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Monoclonal gammopathy of undetermined significance (MGUS) is the asymptomatic precursor of multiple myeloma (MM). Lytic bone lesions and fractures are hallmarks of MM and although there are no lytic lesions in MGUS, it has also been associated with fractures. The causes of fractures in MGUS are currently unclear but potential causes include inherent MGUS bone disease, undiagnosed MM, and peripheral neuropathy (PN). We therefore conducted a large population-based study including 8395 individuals with MGUS and 30 851 matched controls from Sweden.Data on fractures, PN, and confounders were acquired from high-quality registers in Sweden.Monoclonal gammopathy of undetermined significance and PN were independently associated with fractures (hazard ratio [HR]: 1.29; 95% confidence interval [95% CI]: 1.21-1.37; P .001 and HR: 1.34; 95% CI: 1.16-1.55; P .001). Imminent MGUS progression increased the risk of fractures (odds ratio: 1.66; 95% CI: 1.27-2.16; P .001). Fractures were not associated with long-term risk of MGUS progression (HR: 1.08; 95% CI: 0.77-1.53; P = .64).Based on these findings, we speculate that MGUS leads to fractures through at least 3 independent mechanisms: undetected MGUS progression to MM, MGUS inherent bone disease, and PN through falls. These findings highlight the need for further study of MGUS inherent bone disease and can inform further research into fracture prevention in MGUS.

Background Plasma cell disorders (PCDs) are chronic incurable conditions with an opportunity to positively impact outcomes with nutritional changes. Epidemiologic studies show that inflammatory/insulinemic diets are linked to PCDs (Lee IJC 2020), while vegetarians/vegans have a reduced risk (Key AJCN 2014). MGUS/SMM present a unique opportunity for early intervention, given the standard of care is observation. Though patients often inquire about the role of nutrition and whether they should alter habits to eat healthfully, their oncologists are frequently not prepared to address these concerns. The purpose of this survey was to provide insights into patient nutrition perceptions/practices and identify areas for further research. Methods We utilized HealthTree® Cure Hub (HealthTree® Foundation, Lehi, Utah, USA) and invited participants with PCDs to answer questions pertaining to their diet/nutrition and related experience with their oncologist in an online survey. De-identified aggregated responses were reviewed. Results Of 421 participants, 82% reported having dietary questions post-diagnosis, yet 23% stated this was not addressed by their oncologists despite asking. Among those who discussed it with their oncologist, 50% received no specific advice or were recommended a ‘balanced diet’ lacking details. Of the participants that received clear guidance from their oncologists, 88% attempted to follow it, reflecting the positive influence their oncologists can have. Lack of knowledge/conflicting advice were barriers to change for 23%. Although the American Institute of Cancer Research (AICR) has published dietary guidelines, only 34% were aware of them. Patients also more frequently reported following a healthier diet after diagnosis – 75% pre-diagnosis vs 88% post-diagnosis. 78% patients with unhealthy diets pre-diagnosis improved their diet post-diagnosis and 7% with healthy diets pre-diagnosis worsened their diet post-diagnosis. Post-diagnosis, more patients reported consuming whole fruits and vegetables ≥1 times/day and whole grains and seafood ≥3 times/week. Post-diagnosis dietary changes were based on online/media information and advice from non-medical friends in 47%, compared to advice from PCPs/oncologists/nutritionists in 22%. Conclusions Patients with PCDs are interested in dietary advice and make dietary changes when faced with a cancer diagnosis. Most patients currently receive this advice from non-medical sources and report barriers related to lack of consistent information. Oncologists who provide clear guidance can positively impact dietary changes among patients. Our results reflect a missed opportunity between patients’ need for dietary advice and the potential for oncologists to provide helpful counsel. Our findings highlight a need for further research into standardized guideline (AICR) implementation as well as for the development of PCD-specific guidelines. Further disease focused dietary studies are needed to fill this gap.

The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called "SBS-MM1") directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by ~10-20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.

Background Lenalidomide maintenance improves progression-free survival for patients with multiple myeloma, although its optimal duration is unknown. Clearance of minimal residual disease (MRD) in the bone marrow results in superior outcomes, although its attainment or sustainment does not alter clinical decision-making. Studies that have evaluated MRD serially are limited in length. We therefore aimed to evaluate longitudinal changes in MRD-status (dynamics) and their association with progression-free survival in patients with multiple myeloma.In this single-centre, single-arm, phase 2 study, we enrolled patients aged 18 years and older from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) who had newly diagnosed multiple myeloma following unrestricted frontline therapy and an Eastern Cooperative Oncology Group Performance Status of 2 or lower, including patients who started maintenance before study enrolment. All participants received lenalidomide maintenance at 10 mg for 21 days of 28-day cycles until progression or unacceptable toxic effects for up to 5 years on protocol. The primary endpoint was progression-free survival at 60 months per protocol and key secondary endpoints were MRD rates after completion of the 12th, 24th, and 36th cycle of maintenance and the association between progression-free survival and annual measurement of MRD status. MRD was assessed from first-pull bone marrow aspirates at baseline and annually by flow cytometry per International Myeloma Working Group criteria, (limit of detection of at least 1 × 10Between Sept 8, 2015, and Jan 25, 2019, 108 patients (100 evaluable for the primary endpoint) were enrolled. Median follow-up was 40·7 months (95% CI 38·7-45·0). At 60 months, progression-free survival was 64% (95% CI 52-79). Median progression-free survival was unreached (95% CI unreached-unreached). MRD dynamics were assessed using 340 MRD assessments done over 5 years for 103 evaluable patients. Patients who sustained MRD negativity for 2 years (n=34) had no recorded disease progression at median 19·8 months (95% CI 15·8-22·3) past the 2-year maintenance landmark. By contrast, patients who lost their MRD-negative responses (n=10) were more likely to progress than those with sustained MRD negativity (HR infinite; p0·0001) and those with persistent MRD positivity (HR 5·88, 95% CI 1·18-33·33; p=0·015) at the 2-year landmark. Haematological and non-haematological serious adverse events occurred in 19 patients (18%). The most common adverse events of grade 3 or worse were decreased lymphocyte count in 48 (44%) patients and decreased neutrophil count in 47 (44%) patients. One death occurred on study due to sepsis and heart failure and was considered unrelated to the study drug.Serial measurements of MRD allow for dynamic assessment of risk for disease progression. Early intervention should be investigated for patients with loss of MRD negativity. Sustained MRD positivity is not categorically an unfavourable outcome and might portend prolonged stability of low-level disease.Memorial Sloan Kettering and Celgene.

Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.

Purpose: Multiple myeloma is a biologically heterogenous plasma-cell disorder. In this study, we aimed at dissecting the functional impact on transcriptome of gene mutations, copy-number abnormalities (CNA), and chromosomal rearrangements (CR). Moreover, we applied a geno-transcriptomic approach to identify specific biomarkers for personalized treatments. Experimental Design: We analyzed 514 newly diagnosed patients from the IA12 release of the CoMMpass study, accounting for mutations in multiple myeloma driver genes, structural variants, copy-number segments, and raw-transcript counts. We performed an in silico drug sensitivity screen (DSS), interrogating the Cancer Dependency Map (DepMap) dataset after anchoring cell lines to primary tumor samples using the Celligner algorithm. Results: Immunoglobulin translocations, hyperdiploidy and chr(1q)gain/amps were associated with the highest number of deregulated genes. Other CNAs and specific gene mutations had a lower but very distinct impact affecting specific pathways. Many recurrent genes showed a hotspot (HS)-specific effect. The clinical relevance of double-hit multiple myeloma found strong biological bases in our analysis. Biallelic deletions of tumor suppressors and chr(1q)-amplifications showed the greatest impact on gene expression, deregulating pathways related to cell cycle, proliferation, and expression of immunotherapy targets. Moreover, our in silico DSS showed that not only t(11;14) but also chr(1q)gain/amps and CYLD inactivation predicted differential expression of transcripts of the BCL2 axis and response to venetoclax. Conclusions: The multiple myeloma genomic architecture and transcriptome have a strict connection, led by CNAs and CRs. Gene mutations impacted especially with HS-mutations of oncogenes and biallelic tumor suppressor gene inactivation. Finally, a comprehensive geno-transcriptomic analysis allows the identification of specific deregulated pathways and candidate biomarkers for personalized treatments in multiple myeloma.

Introduction Multiple myeloma (MM) patients have an increased risk of severe coronavirus disease 2019 (COVID-19) when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS) precedes MM and related disorders and affects 4.2% of the general population over the age of 50 years. MM and MGUS are associated with immune dysfunction that is believed to contribute to the development of severe COVID-19. Currently, no systematic data on MGUS and COVID-19 have been published. We conducted a large population-based cohort study to evaluate whether MGUS was associated with SARS-CoV-2 infection and the development of severe COVID-19. Methods Data on all SARS-CoV-2 test results and COVID-19 severity was acquired from the COVID-19 Outpatient Clinic at Landspitali - The National University Hospital of Iceland. The first case of COVID-19 in Iceland was diagnosed on February 28 th, 2020. Since then, the Icelandic authorities have followed an aggressive strategy of SARS-CoV-2 testing and contact tracing. All SARS-CoV-2-positive individuals were immediately contacted and those with active infection were enrolled into telehealth monitoring consisting of repeated standardized interviews conducted by a nurse or physician. If clinical deterioration was detected, patients were assessed in person at the COVID-19 Outpatient Clinic and admitted if needed. Study participants were included from the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). The study is an ongoing population-based screening study for MGUS and randomized trial of follow-up strategies. Out of the 148,708 Icelanders who were born 1976 and earlier and were alive on September 9 th 2016, 80,759 (54%) provided informed consent for study participation and 75,422 (94%) of those provided a blood sample for MGUS screening by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. MGUS was determined by current criteria using SPEP and FLC assay data. Individuals who had died, been diagnosed with MM and related disorders, or were undergoing treatment for smoldering MM prior to February 28 th were excluded. First, the association of MGUS and testing positive for SARS-CoV-2 was evaluated. We used a test negative design and included participants who had been tested at least once for SARS-CoV-2 between February 28 th and December 31 st, 2020. The association of MGUS and a positive test for SARS-CoV-2 was assessed using logistic regression, adjusted for sex and age. Next, the association of MGUS and severe COVID-19 was evaluated. Those who tested positive for SARS-CoV-2 were included unless they were hospitalized or living in a nursing home at diagnosis. Participants were followed until discharge from telehealth monitoring or until considered having severe COVID-19. Severe COVID-19 was defined as the composite outcome of the need for outpatient visit or hospital admission and death and as the composite outcome of hospital admission and death. Logistic regression was then performed adjusting for sex and age. Results Of the 75,422 individuals screened for MGUS, 32,047 (42%) were tested for SARS-CoV-2 during the study period of whom 1,754 had MGUS (5.5%). Those with MGUS were older (mean age 66.3 vs 59.1 p Of those who tested positive for SARS-CoV-2, a total of 230 had the composite outcome of requiring an outpatient visit or hospital admission, and death, and 117 had the composite outcome of hospital admission and death. After adjusting for age and sex, MGUS was not found to be associated with either endpoint (OR: 0.99; 95%CI: 0.52-1.91; p=0.99 and OR: 1.13; 95%CI: 0.52-2.46; p=0.76; Table; Figure B) Conclusions: In this large population-based study that included 75,422 individuals screened for MGUS, we did not find MGUS to be associated with SARS-CoV-2 susceptibility or COVID-19 severity. This is contrary to MM which is preceded by MGUS. These findings suggest that immunosuppression in MGUS differs significantly from that of MM and are important since they can inform management and recommendations for individuals with MGUS. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Intellisphere LLC: Consultancy; Daiichi Sankyo: Research Funding; Curio Science LLC: Consultancy; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Amgen: Honoraria; Janssen: Honoraria; Celgene: Research Funding; Janssen: Other: IDMC; Janssen: Research Funding; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

Background: In addition to serum protein electrophoresis (SPEP) and serum immunofixation (IFE), measurement of serum free light chains (FLC) has become the hallmark for detection, prognostication, and monitoring of monoclonal gammopathies. However, serum FLC levels are heavily dependent on kidney function due to discrepancy in the rate of kidney clearance of the FLC. As chronic kidney disease (CKD) is common in the general population, it is possible that a large number of individuals have false FLC results. A kidney reference interval (eGFR < 60) has previously been published based on small numers (N=688) for serum FLC ratio (0.37-3.10) instead of the standard reference interval (0.26-1.65), but no kidney reference exists for kappa (3.3-19.4mg/L) or lambda (5.7-26.3mg/L). The aim of this study was to define and improve the reference interval for individuals with various degree of decreased kidney function and assess its effect on prevalence of light chain monoclonal gammopathy of undetermined significance (LC-MGUS) among CKD patients. Methods: A total of 80,759 participants of the Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) study were included. Participants were screened by SPEP and IFE as well as by serum FLC assay (Freelite®). Serum creatinine (SCr) value closest to the time of screening was used to calculate (CKD-EPI) eGFR. Participants with M-protein, eGFR >60 mL/min/1.73 m2, missing SCr measurements or more than 1 year from the SCr measurement to the iStopMM screening were excluded. Correlation was assessed graphically and using the Spearman correlation coefficient. A nonparametric bootstrapping method was used to calculate the 95% CI. Partitioning was determined based on the proportion of subgroups (sex, age, eGFR) outside the whole group reference interval (4.1%). However, intervals were not partitioned if subgroups included few participants and/or if deemed more applicable and reasonable for clinical practice. LC-MGUS was defined as FLC ratio outside the reference interval and raised FLC level without evidence of monoclonal heavy chain on SPEP or IFE or end-organ damage attributed to the plasma cell proliferative disorder. Results: Of 75,422 individuals who were screened, 6,503 (12%) participants had eGFR < 60 mL/min/1.73 m2, without evidence of monoclonality on SPEP or IFE and were analysed further. The median (IQR) kappa level was 21.7 (16.6-29.4) mg/L, lambda level 19.0 mg/L (14.8-25.0) and FLC ratio 1.16 (0.97-1.39). Serum FLC levels increased with decreasing eGFR: serum free kappa (ρ= -0.44, p < 0.001), lambda (ρ= -0.39, p < 0.001), and FLC ratio (ρ= -0.15, p < 0.001). Using current reference intervals, 60% and 21% of persons had values outside the normal range for kappa and lambda, respectively. The FLC ratio was outside the standard reference interval in 9% and outside the kidney reference interval in 0.6% of participants. Based on these findings, we established new reference intervals for FLC and FLC ratio (Table). Participants on dialysis (N=26) had significantly higher median (IQR) serum free kappa 29.3 mg/L (26.1-57.6, p = 0.01) and lambda 25.1 mg/L (19.5-52.6, p = 0.01) than participants with eGFR 30-59, but no significant difference compared to participants with eGFR < 30 (p = 0.57). The FLC ratio in participants on dialysis was 1.22 (0.96-1.37), which was similar to participants with eGFR 45-59 (p = 0.63) and 30-44 (p = 0.34). Participants on dialysis had significantly lower FLC ratio than participants with eGFR < 30, or 1.31 (1.10-1.57, p = 0.02). Utilising our novel reference intervals, the crude prevalence of LC-MGUS in all participants with eGFR < 60 was 75 (1.2%), with no difference between participants with eGFR of 45-59, 30-44 and < 30, respectively. When the crude rate of LC-MGUS was compared to a rate based on previous reference intervals, the crude rate of both kappa and lambda LC-MGUS increased in participants with eGFR 45-59, eGFR 30-44 and eGFR < 30 (p Conclusion: Current reference intervals for serum FLC and FLC ratio are inaccurate for patients with decreased kidney function. Here we propose new reference intervals for serum FLC and FLC ratio for use in patients with CKD which also seem to be accurate in patients on dialysis. Implementing these novel reference intervals is likely to increase the sensitivity and specificity of the analyses and lead to a more accurate diagnosis of monoclonal gammopathy in individuals with kidney dysfunction. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Daiichi Sankyo: Research Funding. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Amgen: Honoraria; Janssen: Honoraria; Celgene: Research Funding; Janssen: Other: IDMC; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder preceding multiple myeloma and related disorders, present in 4.2% of the population over the age of 50. Although usually asymptomatic, MGUS has been associated with various health-related problems, including thrombosis, infections, fractures, neuropathy, and death. Because MGUS is asymptomatic, its diagnosis is typically incidental, during clinical workup for unrelated medical issues, and therefore most individuals remain undiagnosed. Consequently, MGUS cohorts in past studies may have suffered from more comorbidities than the actual population with MGUS. This might have introduced selection bias in previous studies on MGUS, which extent has not been studied in a systematic way. Therefore, previously reported associations between MGUS and various medical issues might not be as profound as formerly observed. The aim of this study was to compare characteristics of incidentally diagnosed MGUS versus MGUS diagnosed by systematic screening, with particular focus on demographics, comorbidities, and MGUS-related factors. Methods The study is based on the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. iStopMM is a population-based screening study for MGUS and a randomized controlled trial of follow-up strategies that has included 54% (n = 80,759) of the Icelandic population above 40 years of age. In total, 75,422 participants were screened for MGUS by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. Information on which individuals had incidentally diagnosed MGUS (clinical MGUS) prior to participation in iStopMM were gathered from the Icelandic cancer registry and laboratory results from Landspítali University Hospital and Læknasetrið, the only laboratories in Iceland that perform SPEP. M-protein concentration, MGUS isotype and FLC ratio were obtained from the original screening samples. Comorbidity data was acquired from two high-quality national registries: Hospital Discharge Register and Register of Primary Health Care Contacts, with >95% completeness and accuracy. MGUS diagnosed by screening was further classified into MGUS with or without M-proteins (light-chain MGUS). Those with clinical MGUS were used as the reference group in all analyses. Since all individuals with clinical MGUS had M-proteins, individuals with light-chain MGUS were excluded from this study. T-test and chi-square test were used for demographic comparison; linear regression adjusting for sex and age for continuous variables, and logistic regression adjusting for sex and age for comparison of categorical variables, regarding MGUS-related factors and comorbidities. Results The study cohort consisted of 3,300 individuals who had MGUS with M-proteins; 224 individuals with clinical MGUS and 3,076 with screened MGUS. The clinical MGUS group was significantly older (p Discussion In this large population-based study including 75,000 screened individuals, we found clinical MGUS cases to be older, more likely to live in Iceland's capital area, and have a higher M-protein concentration than those found to have MGUS while screened on the iStopMM study. Individuals with clinical MGUS also had a higher number of underlying comorbidities and were 1.5-3.3 times more likely to suffer from arrhythmias, chronic kidney diseases, endocrine disorders, heart failure, neurological diseases, and rheumatological diseases. Our findings highlight the importance of screening studies to evaluate the true epidemiological and biological implications of MGUS and suggest selection bias in prior studies. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Honoraria; Janssen: Other: IDMC; Takeda: Other: IDMC; Janssen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

For patients diagnosed with multiple myeloma (MM) there have been significant treatment advances over the past decade, reflected in an increasing proportion of patients achieving durable remissions. Clinical trials repeatedly demonstrate that achieving a deep response to therapy, with a bone marrow assessment proving negative for minimal residual disease (MRD), confers a significant survival advantage. To accurately assess for minute quantities of residual cancer requires highly sensitive methods; either multiparameter flow cytometry or next generation sequencing are currently recommended for MM response assessment. Under optimal conditions, these methods can detect one aberrant cell amongst 1,000,000 normal cells (a sensitivity of 10-6). Here, we will review the practical use of MRD assays in MM, including challenges in implementation for the routine diagnostic laboratory, standardisation across laboratories and clinical trials, the clinical integration of MRD status assessment into MM management and future directions for ongoing research.

Chromothripsis is detectable in 20-30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study, we interrogate 752 NDMM patients using whole genome sequencing (WGS) to study the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC=0.90) and can be used to identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis was confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC=0.97) and an independent series of 34 NDMM (AUC=0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we were able to predict both the presence of chromothripsis (AUC=0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.

This cohort study assesses the concordance of 3 models to stratify risk for progression to multiple myeloma in an independent cohort of patients with smoldering multiple myeloma.

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate, for the first time, the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n=15) are characterized by later initiation in the patient’s life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.

The landscape of structural variants (SV) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 patients with multiple myeloma by low-coverage long-insert whole-genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (TNFRSF17), SLAM7, and MCL1. Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as CCND1 and MYC. Importantly, in 31% of patients, two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis. Significance: Previous genomic studies in multiple myeloma have largely focused on single-nucleotide variants, recurrent copy-number alterations, and recurrent translocations. Here, we demonstrate the crucial role of SVs and complex events in the development of multiple myeloma and highlight the importance of whole-genome sequencing to decipher its genomic complexity. See related commentary by Bergsagel and Kuehl, p. 221. This article is highlighted in the In This Issue feature, p. 215

In the original version of [this article][1] ([1][2]) as it was published online on July 30, 2020, a reference to the study ([2][3]) reporting 23 patients from Mount Sinai included in this cohort has been inadvertently omitted from the Methods. Information on patients per hospitals in this study is

Objective: Opportunistic infections in chronic lymphocytic leukemia (CLL) have been described in clinical trials, single-center studies, and case reports. We performed a nationwide study to estimate the incidence and impact of inpatient opportunistic infections. Methods: The incidence rate (IR) and incidence rate ratio (IRR) for Swedish CLL patients diagnosed 1994-2013, and matched controls were calculated, as well as the case-fatality ratio (CFR). Results: Among 8989 CLL patients, a total of 829 opportunistic infections were registered (IR 16.6 per 1000 person-years) compared with 252 opportunistic infections in 34 283 matched controls (IR 0.99). The highest incidence in the CLL cohort was for Pneumocystis pneumonia (200 infections, IR 4.03); Herpes zoster (146 infections, IR 2.94), and Pseudomonas (83 infections, IR 1.66) infections. The highest risk relative to matched controls was observed for Pneumocystis pneumonia (IRR 114, 95% confidence interval 58.7-252). The 60-day CFR for CLL patients with opportunistic infections was 23% (188/821), highest for progressive multifocal encephalopathy (5/7, 71%) and aspergillosis (25/60, 42%). Conclusion: We have uniquely depicted the incidence of rare and serious infections in CLL patients and found a relatively high incidence of Pneumocystis pneumonia. Of the most common opportunistic infections, CLL patients with aspergillosis had the poorest prognosis. (Less)

At the end of 2019, a novel coronavirus was identified as the cause of pneumonia cases in Wuhan, a city in the Hubei Province of China. On January 30, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a public health emergency of international concern and, in March 2020, began to characterize it as a pandemic. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) In February 2020, the World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019.

Multiple myeloma is a systemic malignancy of monoclonal plasma cells that accounts for 10% of hematologic cancers. With development of highly effective therapies for multiple myeloma, minimal residual disease (MRD) assessment has emerged as an important end point for management decisions. Currently, serologic assays lack the sensitivity for MRD assessment, and invasive bone marrow sampling with flow cytometry or molecular methods has emerged as the gold standard. We report a sensitive and robust targeted mass spectrometry proteomics method to detect MRD in serum, without the need of invasive, sequential bone marrow aspirates. The method detects Ig-derived clonotypic tryptic peptides predicted by sequencing the clonal plasma cell Ig genes. A heavy isotope-labeled Ig internal standard is added to patient serum at a known concentration, the Ig is enriched in a light chain type specific manner, and proteins are digested and analyzed by targeted mass spectrometry. Peptides from the constant regions of the λ or κ light chains, Ig heavy chains, and clonotypic peptides unique to the patient monoclonal Igs are targeted. This technique is highly sensitive and specific for the patient-specific monoclonal Igs, even in samples negative by multiparametric flow cytometry. Our method can accurately and precisely detect monoclonal protein in serum of patients treated for myeloma and has broad implications for management of hematologic patients.

Parental longevity is associated with an increased life expectancy; results with regard to specific diseases are conflicting. There are limited data focusing on host characteristics and their effect on survival among multiple myeloma (MM) patients and individuals with monoclonal gammopathy of undetermined significance (MGUS). Therefore, our aim was to evaluate the impact of parental longevity on survival of patients with MM and MGUS. A total of 4675 patients with MM, 6812 MGUS patients and 13 398 population-based controls for MM as well as 19 110 controls for MGUS, from 1988 to 2013, were included in the study. Longevity was defined as >90 years of age. Among MM patients, parental longevity was associated with a decreased risk of death [hazard ratio (HR) = 0·92, 95% confidence interval (CI) 0·84–0·99] and the same was true for MGUS patients (HR = 0·87, 95% CI 0·78–0·96). Having one long lived parent significantly decreased the risk of death in both groups, but was not statistically significant when both parents exceeded 90 years of age. In conclusion, parental longevity decreases the risk of death for patients with MM and MGUS which may reflect the importance of the host's genetic and environmental factors in relation to survival. (Less)

Medical records uncover clinical and demographic characteristics associated with severity of COVID-19 in a large multicenter cohort of patients with multiple myeloma., Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos (n = 21), OR = 4.7 (95% confidence interval, 1.3–16.7), and African American Blacks (n = 33), OR = 3.5 (1.1–11.5), as compared with White patients (n = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated (P > 0.05) with adverse outcome: hypertension (n = 56), OR = 2.2 (0.9–5.4); diabetes (n = 18), OR = 0.9 (0.3–2.9); age >65 years (n = 63), OR = 1.8 (0.7–4.6); high-dose melphalan with autologous stem cell transplant

ImportanceNew York City is a global epicenter for the SARS-CoV-2 outbreak with a significant number of individuals infected by the virus. Patients with multiple myeloma have a compromised immune system, due to both the disease and anti-myeloma therapies, and may therefore be particularly susceptible to coronavirus disease 2019 (COVID-19); however, there is limited information to guide clinical management.ObjectiveTo assess risk factors and outcomes of COVID-19 in patients with multiple myeloma.DesignCase-series.SettingFive large academic centers in New York City.ParticipantsPatients with multiple myeloma and related plasma cell disorders who were diagnosed with COVID-19 between March 10th, 2020 and April 30th,2020.ExposuresClinical features and risk factors were analyzed in relation to severity of COVID-19.Main Outcomes and MeasuresDescriptive statistics as well as logistic regression were used to estimate disease severity reflected in hospital admissions, intensive care unit (ICU) admission, need for mechanical ventilation, or death.ResultsOf 100 multiple myeloma patients (male 58%; median age 68, range 41-91) diagnosed with COVID-19, 74 (74%) were admitted; of these 13 (18%) patients were placed on mechanical ventilation, and 18 patients (24%) expired. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes (ICU-admission, mechanical ventilation, or death): hypertension (N=56) odds ratio (OR) 2.3 (95% confidence interval [CI] 0.9-5.9); diabetes (N=18) OR 1.1 (95% CI 0.3-3.2); age >65 years (N=63) OR 2.0 (95% CI 0.8-5.3); high dose melphalan with autologous stem cell transplant Conclusions and RelevanceAlthough multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.

Recent advances in multiple myeloma include numerous approvals of novel therapies with unprecedented efficacy, a rapid and sustained tempo of new drug development, and further refinements to prognostication to include minimal residual disease (MRD) testing and improved risk stratification. The upfront use of immunomodulatory drug and proteasome inhibitor combinations followed by maintenance has resulted in transformative clinical benefit. Four-drug regimens incorporating monoclonal antibodies are reporting unprecedented rates of complete response and MRD negativity in the absence of intensification. In the context of these advances, the added value of high-dose melphalan with autologous stem-cell transplant (HDM-ASCT) is a key question. From a safety standpoint, HDM-ASCT is associated with both acute toxicities that reduce quality of life and long-term toxicities that may limit life expectancy for some patients. The present review discusses the recent advances in induction therapy, the impact of these advances on HDM-ASCT, the evolving role of MRD testing and the short- and long-term risks of HDM-ASCT. Recognising that prospective data remains limited, we suggest that HDM-ASCT not be considered mandatory for eligible newly diagnosed patients who are treated with highly efficacious regimens and achieve deep responses, but rather be held in reserve without early exposure to the clinical and genomic toxicity inherent to this approach.

Caucasian Americans (CA) compared with African Americans (AA) have a twofold increased incidence of multiple myeloma (MM) and have an earlier age of diagnosis. However, there is sparse information regarding underlying biological differences across racial/ethnic groups. We characterized genetic alterations using a targeted next-generation sequencing assay called myTYPE, developed at MSKCC, allowing capture of somatic mutations, IgH translocations, gains/losses, and hyperdiploidy. Samples were obtained from the NIH Plasma Cell Dyscrasia Racial Disparity Cohort. In total, 68 patient samples were successfully sequenced and manually curated based on well-established databases. Of the 68 patient samples (47 CA, 21 AA), 84% had at least one type of genomic alteration. Importantly, the IgH translocation, t(11;14), was observed more frequently in the AA group (0 vs. 29%, p = 0.001). Known oncogenic somatic non-synonymous mutations were found in 18 genes and indels in 2 genes. KRAS mutations were the most common mutation found in 16% of patients followed by NRAS and BRAF mutations. TP53 somatic mutations appeared to be more common in CA but lacked significance. This proof-of-principle study indicates the presence of varying underlying tumor biology between racial groups and supports the need of future prospective trials to capture these molecular characteristics.

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early (6 months; 28%), early (6 to 24 months; 50%), or late (24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P = .002). Older age, relapse with EMD,PR before alloHCT,PR by day +100, and no maintenance were prognostic for inferior postrelapse OS on univariate analysis. On multivariate analysis adjusted for age and sex, very early relapse (hazard ratio [HR], 4.37; 95% confidence interval [CI], 1.42 to 13.5), relapse with EMD (HR, 5.20; 95% CI, 2.10 to 12.9), and DLI for relapse prevention (HR, .11; 95% CI, 2.10 to 12.9) were significant predictors for postrelapse survival. Despite their shared inherent high-risk status, patients with MM have significantly disparate post-HCT relapse courses, with some demonstrating long-term survival despite relapse.

Objective: Infections in chronic lymphocytic leukemia (CLL) have been thoroughly investigated in the setting of clinical trials and single-center studies. However, large cohort studies on real-world data and studies on temporal trends are lacking. We performed a nationwide study on serious bacterial infections in CLL. Methods: Using high-quality Swedish government-based registries, 13 009 CLL patients diagnosed in 1982-2013 and their 49 380 matched controls were included. Results: Overall, CLL patients had an increased risk of serious inpatient bacterial infections with a hazard ratio (HR) 5.32 and 95% confidence interval (95% CI) 5.11-5.53, and the highest risk was observed for septicemia (HR 6.91, 95% CI 6.46-7.39) and lung infections (5.91, 5.64-6.18). The risk of serious inpatient bacterial infections decreased overtime with HR 0.87 (0.81-0.94) and HR 0.76 (0.70-0.82) in 1993-2002 and 2003-2013, respectively, compared to 1982-1992. CLL patients had an increased risk of death following a serious inpatient bacterial infection compared to matched CLL patients, and the risk was highest in the first 12 months after the infection (HR 5.48, 95% CI 5.11-5.90). Conclusion: We have, in this nationwide study, characterized the risk of serious bacterial infections in CLL patients and, importantly, depicted that the risk has decreased overtime. (Less)

Objectives In the field of relapsed or refractory multiple myeloma (RRMM), between-trial or indirect comparisons are required to estimate relative treatment effects between competing interventions based on the available evidence. Two approaches are frequently used in RRMM: network meta-analysis (NMA) and unanchored matching-adjusted indirect comparison (MAIC). The objective of the current study was to evaluate the relevance and credibility of published NMA and unanchored MAIC studies aiming to estimate the comparative efficacy of treatment options for RRMM. Methods Twelve relevant studies were identified in the published literature (n = 7) and from health technology assessment agencies (n = 5). Data from trials were extracted to identify between-trial differences that may have biased results. Credibility of the performed analyses and relevance of the research questions were critically appraised using the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist and feedback based on consultations with clinical experts. Results The identified studies concerned NMAs of randomized controlled trials (RCTs; n = 7), unanchored MAICs (n = 4), or both types of analyses (n = 1). According to clinical expert consultation, the majority of the identified NMAs did not consider differences in prior therapies or treatment duration across the RCTs included in the analyses, thereby compromising the relevance. Conclusion Based on the results and feedback from clinicians, the majority of NMAs did not consider prior treatment history or treatment duration, which resulted in nonrelevant comparisons. Furthermore, it may have compromised the credibility of the estimates owing to differences in effect-modifiers between the different trials. Pairwise comparisons by means of unanchored MAICs require clear justification given the reliance on non-randomized comparisons.

Patients treated with chemotherapy (CT) and/or autologous stem-cell transplantation (ASCT) are at risk for therapy-related myeloid neoplasms (tMN). Certain cytotoxic agents introduce mutations within distinct trinucleotide contexts resulting in a unique barcode for each exposed cell. We leveraged mutational signatures to investigate the role of CT in the genomic landscape of tMN with respect to antecedent clonal hematopoiesis (CH). We analyzed 32 tMN and 2 tALL from 33 patients and interrogated for copy number abnormalities (CNA), structural variants (SV), single nucleotide variants (SNV), and mutational signatures. For 7 patients with tMN post-melphalan/ASCT, we investigated antecedent CH using targeted sequencing on pre-melphalan samples, including autograft products. CH variants that became clonal in tumor were seen in 5/7 pre-melphalan/ASCT samples (TP53, RUNX1, NCOR1, NF1, CREBBP, DNMT3A, and PPM1D). Complex SV were seen in 7 tMNs; including chromothripsis in 6 (19.4%). In 4 cases, chromothripsis involved chromosome 19 with hyper-amplification of the SMARCA4 locus (≥5 copies). Mutational signature analysis revealed 6 known single base substitution (SBS) signatures in tMN including melphalan (SBS-MM1) and platinum signatures (SBS31, SBS35, and E-SBS37). TMNs with CT signatures had higher mutation burden than those without (p = 0.004). 17 patients with exposure to agents other than melphalan/platinum did not have increased mutational burden with respect to de novo AML (TCGA; NEJM, 2013). All patients with prior platinum exposure (including tALL, n=9) had platinum SBS signatures while only 2 of 7 patients with prior melphalan/ASCT had a melphalan signature (SBS-MM1). Detection of CT signatures in bulk sequencing relies on one cell, with its barcode of mutations, to expand to clonal dominance. Given pre-existent CH, including in 3/3 autograft products, absence of a CT signature despite melphalan exposure implies progression by a clone that escaped CT exposure with stem-cell collection and reinfusion. Conversely, all platinum-exposed tAML had signature evidence of exposure confirming existence of CH prior to exposure and supporting post-CT single-cell expansion. TMNs from 3 patients exposed to sequential platinum and melphalan/ASCT had platinum but not melphalan signatures confirming single-cell expansion of the pre-tMN CH clone post-platinum but with escape from exposure to melphalan via leukapheresis. Chromothripsis events bore only non-duplicated CT-induced mutations, indicative of acquisition prior to, and not directly caused by, CT exposure. These disparities suggest that ASCT provides a mechanism for CH clones to escape CT and re-engraft with transplant. Coupled with driver events accrued prior to CT, this suggest that CT-induced mutagenesis may be less important than other factors, such as CT-induced immunosuppression, in the expansion of pre-TMN CH clones. Citation Format: Benjamin Diamond, Bachisio Ziccheddu, Eileen M. Boyle, Kylee Maclachlan, Justin Taylor, Justin M. Watts, Sydney X. Lu, David G. Coffey, Niccolo Bolli, Elli Papaemmanuil, Kelly Bolton, Jae H. Park, Heather Landau, Karuna Ganesh, Mikkael A. Sekeres, Stephen Nimer, David J. Chung, Caleb H. Ho, Mikhail Roshal, Alexander Lesokhin, Gareth Morgan, Ola Landgren, Francesco Maura. Chemotherapy-related mutational signatures reveal the origins of therapy-related myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5747.

Translocation t(11;14) positive multiple myeloma (MM) is sensitive to venetoclax, yet the drug lacks FDA approval in MM. Selinexor is an inhibitor of nuclear exporter XPO1 and is approved in relapsed refractory MM. We recently analyzed RNA-seq from 859 MM patient samples (MMRF CoMMpass study) and compared them to healthy bone marrow samples (GSE114922). After correcting for batch effects, differential gene expression analysis found apoptosis and cell cycle regulation amongst the top upregulated gene pathways in MM. We therefore hypothesized that MM would be sensitive to the combination of the pro-apoptotic drug, venetoclax, and selinexor, which causes cell cycle arrest. Using a panel of 8 MM cell lines (U266-B1, KMS12BM, SKMM2, RPMI-8226, LP1, OPM2, KMS12PE, and NCIH929), we performed cell viability assays in increasing concentrations of selinexor, venetoclax, and a combination of the two drugs at 72 hours. Overall, the combination showed synergy in MM cell lines but strikingly, cell lines that possessed t(11;14) were more sensitive to the drug combination and showed enhanced synergy compared to the non-t(11;14). Average Bliss model synergy score were 0.5 in non-t(11;14) and 10.2 in t(11;14) MM cells (>10 indicates synergistic effects and To better understand molecular mechanisms underlying the observed synergistic effect in t(11;14), we performed western blot analysis in these cell lines treated with selinexor, venetoclax, the combination, or DMSO control for 24 hours. We measured protein levels of Cyclin D1, which is overexpressed in t(11;14) and a cargo of XPO1. We confirmed Cyclin D1 overexpression in t(11;14) cells lines but not in non-t(11;14) cells. Cyclin D1 levels decreased with selinexor, and the reduction was enhanced by adding venetoclax. Additionally, we measured levels of XPO1, p53, MCL-1, and p65, which we have previously shown to be altered by selinexor treatment. While venetoclax monotherapy caused increased MCL-1 expression, this was abrogated by combining with selinexor and the effects were statistically more significant in t(11;14) cell lines. Concurrently, two patients with relapsed, refractory t(11;14) MM and disease progression after multiple lines of therapy were treated with venetoclax; however, after initial response, they developed resistance and progressive disease. Based off our preclinical results, selinexor was added to venetoclax and recaptured responses (VGPR and MR, respectively) suggesting a beneficial effect of the combination over single agent venetoclax. To our knowledge, this is the first report of patients with MM treated with the combination of selinexor and venetoclax. Further clinical evaluation of this combination in t(11;14) MM is planned and samples will be collected to better understand the mechanistic correlation between XPO1, BCL2/MCL-1, and Cyclin D1 levels and response. Citation Format: Sana Chaudhry, Nina Nguyen, Rimpi Khurana, Tulasigeri M. Totiger, Skye Montoya, Jumana Afaghani, Terrence Bradley, Francesco Maura, Dickran Kazandjian, Jennifer Chapman, Stephan Schürer, Ola Landgren, James Hoffman, Justin Taylor. Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4067.

Multiple myeloma is a rare plasma cell cancer, and incidence rates among patients of African descent are about twice those among patients of European descent. Rates of multiple myeloma vary among different populations, but the reasons for the racial disparities in multiple myeloma are largely unknown. Epidemiology has identified risk factors for multiple myeloma including race, advanced age, gender, family history, and exposure to different genetic toxins including radiation. Race and ancestry play a large role in predicting the risk for multiple myeloma, yet there exists a paucity of literature that explores the molecular contribution of race and ancestry to disease. In this review, we describe the relevant literature that describes the observed racial differences according to distinct tumor immunobiological and ancestral differences in populations.

The incidence of multiple myeloma is characterized by a steep increase with advancing age. Dramatic improvements in survival have been reported in clinical trials; however, elderly patients are generally underrepresented in these. The aims of this study are to review patterns of incidence and survival in multiple myeloma in the general population. We searched PubMed for population-based studies on trends in incidence and survival published between January 1, 2000 and June 30, 2017 and based on regional or national cancer registries and report the following results of the review. The age-adjusted incidence of multiple myeloma has increased during the second half of the twentieth century in some countries but remained stable in areas with high case ascertainment and access to universal medical care. The crude incidence is increasing globally due to an aging population. Survival rates have improved, and 5-year relative survival rates are now around 50% and over 60% in patients 65-70 years or younger. Preliminary data suggest a 3-fold increase in the prevalence of multiple myeloma. We conclude that the number of multiple myeloma patients is increasing in the general population due to (i) aging populations and (ii) more patients living longer due to modern drugs.

CD99(MIC2) is a widely expressed cell surface glycoprotein and functions as a tumor suppressor involved in downregulation of SRC family of tyrosine kinase. CD99 expression is tightly regulated through B cell development. The principal aims of this study were to investigate the clinical utility of CD99 expression (i) in distinguishing normal plasma cells from primary plasma cell neoplasms; (ii) in detection of minimal residual disease in primary plasma cell neoplasms; (iii) in distinguishing plasma cell component of B-cell lymphomas from primary plasma cell neoplasms. We analyzed expression of CD99 by flow cytometry and immunohistochemistry in lymph nodes, peripheral blood and bone marrow samples. CD99 showed stage-specific expression with highest expression seen in precursor B and plasma cells. In contrast to the uniform bright expression on normal plasma cells, CD99 expression on neoplastic plasma cells was lost in 39 out of 56 (69.6%) cases. Furthermore, eight out of 56 samples (14%) showed visibly (more than ten-fold) reduced CD99 expression. Overall, CD99 expression was informative (absent or visibly dimmer than normal) in 84% of primary plasma cell neoplasm. In the context of minimal residual disease detection, CD99 showed superior utility in separating normal and abnormal plasma cells over currently established antigens CD117, CD81 and CD27 by principal component analysis. Preservation of CD99 expression was strongly associated with Cyclin D1 translocation in myeloma (p

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation. Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.

Based on available data, most multiple myeloma patients have residual myeloma cells in their autologous hematopoietic progenitor cells (HPC) grafts during collection for autologous stemcell transplant. However, available literature is based on older induction regimens, e.g., adriamycin and dexamethasone (VAD). In that setting, attempts to clean the grafts of residual myeloma cells were unsuccessful and did not improve clinical outcome but rather worsened the recovery of blood counts post-high dose melphalan (HDM) resulting in increased risk of severe post-transplant infections. Recently, the modern carfilzomib, lenalidomide and dexamethasone (KRd) regimen has been developed. KRd shows rapid, deep and durable responses in newly diagnosed myeloma patients reflected in rates of up to 60% minimal residual disease (MRD) negativity when evaluating the individual patient’s bone marrow aspirate. To date, no information is available regarding the use of KRd and its impact on residual myeloma cells in autologous HPC grafts. To expand our knowledge on this topic, we designed a prospective study to compare the patient’s MRD status in the bone marrow with MRD status in the corresponding HPC graft. Furthermore, we were interested in evaluating the yield of HPC in relation to the number of given cycles of KRd combination therapy. Collection of HPC between 4 and 8 completed cycles of KRd had very similar HPC yield. Using MRD assays with sensitivity of 1 × 10(−5) we found that treatment with KRd results in an unprecedented purity of the stem cell graft; specifically, 29 of 30 (97%) patients had an MRD negative graft.

Guidelines recommend vaccination starting 12 months after autologous hematopoietic stem cell transplant (aHCT), but there is varying practice for patients on maintenance therapy, with some centers not immunizing at all. Because of decreased vaccine rates among the general population causing loss of herd immunity, we aimed to establish the safety and efficacy of revaccinating multiple myeloma patients on lenalidomide maintenance (LM). Of the 122 patients who were vaccinated after aHCT between 2010 and 2014 at Memorial Sloan Kettering Cancer Center, 91 (75%) were on LM. Vaccine responses were defined by increases between pre- and postvaccination titers. Reponses varied by vaccine type with 76% responding to pertussis, 70% diphtheria, 60% tetanus, 71% Haemophilus influenzae, and 58% pneumococcal. All patients retained minimal levels of polio immunity, but 27% responded with increased titers. Fewer patients received hepatitis A and B, but of those who did, 30% responded to hepatitis A and 40% to hepatitis B. No differences were seen in rates of response for those on LM at time of vaccination compared with those who were not. There were no vaccine-related adverse effects. Reimmunization with inactivated vaccines in patients on LM is therefore both safe and effective, offering this population immunity to vaccine-preventable diseases.

In this issue of Blood, Slager et al report novel results from a large familial screening study including 1045 relatives from 310 families that include a patient with chronic lymphocytic leukemia (CLL).

Recent advances in the treatment of multiple myeloma have led to significant improvements in overall survival. One contributor to this progress was the 2012 FDA approval of carfilzomib for the trea...

The past decade, several highly efficacious drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are less toxic than older chemotherapy drugs. Using modern combination therapy in newly diagnosed multiple myeloma patients, high proportions of newly diagnosed multiple myeloma patients obtain minimal residual disease (MRD) negativity and MRD testing has rapidly become an integral part of clinical trials focusing on patients in this setting. Only recently, MRD negativity was reported in clinical trials focusing on older newly diagnosed multiple myeloma patients (ie, nontransplant candidates), as well as studies focusing on patients with relapsed or refractory multiple myeloma. In the past, deeper responses were rarely seen in these patient categories due to inferior therapies and lack of MRD assays. The reason for the rapidly increased interest in MRD testing in all types of clinical trials is the fact that MRD negativity is closely correlated with longer progression-free survival which has been documented in recent meta-analyses. Consequently, MRD negativity has the potential to soon become a regulatory surrogate end-point for drug approval. This review dissects and discusses current data on MRD in multiple myeloma, it outlines new hypotheses, which can be tested in future clinical studies, and it discusses opportunities and future avenues for translational research. The goal of this article is to stimulate critical analysis of our current treatment landscape and development of future translational research involving MRD testing.

Objectives To characterize the effect of three humanized IgG κ monoclonal antibodies (daratumumab, isatuximab, and elotuzumab) on the interpretation of results generated by protein electrophoresis, immunofixation, free light chain, and heavy/light chain assays performed on human serum. Methods Healthy volunteer serum and serum from multiple myeloma patients were supplemented with clinically relevant concentrations of each of the three monoclonal antibodies. These specimens then underwent analysis via serum protein electrophoresis, immunofixation, serum free light chain quantification, heavy/light chain quantification, total IgG, and total protein. In addition, serum specimens from patients who had undergone treatment with elotuzumab for multiple myeloma underwent similar analysis. Results Addition of the study drugs to serum from both the healthy donor as well as multiple myeloma patients resulted in a visible and quantifiable M-protein on SPEP and a visible IgGκ band by IFE. Increases were also noted in total IgG, IgGκ, and IgGκ/IgGλ-ratios. Analysis of serum from multiple myeloma patients receiving study drug showed similar findings with an additional IgGκ band and quantifiable M-protein with similar migration patterns in specimens drawn after administration. Conclusion The treatment of multiple myeloma patients with monoclonal antibodies results in a visible and quantifiable M-protein that has the potential to falsely indicate poor response to therapy.

Background: The progression of multiple myeloma (MM) during ongoing therapy is driven by a complex interplay between tumor cells and their surrounding immune microenvironment. We were motivated to conduct a comprehensive and orthogonal investigation of the cellular and humoral immunity of patients with MM treated with lenalidomide maintenance therapy. We compared patients who achieved sustained minimal residual disease (MRD) negativity during the first year of maintenance therapy to those who lost or were unable to attain an MRD negative state. Methods: As part of our prospective phase II clinical trial designed to investigate the MRD dynamics and the efficacy of continuous lenalidomide maintenance in MM (NCT02538198, Lancet Haematology 2021; 8:e422-32), we conducted a pre-planned correlative investigation to elucidate the roles of cellular and humoral immunity. We leveraged single-cell RNA sequencing (scRNAseq) coupled with V(D)J sequencing of peripheral blood mononuclear cells and CyTOF mass cytometry of bone marrow samples collected before and approximately one year after starting maintenance therapy (median 342 days). Proteomic analysis of 92 immuno-oncology related proteins within bone marrow plasma was performed using Olink. Reference-based mapping was used to perform automated cell classification of 31 immune cell subtypes using scRNAseq. A custom 38-marker panel enabled the identification of 21 immune cell subtypes by CyTOF. A total of 40 peripheral blood samples from 20 patients were analyzed by scRNAseq, 28 bone marrow aspirates from 14 patients were analyzed by CyTOF, and 34 plasma samples from 16 patients were analyzed by Olink. Results: Prior to maintenance therapy, 11 (46%) patients completed planned induction therapy and high-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT); 13 (54%) received planned induction therapy without HDM-ASCT. Through the integration of scRNAseq and CyTOF by bioinformatic analyses, we were able to characterize the cellular composition and phenotypic states of the immune microenvironment before maintenance therapy and after exposure to lenalidomide. Profound and sustained immunosuppression was observed among patients exposed to HDM-ASCT, which associated with accelerated seeding of MM recurrence (Nature Communications 2020;11:3617). Independent of prior exposure to HDM-ASCT, we found differential abundance of immune cell composition to be associated with sustained versus unsustained MRD negativity. Additionally, patients who achieved and sustained MRD negativity (compared to patients with unsustained MRD negativity) had increased frequency of circulating naïve CD8+ T cells in their baseline sample, as well as elevated levels of circulating naïve CD4+ T cells during therapy. When investigating the dynamics of the immune microenvironment longitudinally, circulating regulatory T cells were found to increase during maintenance therapy among patients who had early progression. In the bone marrow, NK cells were more abundant in patients who achieved but could not sustain MRD negativity while vascular endothelial growth factor (VEGF) levels were increased in patients with sustained MRD negativity. We compared our results to a separate report describing the immune microenvironment in patients with MM and healthy donors (Zavidij et al. Nature Cancer 2020;1:493-506) and found the immune landscape of MM patients with sustained MRD negativity to gradually normalize. In contrast, immunosuppression remained present at baseline and during follow-up in MM patients with unsustained MRD negativity. Conclusions: Our findings represent the first detailed characterization of the longitudinal dynamics of the immune microenvironment in relation to low-burden disease in patients with MM treated with lenalidomide maintenance therapy. As expected, HDM-ASCT exposure translated into long-term cellular and humoral immunosuppression, which correlated with dynamics of MM recurrence. Independent of the profound impact of HDM-ASCT on host immunity, the composition of the immune microenvironment varied according to the depth of response. Patients with unsustained MRD negativity had hallmarks of immune dysregulation at baseline and during lenalidomide maintenance, while those who achieved and sustained MRD negativity showed gradual normalization of the immune microenvironment. Disclosures Maura: Medscape: Consultancy, Honoraria; OncLive: Honoraria. Smith: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: CAR T cells for MM; Sanofi: Patents & Royalties: GPRC5D antibody based therapies; Novarits: Consultancy; Chimeric Therapeutics: Consultancy; Fate Therapeutics: Research Funding; Eureka Therapeutics: Consultancy. Lesokhin: bristol myers squibb: Research Funding; Genetech: Research Funding; Trillium Therapeutics: Consultancy; pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Serametrix, Inc: Patents & Royalties; Behringer Ingelheim: Honoraria; Iteos: Consultancy. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Green: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; JANSSEN Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Landgren: Celgene: Research Funding; Janssen: Other: IDMC; Janssen: Honoraria; Janssen: Research Funding; Amgen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria.