Lenalidomide plus rituximab (R2 ) in previously untreated marginal zone lymphoma: subgroup analysis and long-term follow-up of an open-label phase 2 trial.

Lack of consensus for first-line marginal zone lymphoma (MZL) treatment and toxicities associated with currently available systemic therapies have inspired evaluation of immunotherapeutic agents yielding robust outcomes with improved tolerability. We previously reported durable efficacy with first-line lenalidomide and rituximab (R2 ) in follicular lymphoma, MZL and small lymphocytic lymphoma with a subsequent long-term follow-up shown here in MZL patients. This phase 2 investigator-initiated study included previously untreated, stage III/IV MZL patients treated with lenalidomide 20 mg/day on days 1-21 and rituximab 375 mg/m2 on day 1 of each 28-day cycle, continuing in responders for ≥6-12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression-free survival (PFS). The ORR was 93% with 70% attaining CR/CR unconfirmed. At median follow-up of 75·1 months, median PFS was 59·8 months and 5-year OS was 96%. Most non-haematological adverse events (AE) were grade 1/2. Grade 3 haematological AEs were neutropenia (33%) and leucopenia (7%), and grade 4 were leucopenia (3%) and thrombocytopenia (3%). Two patients died of secondary malignancies; no treatment-related fatalities occurred. With extended follow-up, outcomes for MZL patients receiving R2 were robust with no unexpected late or delayed toxicities.

Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.

Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.

Follicular Lymphoma: Past, Present, and Future.

OPINION STATEMENT: Even in the modern era, follicular lymphoma (FL) remains largely an incurable but treatable disease with both standard and novel treatment modalities. Despite the abundance of efficacious treatment modalities currently available, there is no universally agreed upon standard approach to treatment for patients with FL, particularly in the relapsed/refractory (R/R) setting. There is an increasing need for better tools to risk-stratify patients and to identify those likely to experience relapse early. Additionally, the use of gene expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis; however, much of this knowledge is not currently applicable on a day to day basis in the clinic setting. Further studies are needed to determine a validated, clinically relevant predictive model that incorporates patient factors and molecular factors that will guide clinicians on the most effective treatment strategy. With many questions left unanswered, it is our opinion that the treatment of FL and sequencing of therapy in the R/R setting should be a personalized approach that balances patient-specific factors such as preferences and comorbidities with treatment-related factors such as known response rates and toxicity profiles.

Management and Outcomes of Patients with Refractory Solitary Plasmacytoma after Treatment with Definitive Radiation Therapy.

PURPOSE: Radiation therapy (RT) is the standard treatment for solitary plasmacytoma (SP); however, the optimal management of RT-refractory SPs is unknown. We examined outcomes after early systemic therapy, surgical resection, or observation for patients with RT-refractory disease and assessed the potential impact of treatment selection on disease outcomes. METHODS AND MATERIALS: We retrospectively reviewed patients with SP treated with definitive radiation and evaluated at a single institution with persistent disease on imaging or biopsy. Descriptive statistics were used to characterize patient and disease characteristics and treatment outcomes. RESULTS: Of 102 total SP patients, 17 (17%) were RT-refractory. The median RT dose was 45 Gy, and median follow-up was 71 months from end of RT. Fifteen patients had additional treatment for refractory disease at a median time of 9.5 months after RT, with the following subsequent interventions: surgical resection (n = 4), additional RT (n = 2), systemic therapy without evidence of multiple myeloma (MM; n = 4), systemic therapy for progression to MM (n = 5), and observation (n = 2). Of 4 patients treated with surgical resection, 3 progressed to MM 22 to 43 months after diagnosis. Of 2 patients treated with additional RT, neither responded, and both had pathologic confirmation of residual disease after the second course. Four patients treated with systemic therapy without MM all had complete responses on positron emission tomography and no subsequent MM progression. Eight patients were initially observed after RT for ≥12 months (n = 8) or ≥24 months (n = 6). Of the 2 patients in continued observation, both had stable/unchanged avidity after radiation treatment for 12 and 22 months and ultimately had a slow decrease of disease avidity over multiple years. CONCLUSIONS: Patients with RT-refractory SPs can achieve good local control with alternative therapies, such as surgery or systemic therapy, if needed. Additional RT does not seem to be effective. Given the known high rates of progression from SP to MM, close observation of asymptomatic persistent disease until disease progression is likely sufficient in most cases.

Single cell clonotypic and transcriptional evolution of multiple myeloma precursor disease.

Multiple myeloma remains an incurable disease, and the cellular and molecular evolution from precursor conditions, including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, is incompletely understood. Here, we combine single-cell RNA and B cell receptor sequencing from fifty-two patients with myeloma precursors in comparison with myeloma and normal donors. Our comprehensive analysis reveals early genomic drivers of malignant transformation, distinct transcriptional features, and divergent clonal expansion in hyperdiploid versus non-hyperdiploid samples. Additionally, we observe intra-patient heterogeneity with potential therapeutic implications and identify distinct patterns of evolution from myeloma precursor disease to myeloma. We also demonstrate distinctive characteristics of the microenvironment associated with specific genomic changes in myeloma cells. These findings add to our knowledge about myeloma precursor disease progression, providing valuable insights into patient risk stratification, biomarker discovery, and possible clinical applications.

The role of belantamab mafodotin for patients with relapsed and/or refractory multiple myeloma.

Belantamab mafodotin (belamaf) is a first-in-class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) that recently gained regulatory approval for the treatment of relapsed and/or refractory multiple myeloma (RRMM) patients who have received at least four prior therapies including an anti-CD38 monoclonal antibody (mAb), a proteasome inhibitor (PI), and an immunomodulatory drug (IMiD). As the first BCMA-targeted therapy to be approved in multiple myeloma along with its "off-the-shelf" outpatient administration, belamaf addresses a significant unmet need in RRMM that is refractory to IMiD, PI, and anti-CD38 mAb therapy, otherwise known as triple-class refractory myeloma. Belamaf is also associated with frequent corneal ocular adverse events, which represents a unique toxicity in multiple myeloma therapeutics, and its administration requires a multidisciplinary approach with oncologists and eye care specialists to safely and effectively manage patients on belamaf therapy. In this review, we discuss the preclinical and clinical data leading to the regulatory approval of belamaf, the monitoring and mitigation strategies of corneal ocular adverse events, and its current and future role in the RRMM treatment landscape.