Genomic Classification and Individualized Prognosis in Multiple Myeloma.

PURPOSE: Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS: To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS: Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. CONCLUSION: Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.

Mode of progression in smoldering multiple myeloma: a study of 406 patients.

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Ethical Challenges with Multiple Myeloma BCMA Chimeric Antigen Receptor T Cell Slot Allocation: A Multi-Institution Experience.

Chimeric antigen receptor T cell (CAR-T) therapies are Food and Drug Administration (FDA)-approved for patients with triple refractory multiple myeloma (MM). Real-world access to CAR-T therapy remains challenging owing to supply chain limitations impacting manufacturing. The goal of this study was to evaluate the extent of this issue and how major centers are handling the challenges of CAR-T manufacturing slot allocation. MM CAR-T physician leaders at each CAR-T treatment center across the United States were surveyed. We received responses from 17 of 20 centers. A median of 1 slot is allocated per month per center, and the median number of patients per center on the waitlist since the FDA's approval of idecabtagene vicleucel is 20 (range, 5 to 100). As a result, patients remain on the waitlist for a median of 6 months (range, 2 to 8 months) prior to leukapheresis. For patient selection, all centers reported using a committee of experienced CAR-T physicians to ensure consistency. To ensure transparency, 15 centers make selection criteria, selection timelines, and priority scores readily available for CAR-T providers. Centers also reported using ethical values for selection: (1) equal treatment: time spent on waiting list (n = 12); (2) priority to the worst-off: limited therapeutic options (n = 14), MM burden (n = 11), high Hematopoietic Cell Transplantation Comorbidity Index (n = 5); (3) maximize benefit: most likely to complete apheresis (n = 13) or infusion (n = 13) or to achieve response (n = 8); and (4) social value: younger patients (n = 3). Maximizing benefit was considered the most important criterion by 10 centers. This study is the first attempt to evaluate existing issues with CAR-T access for patients with MM and the variability and challenges in patient selection. Integrating ethical resource allocation strategies, similar to those described here, into formal institutional policies would help streamline access to CAR-T therapy and protect the needs of both current and future patients and physicians.

Risk factors for severe infection and mortality In patients with COVID-19 in patients with multiple myeloma and AL amyloidosis.

Patients with multiple myeloma (MM) have a lower efficacy from COVID-19 vaccination and a high rate of mortality from COVID-19 in hospitalized patients. However, the overall rate and severity of COVID-19 infection in all settings (including non-hospitalized patients) and the independent impact of plasma cell-directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID-19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one-fourth of the COVID-19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID-19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID-19 infection, without any COVID-related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID-19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2-0.8); p = .008].

Impact of belantamab mafodotin-induced ocular toxicity on outcomes of patients with advanced multiple myeloma.

Belantamab 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.

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.

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.

Single-Cell Proteomics and Tumor RNAseq Identify Novel Pathways Associated With Clofazimine Sensitivity in PI- and IMiD- Resistant Myeloma, and Putative Stem-Like Cells.

Multiple myeloma (MM) is an incurable plasma cell malignancy with dose-limiting toxicities and inter-individual variation in response/resistance to the standard-of-care/primary drugs, proteasome inhibitors (PIs), and immunomodulatory derivatives (IMiDs). Although newer therapeutic options are potentially highly efficacious, their costs outweigh the effectiveness. Previously, we have established that clofazimine (CLF) activates peroxisome proliferator-activated receptor-γ, synergizes with primary therapies, and targets cancer stem-like cells (CSCs) in drug-resistant chronic myeloid leukemia (CML) patients. In this study, we used a panel of human myeloma cell lines as in vitro model systems representing drug-sensitive, innate/refractory, and clonally-derived acquired/relapsed PI- and cereblon (CRBN)-negative IMiD-resistant myeloma and bone marrow-derived CD138+ primary myeloma cells obtained from patients as ex vivo models to demonstrate that CLF shows significant cytotoxicity against drug-resistant myeloma as single-agent and in combination with PIs and IMiDs. Next, using genome-wide transcriptome analysis (RNA-sequencing), single-cell proteomics (CyTOF; Cytometry by time-of-flight), and ingenuity pathway analysis (IPA), we identified novel pathways associated with CLF efficacy, including induction of ER stress, autophagy, mitochondrial dysfunction, oxidative phosphorylation, enhancement of downstream cascade of p65-NFkB-IRF4-Myc downregulation, and ROS-dependent apoptotic cell death in myeloma. Further, we also showed that CLF is effective in killing rare refractory subclones like side populations that have been referred to as myeloma stem-like cells. Since CLF is an FDA-approved drug and also on WHO's list of safe and effective essential medicines, it has strong potential to be rapidly re-purposed as a safe and cost-effective anti-myeloma drug.

Clinical activity of single-dose systemic oncolytic VSV virotherapy in patients with relapsed refractory T-cell lymphoma.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-ß (IFN-ß) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNß-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 × 1011 TCID50), and 6 were treated at DL4 (1.7 × 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-ß, a biomarker of VSV-IFNß-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-ß of 18 213 pg/mL, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNß-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. This trial is registered at www.clinicaltrials.gov as #NCT03017820.

Implications of MYC Rearrangements in Newly Diagnosed Multiple Myeloma.

PURPOSE: Rearrangements involving the MYC protooncogene are common in newly diagnosed multiple myeloma, but their prognostic significance is still unclear. The purpose of this study was to assess the impact of MYC rearrangement on clinical characteristics, treatment response, and survival in patients with newly diagnosed multiple myeloma. EXPERIMENTAL DESIGN: This is a retrospective study including 1,342 patients seen in Mayo Clinic in Rochester, MN, from January 2006 to January 2018, who had cytogenetic testing by FISH at diagnosis, including MYC testing using the break apart FISH probe (8q24.1). RESULTS: A rearrangement involving MYC was found in 8% of patients and was associated with elevated ß2-microglobulin, ≥50% bone marrow plasma cells, IgA multiple myeloma, and the cooccurrence of trisomies. There were no differences in overall response rates between patients with and without MYC rearrangement when induction chemotherapy was proteasome inhibitor (PI)-based, immunomodulatory drug (IMiD)-based or PI + IMiD-based. Overall survival was shorter in patients with MYC rearrangement compared with patients without MYC rearrangement (5.3 vs. 8.0 years, P < 0.001). MYC rearrangement was associated with increased risk of death on multivariate analysis when high-risk cytogenetic abnormalities, ISS stage III, and ≥70 years of age were included (risk ratio: 1.5; P = 0.007). CONCLUSIONS: MYC rearrangement is associated with high disease burden and is an independent adverse prognostic factor in patients with newly diagnosed multiple myeloma.

Clinical characteristics and treatment outcomes of newly diagnosed multiple myeloma with chromosome 1q abnormalities.

A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities in multiple myeloma (MM). It is unclear whether +1q is independently associated with decreased overall survival (OS). The objective of this study was to evaluate the impact of +1q on clinical characteristics, treatment response, and survival outcomes. We included 1376 Mayo Clinic patients diagnosed with MM from 2005 to 2018 who underwent fluorescence in situ hybridization testing at diagnosis with a panel including the +1q probe. A gain in 1q was found in 391 patients (28%) and was associated with anemia, hypercalcemia, high tumor burden, International Staging System (ISS) stage 3, high-risk (HR) translocations, and chromosome 13 abnormalities. There was no difference in overall response or deeper responses to proteasome inhibitor (PI)-, immunomodulatory drug (iMiD)-, or PI plus IMiD-based induction. Time to next treatment was shorter in patients with +1q compared with those without +1q (19.9 vs 27.7 months; P < .001). On univariate analysis, +1q was associated with increased risk of death (risk ratio [RR], 1.9; P < .001), and decreased OS was seen in all treatment groups. +1q was independently associated with decreased OS on multivariate analysis when other HR cytogenetic abnormalities, ISS stage 3, and age ≥70 years were included (RR, 1.5; P < .001). Gain of >1 copy of 1q was not associated with worse OS compared with gain of 1 copy (4.9 vs 4.3 years; P = .21). +1q was associated with high tumor burden, advanced disease stage, and HR translocations. It is independently associated with decreased OS, even in the setting of novel therapy and transplant.

Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response.

Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response. This study was designed to evaluate these associations. This is a retrospective study including 2027 Mayo Clinic patients diagnosed with MM between February 2004 and February 2018 who had cytogenetic testing by FISH at diagnosis. Translocations t(4;14), t(14;16), t(6;14), and t(14;20) were associated with anemia, beta2microglobulin >5.5 µg/ml and ≥50% bone marrow plasma cells; t(4;14) was associated with higher serum monoclonal protein and plasma cell proliferation. Overall response rate to proteasome inhibitor (PI)-based treatment was higher for IgH translocations compared to trisomies (83% vs. 71%, P = 0.002), but was higher for trisomies with immunomodulatory drug (IMiD)-based treatment (87% vs. 75%, P < 0.001). Time to next treatment was longer with trisomies than IgH translocation with IMiD-based (32.1 vs. 18.4 months, P < 0.001) and PI + IMiD-based (44.0 vs. 27.4 months, P = 0.003) treatments. Outcomes were superior with PI + IMiD combinations in all groups. Our results show that t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high-risk disease characteristics, and IgH translocations and trisomies may be associated with better responses to PIs and IMiDs, respectively.

Treatment With Bortezomib-based Therapy, Followed by Autologous Stem Cell Transplantation, Improves Outcomes in Light Chain Amyloidosis: A Retrospective Study.

BACKGROUND: The hematologic response is critical in patients with light chain amyloidosis because a good response is known to improve organ response and overall survival. We present a retrospective analysis to compare the hematologic and organ response in patients who received bortezomib-based therapy before autologous stem cell transplantation (ASCT) versus those who received non-bortezomib-based therapy before ASCT and those who underwent ASCT at diagnosis. PATIENTS AND METHODS: Of a total of 63 patients who underwent ASCT for light chain amyloidosis, 34 received bortezomib-based therapy before ASCT (Bor-ASCT) and 29 did not receive bortezomib therapy (non-Bor-ASCT). A greater number of patients had involvement of ≥ 3 organs and cardiac involvement in the Bor-ASCT group, suggesting a greater risk at baseline in the Bor-ASCT group. RESULTS: At 3, 6, and 12 months after ASCT, the hematologic response was better in the Bor-ASCT group, with a statistically significance difference at 6 months (partial response or better in 82% vs. 20%; P = .002) and 12 months (partial response or better in 76% vs. 33%; P = .02). Organ responses (66% vs. 21%; P < .001) and median overall survival (not reached vs. 53 months; P = .001) were also greater in the Bor-ASCT group. CONCLUSION: Our study has shown that bortezomib-based therapy before ASCT improves the hematologic response, organ response and overall survival, potentially by decreasing the light chain load before ASCT.

Antigen-mediated regulation in monoclonal gammopathies and myeloma.

A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies. Here, we show that recombinant Ig (rIg) cloned from sort-purified single tumor cells from lipid-reactive sporadic and GD-associated gammopathy specifically bound lysolipids. Liposome sedimentation and binding assays confirmed specific interaction of lipid-reactive monoclonal Ig with lysolipids. The clonal nature of lysolipid-binding Ig was validated by protein sequencing. Gene expression profiling and cytogenetic analyses from 2 patient cohorts showed enrichment of nonhyperdiploid tumors in lipid-reactive patients. In vivo antigen-mediated stimulation led to an increase in clonal Ig and plasma cells (PCs) in GD gammopathy and also reactivated previously suppressed antigenically related nonclonal PCs. These data support a model wherein antigenic stimulation mediates an initial polyclonal phase, followed by evolution of monoclonal tumors enriched in nonhyperdiploid genomes, responsive to underlying antigen. Targeting underlying antigens may therefore prevent clinical MM.

Novel inhibitors are cytotoxic for myeloma cells with NFkB inducing kinase-dependent activation of NFkB.

NFkB activity is critical for survival and proliferation of normal lymphoid cells and many kinds of B-cell tumors, including multiple myeloma (MM). NFkB activating mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NFkB. Mutations that activate NFkB-inducing kinase (NIK) protein are the most prevalent among the many kinds of NFkB mutations in MM tumors. NIK is the main activating kinase of the alternative NFkB pathway, although over-expression of NIK also can activate the classical pathway. Two NIK inhibitors and an isomeric control were tested with human myeloma cell lines. These specific NIK inhibitors are selectively cytotoxic for cells with NIK-dependent activation of NFkB. Combination therapy targeting NIK and IKKbeta (as a main kinase of the classical NFkB pathway) represents a promising treatment strategy in MM. NIK inhibitors can also be useful tool for assessing the role of NIK and alternative NFkB pathway in different cells.

Complex IGH rearrangements in multiple myeloma: Frequent detection discrepancies among three different probe sets.

Primary IGH translocations involving seven recurrent partner loci and oncogenes are present in about 40% of multiple myeloma tumors. Secondary IGH rearrangements, which occur in a smaller fraction of tumors, usually are complex structures, including insertions or translocations that can involve three chromosomes, and often with involvement of MYC. The main approach to detect IGH rearrangements is interphase-but sometimes metaphase-FISH strategies that use a telomeric variable region probe and a centromeric constant region/ Eα enhancer or 3' flanking probe to detect a separation of these two probes, or a fusion of these probes with probes located at nonrandom partner sites in the genome. We analyzed 18 myeloma cell lines for detection discrepancies among Vysis, Cytocell, and in-house IGH probe sets that hybridize with differing sequences in the IGH locus. There were no detection discrepancies for the three telomeric IGH probes, or for unrearranged IGH loci or primary IGH translocations using the centromeric IGH probes. However, the majority of complex IGH rearrangements had detection discrepancies among the three centromeric IGH probes.

Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial.

Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).