Bergsagel, P. Leif

Abstract Bortezomib, a proteasome inhibitor (PI), has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and is often used in combination with cyclophosphamide and dexamethasone. Ixazomib is the first oral PI to be approved in routine practice but has not yet been evaluated in the upfront treatment setting. Newly diagnosed AL amyloidosis patients with measurable disease and adequate organ function were enrolled. The primary objective was to determine the hematologic response rate of ixazomib in combination with cyclophosphamide and dexamethasone. Treatment was given for 12 cycles, followed by ixazomib maintenance until progression. Thirty-five patients were included; their median age was 67 years, and 69% were male. Major organ involvement included heart (66%) and kidneys (54%). A median of 4 induction cycles (range, 1-12) were administered. The overall hematologic response to induction was 63% and included complete response in 11.4% and very good partial response in 37.1% of patients. One patient was upstaged to complete response during maintenance. The most common reason for going off study was the institution of alternate therapy (61%). With a median follow-up of 29.7 months for the living patients, the 2-year progression-free survival and overall survival were 74% and 78%, respectively. The median time to alternate therapy was 7.5 months. Grade ≥3 hematologic and nonhematologic adverse events occurred in 23% and 49% of patients. Given ixazomib’s favorable toxicity profile, which is an important advantage for the typically frail AL population, further evaluation of ixazomib in other combinations in the upfront setting is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01864018.

SummaryBelantamab mafodotin (BLMF) is a B‐cell maturation antigen‐directed antibody‐drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF‐induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity‐related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2–not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Summary: The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.

Multiple myeloma is a disorder of the monoclonal plasma cells and is the second most common hematologic malignancy. Despite improvements in survival with newer treatment regimens, multiple myeloma remains an incurable disease and most patients experience multiple relapses. Multiple myeloma disease initiation and progression are highly dependent on complex genetic aberrations. This review will summarize the current knowledge of these genetic aberrations, how they affect prognosis and the response to treatment, and review sensitive molecular techniques for multiple myeloma workup, with the ultimate goal of detecting myeloma progression early, allowing for timely treatment initiation.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

Abstract Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.

Abstract Purpose: Structural variants (SV) of the MYC gene region are common in multiple myeloma and influence disease progression. However, the prognostic significance of different MYC SVs in multiple myeloma has not been clearly established. Experimental Design: We conducted a retrospective study of multiple myeloma comparing MYC SV subtypes identified by next-generation sequencing (NGS) and FISH to MYC expression and disease survival using 140 cases from Mayo Clinic and 658 cases from the MMRF CoMMpass study. Results: MYC SVs were found in 41% of cases and were classified into nine subtypes. A correlation between the presence of a MYC SV and increased MYC expression was identified. Among the nine MYC subtypes, the non-immunoglobulin (non-Ig) insertion subtype was independently associated with improved outcomes, while the Ig insertion subtype, specifically involving the IgL gene partner, was independently associated with poorer outcomes compared with other MYC SV subtypes. Although the FISH methodology failed to detect approximately 70% of all MYC SVs, those detected by FISH were associated with elevated MYC gene expression and poor outcomes suggesting a different pathogenic role for FISH-detected MYC subtypes compared with other MYC subtypes. Conclusions: Understanding the impact of different MYC SVs on disease outcome is necessary for the reliable interpretation of MYC SVs in multiple myeloma. NGS approaches should be considered as a replacement technique for a more comprehensive evaluation of the multiple myeloma clone.