and fixed groups, respectively. Cytokine release syndrome and neurotoxicity rates were similar. Infections were more frequent and severe in the fixed cohort (75% any grade; 69% grade ≥ 3). Conclusions: Fixed-duration teclistamab after deep response appears feasible in appropriately selected patients, with comparable early survival outcomes to continuous treatment. Prospective studies are needed to define selection criteria, immune recovery markers, and optimal discontinuation timing.