Faculty Bibliography

Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, but also on what treatment patients received. To establish the true incidence of FHR, we analysed uniformly treated, transplant-eligible (TE) patients from the UK NCRI Myeloma-XI trial that had been profiled for IMS/IMWG defined high-risk cytogenetic aberrations (HRCA) and the SKY92 gene expression HR signature (GEP-HR). 135 TE MyXI patients meeting these criteria were studied, with a median follow-up of 88 months. 25 patients (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post-autologous stem-cell transplantation. Hereof, 15 (60%) were classified as IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with both IMS/IMWG- & GEP-standard risk (SR), 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR criteria. The combination of IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG-HR and GEP-HR was associated with very short overall survival compared to the absence of both (HR=13.1, 95%-CI: 6.5-26.1, P<0.0001), followed by GEP-HR only (HR=5.1, 95%-CI: 2.4-11.1, P<0.0001) and IMS/IMWG-HR only (HR=3.2, 95%-CI: 1.6-6.2, P=0.0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. ISRCTN49407852, NCT01554852.

Bispecific antibodies (BsAbs) and chimeric antigen receptor T-cells (CAR-T) are T-cell engagers (TCEs) becoming increasingly important for treatment of multiple myeloma. The purpose of this paper is to review TCE side effects and their management. In doing so, we will demonstrate that outpatient delivery of TCEs can be safe and advantageous for patients and healthcare systems. The initial introduction of TCE therapy has been limited to the inpatient setting due to risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These complications, which typically occur in the first few weeks of initiating therapy, are mediated by an exaggerated inflammatory response triggered by TCE binding to tumor cells. BsAb trials have demonstrated a high overall incidence of CRS, though severe cases are rare as is development of ICANS. The incidence and severity of CRS and ICANS seem to be higher with CAR-T therapy. Predictors of development and severity of CRS and ICANS include disease bulk, lymphodepletion strategy, CAR-T construct used, and pattern of expression of the tumor antigen. Prevention strategies include step-up dosing, disease bulk reduction, prophylactic steroid use and premedication. Treatment strategies include the use of steroids and cytokine binders/blockers, such as anti-IL6 and anti-IL1 agents. Effective prophylaxis and management of CRS and ICANS has reduced the impact of these complications and opened the potential for outpatient delivery. Outpatient delivery of TCEs is possible with appropriate preventative strategies, education, and established pathways for prompt transition to inpatient management if needed.

Despite significant improvements in survival of patients with multiple myeloma (MM), outcomes remain heterogeneous, and a significant proportion of patients experience suboptimal outcomes. Importantly, traditional prognostic factors based on data from patients treated with older therapies no longer capture prognosis accurately in the contemporary era of novel triplet or quadruplet therapies. Therefore, risk stratification requires refinement in the context of available and investigational treatment options in routine practice and clinical trials, respectively. The current identification of high-risk MM (HRMM) in routine practice is based on the Revised International Staging System, which stratifies patients using a combination of widely available serum biomarkers and chromosomal abnormalities assessed via fluorescence in situ hybridization. In recent years, a substantial body of evidence concerning additional clinical, biological, and molecular/genomic prognostic factors has accumulated, along with new MM risk stratification tools and consensus reports. The International Myeloma Society, along with the International Myeloma Working Group, convened an Expert Panel with the primary aim of revisiting the definition of HRMM and formulating a practical and data-driven consensus definition, based on new evidence from molecular/genomic assays, updated clinical data, and contemporary risk stratification concepts. The Panel proposes the following Consensus Genomic Staging (CGS) of HRMM which relies upon the presence of at least one of these abnormalities: (1) del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32); (3) monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or (4) β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL).

Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole-genome sequence samples (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode we demonstrate that a single RT-surviving cell may seed distant relapse.

We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.

Patients participating in clinical trials are highly selected and may not represent the general population. The pivotal study of teclistamab (MajesTEC-1), a B-cell maturation antigen (BCMA)xCD3 bispecific antibody, demonstrated impressive response rates and progression free survival in relapsed/refractory multiple myeloma (RRMM) with acceptable toxicity. We performed a retrospective study of 58 patients treated as standard of care at four US academic centers to determine how these results translated to the real-world. Most patients (87.9%) would not have been eligible for the MajesTEC-1 study due to either disease related factors, patient related comorbidities or socio-economic/geographical factors. Despite these 'less-favorable' characteristics we observed similar efficacy and toxicity to MajesTEC-1. A meta-analysis with six other published real-world series (n = 546) confirmed these results. These data support the significant clinical activity of teclistamab in RRMM and highlights the importance of real-world data to accompany the pivotal trial data to further inform daily clinical practice.

BACKGROUND:The bone marrow (BM) niche contains non-hematopoietic elements including mesenchymal stromal cells (MSC) and bone marrow endothelial cells (BMEC) which provide mechanical support, and control hematopoietic cell growth and differentiation. Although it is known that multiple myeloma (MM) cells interact closely with the BM microenvironment, little is known about the impact of MM on non-hematopoietic niche-forming cells. METHODS:To address the role of the niche in MM pathogenesis, we utilized the 5TGM1 murine model. During the asymptomatic precursor stage of the model, we isolated the rare non-hematopoietic cells and performed single cell RNA sequencing. Using in-silico methods we characterized the individual cellular components of the niche, their relative abundance and differentiation state before and after exposure to MM cells as well as their intercellular interactions. RESULTS:MM engraftment increased the abundance of MSC-lineage cells, BMECs and enhanced endothelial to mesenchymal transition. An inflammatory and oxidative stress signal was identified together with polarization of MSC differentiation away from osteocyte formation towards adipocytes which provide growth factors that are known to support MM expansion. BMEC differentiation was polarized towards sinusoidal endothelial cells with a pro-angiogenic/pro-inflammatory phenotype. CONCLUSIONS:MM cells impact the BM niche by generating a pro-inflammatory microenvironment with MSC differentiation being changed to generate cell subsets that favor MM growth and survival. In order to induce remission and improve long-term outcome for MM patients these inflammatory and oxidative stress signals need to be reduced and normal niche differentiation trajectories restored.

OBJECTIVES/OBJECTIVE:To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS:INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS:Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION/CONCLUSIONS:IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.

PURPOSE/UNASSIGNED:Early intervention for high-risk smoldering multiple myeloma (HR-SMM) achieves deep and prolonged responses. It is unclear if beneficial outcomes are due to the treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered. EXPERIMENTAL DESIGN/UNASSIGNED:In this study, we interrogated whole-genome and whole-exome sequencing for 54 patients across two HR-SMM interventional studies (NCT01572480 and NCT02279394). RESULTS/UNASSIGNED:We reveal that the genomic landscape of treated HR-SMM is generally simple as compared with newly diagnosed multiple myeloma counterparts with less inactivation of tumor suppressor genes, RAS pathway mutations, MYC disruption, and APOBEC contribution. The absence of these events parallels that of indolent precursor conditions, possibly explaining overall excellent outcomes. However, some patients harboring genomic complexity fail to sustain response and experience resistant, progressive disease. Overall, clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease. CONCLUSIONS/UNASSIGNED:Genomic profiling can contextualize the advantage of early intervention in SMM and guide personalization of therapy. See related commentary by Weinhold and Rasche, p. 4263.

Advanced practice providers (APPs) are critical to the hematology workforce. However, there is limited knowledge about APPs in hematology regarding specialty-specific training, scope of practice, challenges and opportunities in APP-physician interactions, and involvement with the American Society of Hematology (ASH). We conducted APP and physician focus groups to elucidate major themes in these areas and used results to inform development of 2 national surveys, 1 for APPs and 1 for physicians who work with APPs. The APP survey was distributed to members of the Advanced Practitioner Society of Hematology and Oncology, and the physician survey was distributed to physician members of ASH. A total of 841 APPs and 1334 physicians completed the surveys. APPs reported most hematology-specific knowledge was obtained via on-the-job training and felt additional APP-focused training would be helpful (as did physicians). Nearly all APPs and physicians agreed that APPs were an integral part of their organizations and that physician-APP collaborations were generally positive. A total of 42.1% of APPs and 29.3% of physicians reported burnout, and >50% of physicians felt that working with APPs had reduced their burnout. Both physicians and APPs reported interest in additional resources including "best practice" guidelines for APP-physician collaboration, APP access to hematology educational resources (both existing and newly developed resources for physicians and trainees), and greater APP integration into national specialty-specific professional organizations including APP-focused sessions at conferences. Professional organizations such as ASH are well positioned to address these areas.