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Purpose:Duration of first remission is important for the survival of patients with multiple myeloma.Experimental Design:From the CoMMpass study (NCT01454297), 926 patients with newly diagnosed multiple myeloma, characterized by next-generation sequencing, were analyzed to evaluate those who experienced early progressive disease (PD; time to progression, TTP ≤18 months).Results:After a median follow-up of 39 months, early PD was detected in 191/926 (20.6%) patients, 228/926 (24.6%) patients had late PD (TTP >18 months), while 507/926 (54.8%) did not have PD at the current follow-up. Compared with patients with late PD, patients with early PD had a lower at least very good partial response rate (47% vs. 82%, P < 0.001) and more frequently acquired double refractoriness to immunomodulatory drugs (IMiD) and proteasome inhibitors (PI; 21% vs. 8%, P < 0.001). Patients with early PD were at higher risk of death compared with patients with late PD and no PD (HR, 3.65; 95% CI, 2.7–4.93; P < 0.001), showing a dismal median overall survival (32.8 months). In a multivariate logistic regression model, independent factors increasing the early PD risk were TP53 mutation (OR, 3.78, P < 0.001), high lactate dehydrogenase levels (OR, 3.15, P = 0.006), λ-chain translocation (OR, 2.25, P = 0.033), and IGLL5 mutation (OR, 2.15, P = 0.007). Carfilzomib-based induction (OR, 0.15, P = 0.014), autologous stem-cell transplantation (OR, 0.27, P < 0.001), and continuous therapy with PIs and IMiDs (OR, 0.34, P = 0.024) mitigated the risk of early PD.Conclusions:Early PD identifies a high-risk multiple myeloma population. Further research is needed to better identify baseline features predicting early PD and the optimal treatment approaches for patients at risk.

Supplementary Appendix: Additional methods. Carfilzomib-treated patients - Trial design; Table S1. List and classification method of the analyzed variables; Table S2. Induction treatment classification; Table S3. List of the 21 genes analyzed and mutation frequency; Table S4. Distribution of upfront treatment and ASCT in CT subgroups; Table S5. Distribution of variables in Early PD vs reference population; Figure S1. Multivariate logistic regression model evaluating risk factors associated with death within 24 months; Figure S2. Sub-analysis on patients with or without baseline del(17p) and/or TP53 mutation; Figure S3. TP53 and IGLL5 mutations at diagnosis and at first relapse in available longitudinal samples; Figure S4. Epanechnikov kernel-smoothed estimated hazard rates of progressive disease (PD) over time; Figure S5. Comparison of Seq-FISH and conventional FISH in a subgroup of patients enrolled in clinical trials and analyzed in the same centralized laboratory.

Given the significance of the immune system and the important role of therapies within the context of the immune system in plasma cell disorders, the International Myeloma Society annual workshop convened a session dedicated to this topic. A panel of experts covered various aspects of immune reconstitution and vaccination. The top oral presentations were highlighted and discussed. This is a report of the proceedings.

The central role of eukaryotic translation initiation factor 4E (eIF4E) in controlling mRNA translation has been clearly assessed in the last decades. eIF4E function is essential for numerous physiological processes, such as protein synthesis, cellular growth and differentiation; dysregulation of its activity has been linked to ageing, cancer onset and progression and neurodevelopmental disorders, such as autism spectrum disorder (ASD) and Fragile X Syndrome (FXS). The interaction between eIF4E and the eukaryotic initiation factor 4G (eIF4G) is crucial for the assembly of the translational machinery, the initial step of mRNA translation. A well-characterized group of proteins, named 4E-binding proteins (4E-BPs), inhibits the eIF4E–eIF4G interaction by competing for the same binding site on the eIF4E surface. 4E-BPs and eIF4G share a single canonical motif for the interaction with a conserved hydrophobic patch of eIF4E. However, a second non-canonical and not conserved binding motif was recently detected for eIF4G and several 4E-BPs. Here, we review the structural features of the interaction between eIF4E and its molecular partners eIF4G and 4E-BPs, focusing on the implications of the recent structural and biochemical evidence for the development of new therapeutic strategies. The design of novel eIF4E-targeting molecules that inhibit translation might provide new avenues for the treatment of several conditions.

Reliable point-of-care (POC) rapid tests are crucial to detect infection and contain the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The emergence of several variants of concern (VOC) can reduce binding affinity to diagnostic antibodies, limiting the efficacy of the currently adopted tests, while showing unaltered or increased affinity for the host receptor, angiotensin converting enzyme 2 (ACE2). We present a graphene field-effect transistor (gFET) biosensor design, which exploits the Spike-ACE2 interaction, the crucial step for SARS-CoV-2 infection. Extensive computational analyses show that a chimeric ACE2-Fragment crystallizable (ACE2-Fc) construct mimics the native receptor dimeric conformation. ACE2-Fc functionalized gFET allows in vitro detection of the trimeric Spike protein, outperforming functionalization with a diagnostic antibody or with the soluble ACE2 portion, resulting in a sensitivity of 20 pg/mL. Our miniaturized POC biosensor successfully detects B.1.610 (pre-VOC), Alpha, Beta, Gamma, Delta, Omicron (i.e., BA.1, BA.2, BA.4, BA.5, BA.2.75 and BQ.1) variants in isolated viruses and patient's clinical nasopharyngeal swabs. The biosensor reached a Limit Of Detection (LOD) of 65 cps/mL in swab specimens of Omicron BA.5. Our approach paves the way for a new and reusable class of highly sensitive, rapid and variant-robust SARS-CoV-2 detection systems.

Over the last decade, the development of effective treatment approaches for multiple myeloma (MM) has been associated with higher response rates and longer survival. In patients who achieve complete response, several high sensitivity techniques have been studied to assess minimal residual disease (MRD) and detect residual neoplastic cells within the bone marrow (by flow cytometry or molecular biology techniques) or outside the bone marrow (by imaging or circulating disease markers in the peripheral blood). This is of utmost importance, since residual disease can drive clinical relapse. This review focuses on the progress made in the assessment of MRD in MM. The achievement of MRD negativity after therapy is considered prognostically important for MM patients, and data from clinical trials and meta-analyses have confirmed that it is strongly associated with better survival. Along with well-known techniques, such as next-generation sequencing (NGS), next-generation flow (NGF), and positron emission tomography/computed tomography (PET/CT), other methods such as mass spectrometry (MS) and circulating tumor cells are under study. Intensive treatment regimens at diagnosis can lead up to 70% of MRD negativity in MM patients, although the current proportion of curable patients is still unknown. Today, clinicians who treat MM deal with MRD assessment in routine clinical practice. Its appropriate use in therapeutic decision making may be the most fascinating and challenging issue to be addressed over the next few years.

PURPOSE Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+. PATIENTS AND METHODS The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated. RESULTS In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, t(4;14) 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value. CONCLUSION The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.

Background. The Revised International Staging system (R-ISS) is the standard risk stratification model used for newly diagnosed (ND) multiple myeloma (MM) (Palumbo et al. JCO 2015). R-ISS identifies 3 groups of patients (pts) with different PFS and OS. However, 60% of pts are considered as intermediate-risk (R-ISS II), possibly including pts with different risk of progression/death. Recently, 1q copy number alterations (CNAs), which were not included in the R-ISS, proved to be a poor prognostic factor in NDMM pts. The European Myeloma Network (EMN), under the umbrella of the HARMONY project, collected more than 7000 patient data from European clinical trials. The aim of this analysis is to revise the R-ISS risk stratification model, by analyzing the prognostic value of each single baseline risk feature, including 1q CNAs, to improve prognostication in NDMM pts. Methods. Data from 15 European clinical trials enrolling NDMM pts from 2005 to 2014 were collected through EMN and registered in HARMONY platform. HARMONY is a European public-private partnership focusing on hematologic malignancies with unmet medical needs, including MM. OMOP Common Data Model was used to harmonize data. All pts received an immunomodulatory agent (IMiD) and/or a proteasome inhibitor (PI) upfront. In a multivariate Cox regression analysis adjusted for age, sex and therapy, we evaluated the impact of each risk feature on overall survival (OS) and progression-free survival (PFS). The hazard of death conferred by the most significant variables was used to create an additive risk score. Results. 7077 NDMM pts were registered in the HARMONY platform and included in the analysis. Data were mature with a median follow-up of 75 months; median age was 62 years. The majority of pts were transplant-eligible (65%). 40% of the pts received IMiDs only, 15% PIs only, 46% both drug classes during their first-line treatment. In a multivariate Cox model, ISS (II vs I HR 1.55 p These prognostic variables were simultaneously present in 2227 pts and the most frequent reason of exclusion of the remaining pts was 1q CNAs that was missing in some of the trials. We exploited the OS impact of these risk features in pts with complete data to create an additive scoring system (Table 1). Pts were then stratified into 4 groups: Low [(n=429 (19.3%), score 0)], Low-Intermediate [(n=686 (30.8%), score 0.5-1], Intermediate-High [(n=917 (41.2%), score 1.5-2.5] and High [(n=195 (8.8%), score 3-5]. Each group showed significantly different OS (Figure 1A) and PFS (Figure 1B). Median OS was not reached vs 109.2 vs 68.5 vs 37.9 months and median PFS was 68 vs 45.5 vs 30.2 vs 19.9 months in the above 4 risk groups, respectively. With this new stratification model, R-ISS stage II pts (n=1372) were better distributed into Low-Intermediate (n=517), Intermediate-High (n=811) and High risk (n=44) groups, confirming that this wide group included heterogeneous pts with a different risk of progression and/or death. This new risk stratification maintained its prognostic value in subgroup analysis of transplant-eligible and transplant-ineligible pts and in pts receiving IMiDs, PIs or both. Conclusion. This analysis on a large number of patient data collected thanks to a well-established European collaboration demonstrated that the existing R-ISS stratification model may be improved. This additive scoring system based on the impact of single risk features could be the future risk stratification model for NDMM, so called "R2-ISS". About half of the pts can be classified as Low or Low-Intermediate risk and about half of the pts can be classified as Intermediate-High or High risk, representing an opportunity to design risk-adapted approaches in a meaningful number of pts. Moreover, such additive risk score easily allows the inclusion of new prognostic variables in the future as they continue to emerge. The inclusion of new patient data is ongoing, and validation in an independent cohort is planned. Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Zamagni:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Mateos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; PharmaMar-Zeltia: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria. van de Donk:Takeda: Other: Ad Board; Genentech: Other: Ad Board; Bayer: Other: Ad Board; BMS: Other: Ad Board, Research Funding; Amgen: Other: Ad Board, Research Funding; Celgene: Other: Ad Board, Research Funding; Novartis: Other: Ad Board; Janssen: Other: Ad Board, Research Funding. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. Salwender:Takeda: Honoraria; Bristol-Myers Squibb/Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; AbbVie: Honoraria. Blade Creixenti:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Dürig:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Bringhen:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Novartis: Honoraria, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Cook:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; IQVIA: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Roche: Consultancy; Karyopharm: Consultancy. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Multiple Myeloma (MM) is a hematologic malignancy characterized by a wide clinical and biological heterogeneity leading to different patient outcomes. Various prognostic tools to stratify newly diagnosed (ND)MM patients into different risk groups have been proposed. At baseline, the standard-of-care prognostic score is the Revised International Staging System (R-ISS), which stratifies patients according to widely available serum markers (i.e., albumin, β 2-microglobulin, lactate dehydrogenase) and high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization. Though this score clearly identifies a low-risk and a high-risk population, the majority of patients are categorized as at “intermediate risk”. Although new prognostic factors identified through molecular assays (e.g., gene expression profiling, next-generation sequencing) are now available and may improve risk stratification, the majority of them need specialized centers and bioinformatic expertise that may preclude their broad application in the real-world setting. In the last years, new tools to monitor response and measurable residual disease (MRD) with very high sensitivity after the start of treatment have been developed. MRD analyses both inside and outside the bone marrow have a strong prognostic impact, and the achievement of MRD negativity may counterbalance the high-risk behavior identified at baseline. All these techniques have been developed in clinical trials. However, their efficient application in real-world clinical practice and their potential role to guide treatment-decision making are still open issues. This mini review will cover currently known prognostic factors identified before and during first-line treatment, with a particular focus on their potential applications in real-world clinical practice.

Background: Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. Methods: UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (

Elderly transplant-ineligible (NTE) patients represent the majority of patients affected by multiple myeloma (MM). Elderly patients are a highly heterogeneous population, with large variability in health and functional status. Thus, choosing their optimal treatment is challenging. A wide range of first-line treatments is available, and novel-agent combinations, including monoclonal antibodies (mAbs), have recently entered clinical practice. The combination of the anti-CD38 mAb daratumumab with bortezomib, melphalan and prednisone (Dara-VMP) or lenalidomide and dexamethasone (Dara-Rd) demonstrated impressive advantages in terms of progression-free survival and minimal residual disease negativity, as compared to VMP and Rd, without safety concerns. Another anti-CD38 mAb, isatuximab, is showing encouraging results, and new isatuximab-based combinations might enter clinical practice in the future. Nevertheless, available data come from clinical trials with selected patient populations and, to date, the manageability of these regimens in real-life patients or in frail patients remains unknown. Frailty-tailored treatments, including mAbs, are under evaluation in preliminary studies. In this review, we analyze recently approved mAb-based treatments for NTE newly diagnosed MM patients and new combinations under evaluation, focusing on the efficacy and safety of these regimens and on open issues regarding the choice of therapy for elderly patients.

Fast, reliable and point-of-care systems to detect the SARS-CoV-2 infection are crucial to contain viral spreading and to adopt timely clinical treatments. Many of the rapid detection tests currently in use are based on antibodies that bind viral proteins1. However, newly appearing virus variants accumulate mutations in their RNA sequence and produce proteins, such as Spike, that may show reduced binding affinity to these diagnostic antibodies, resulting in less reliable tests and in the need for continuous update of the sensing systems2. Here we propose a graphene field-effect transistor (gFET) biosensor which exploits the key interaction between the Spike protein and the human ACE2 receptor. This interaction is one of the determinants of host infections and indeed recently evolved Spike variants were shown to increase affinity for ACE2 receptor3. Through extensive computational analyses we show that a chimeric ACE2-Fc construct mimics the ACE2 dimer, normally present on host cells membranes, better than its soluble truncated form. We demonstrate that ACE2-Fc functionalized gFET is effective for in vitro detection of Spike and outperforms the same chip functionalized with either a diagnostic antibody or the soluble ACE2. Our sensor is implemented in a portable, wireless, point-of-care device and successfully detected both alpha and gamma virus variants in patient’s clinical samples. As incomplete immunization, due to vaccine roll-out, may offer new selective grounds for antibody-escaping virus variants4, our biosensor opens to a class of highly sensitive, rapid and variant-robust SARS-CoV-2 detection systems.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The MMRF CoMMpass study is a longitudinal, observational clinical study of newly diagnosed multiple myeloma patients where tumor samples are characterized using whole genome, exome, and RNA sequencing at diagnosis and progression, and clinical data is collected every three months. Analyses of the baseline cohort identified genes that are the target of recurrent gain- and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high- risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10−4−10−5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p p

Background. Proteasome inhibitor (PI)-based induction/consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2 plus autologous stem-cell transplantation (MEL200-ASCT). High response rates have been reported with carfilzomib (K) plus lenalidomide-dexamethasone (KRd) or cyclophosphamide-dexamethasone (KCd). Lenalidomide (R) alone is a standard of care for post-ASCT maintenance; K maintenance showed promising results in phase I/II studies, but no data on KR maintenance vs R are available. Aims. The aims of this analysis were to evaluate the progression-free survival (PFS) of KRd induction-ASCT-KRd consolidation (KRd_ASCT) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd_ASCT) and the PFS of KR vs R maintenance. Secondary aims were efficacy in different subgroups of pts and safety of the maintenance phase. Methods. NDMM pts ≤65 years were randomized [R1: 1:1:1, stratification International Staging System (ISS) and age] to: KRd_ASCT: 4 28-day cycles with KRd induction (K 20/36 mg/m2 IV days 1,2,8,9,15,16; R 25 mg days 1-21; dexamethasone [d] 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd_ASCT: 4 28-day induction cycles with KCd (K 20/36 mg/m2 IV days 1,2,8,9,15,16; cyclophosphamide 300 mg/m2 days 1,8,15; d 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized (R2) to maintenance with KR (K 36 mg/m2 days 1,2,15,16, subsequently amended to 70 mg/m2 days 1,15 for up to 2 years; plus R 10 mg days 1-21 every 28 days until progression) or R alone (10 mg days 1-21 every 28 days until progression). Centralized minimal residual disease (MRD) evaluation (8-color second-generation flow cytometry, sensitivity 10-5) was performed in pts achieving ≥very good partial response before maintenance and every 6 months (m) during maintenance. Data cut-off was June 30, 2020. Results. 474 NDMM pts were randomized (KRd_ASCT, n=158; KRd12, n=157; KCd_ASCT, n=159) and analyzed. Pt characteristics were well balanced. Intention-to-treat (ITT) data of pre-maintenance MRD (KRd_ASCT, 62%; KRd12 56%, KCd_ASCT 43%) and safety of the induction/consolidation phases in the 3 arms were already reported (F. Gay et al. ASH 2018; S. Oliva et al. ASH 2019). After a median follow-up from R1 of 45 m, median PFS was not reached with KRd_ASCT, 57 m with KRd12 and 53 m with KCd_ASCT (KRd_ASCT vs KCd_ASCT: HR 0.53, P During maintenance, a similar proportion of pts experienced ≥1 grade (G)3-4 hematologic adverse events (AEs)/serious AEs (SAEs) in the 2 arms (KR 22% vs R 23%); the most frequent were neutropenia (KR 18% vs R 21%) and thrombocytopenia (KR 3% vs R 3%). Rate of ≥1 G3-4 non-hematologic AEs/SAEs was higher with KR (27%) compared with R (15%), P=0.012; the most frequent were infections (KR 4% vs R 7%); all other events were reported in ≤5% of pts and included: gastrointestinal (KR 5% vs R 2%), cardiac (KR 4% vs R 1%), hypertension (KR 3% vs R 0%), and thrombotic microangiopathy (3% vs 0%). 4 pts developed a second primary malignancy in KR (breast 1 pt; thyroid 1 pt; myelodysplastic syndrome 1 pt; non-melanoma skin cancer 1pt) vs 1 pt in R (acute lymphoblastic leukemia). Dose reductions of R were reported in 23% of KR and 29% of R pts; dose reductions of K were reported in 20% of pts. The rate of discontinuation due to AEs was similar in the 2 arms (KR 10% vs R 9%). Conclusions. Treatment with KRd_ASCT significantly improved PFS compared with both KRd12 and KCd_ASCT. Maintenance with KR also improved PFS vs R. Figure Disclosures Gay: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto:Celgene: Honoraria; Amgen: Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Belotti:Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. De Sabbata:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Liberati:VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; INCYTE: Honoraria; JANSSEN: Honoraria; CELGENE: Honoraria; AMGEN: Honoraria; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau. Boccadoro:AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

Background Copy-number alterations of chromosome 1q are frequently found in multiple myeloma (MM) and are associated with poor prognosis. Recently, it has been demonstrated that the number of 1q copies correlates with a high-risk behavior (BA Walker et al, Leukemia 2019, TM Schmidt et al, Blood Cancer J 2019), but no data are available in carfilzomib-treated patients (pts). Here we aim at dissecting the role of Gain1q (3 copies of 1q) vs amplification 1q (Amp1q, ≥4 copies of 1q) in carfilzomib-treated NDMM pts enrolled in the randomized FORTE trial (NCT02203643). Methods Fluorescence in situ hybridization (FISH) in CD138+ purified bone marrow plasma cells (BMPCs) was centralized and performed at baseline. Two hundred BMPC nuclei from each sample were scored. The cut-off level for Gain1q was 10% of nuclei with ≥3 copies of 1q (mean plus 3 standard deviations of 1q alterations in BMPC from 15 healthy donors). The cut-off for Amp1q was 20% of nuclei with ≥4 copies of 1q. In the FORTE trial, transplant-eligible NDMM pts were randomized to receive carfilzomib (K) lenalidomide (R) dexamethasone (d) induction followed by autologous stem-cell transplantation (ASCT) and KRd consolidation (KRd_ASCT), 12 KRd cycles (KRd12) or K-cyclophosphamide(C)-d induction, followed by ASCT and KCd consolidation (KCd_ASCT). After consolidation, pts were further randomized to receive KR vs R maintenance. Results A total of 474 pts were enrolled. Median follow-up from 1st randomization was 45 months (m). Evaluation of 1q by FISH was missing in 70 pts (15%), while in 4 pts (1%) FISH was present but the number of 1q copies was not evaluable. Among evaluable pts, chromosome 1q was normal in 219 (55%) pts, Gain1q was found in 129 (32%) pts, while Amp1q in 52 (13%). Gain1q- and Amp1q-positive pts were well distributed among treatment arms. Baseline characteristics associated with Amp1q, compared to Gain1q, were LDH >upper limit of normal (P=0.002) and low hemoglobin (P=0.029) and platelets (P=0.044). Best response to therapy was not significantly different in Normal 1q vs Gain1q vs Amp1q groups (≥very good partial response rates: 85% vs 84% vs 77%; stringent complete response rates: 52% vs 50% vs 38%). Best overall minimal residual disease negativity by flow cytometry (sensitivity 10-5) pre-maintenance was also not significantly different (55% vs 55% vs 44%, respectively). In a multivariate analysis adjusted for treatment and Revised International Staging System (R-ISS), the risk of progression/death was significantly higher in the presence of Gain1q vs Normal 1q (HR 1.65, 95% CI 1.14-2.37, P=0.007) and the highest in the presence of Amp1q as compared to both Normal 1q (HR 3.04, 95% CI 1.99-4.65, P Median progression-free-survival (PFS) was not reached in the Normal 1q group, while Gain1q (53 m) and especially Amp1q (21.8 m) groups performed very poorly. The presence of Amp1q vs Normal 1q (HR 5.88, 95% CI 3.10-11.17, P Subgroup analysis on the presence/absence of concomitant high-risk features was performed. Gain1q predicted a lower PFS compared to Normal 1q in the presence of concomitant standard-risk features (ISS 1, ISS 2, standard-risk cytogenetics) but not in the presence of high-risk disease (ISS 3, high-risk cytogenetics). On the other hand, the worse prognosis of Amp1q pts was confirmed across all subgroups. A subgroup analysis according to the upfront treatment received was performed. Interestingly, treatment with KRd_ASCT completely abrogated the risk conferred by Gain1q (HR 1.25 vs Normal 1q, 95% CI 0.58-2.7, P=0.565), while Amp1q-positive pts still showed a very poor outcome (median PFS 17 m, HR 6.03 vs Normal 1q, 95% CI 2.78-13.1, P In KCd_ASCT and KRd12-treated pts, the 3 groups performed similarly to the overall population. Conclusion This is a first report on the prognostic role of the number of 1q copies in carfilzomib-treated NDMM pts. Having ≥4 copies of 1q universally predicts a very poor PFS and OS despite the use of a 2nd generation proteasome inhibitor upfront. On the other hand, KRd_ASCT completely abrogated the PFS disadvantage conferred by 3 copies of 1q. RNA sequencing on representative samples of Normal 1q vs Gain1q vs Amp1q is in progress to explore differentially expressed genes in Amp1q pts that could be exploited in future treatment strategies. Figure 1 Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Giuliani:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Participation in congresses, Research Funding; Janssen Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Other: Clinical study sponsorship; participation in congresses, Research Funding; Millennium Pharmaceutical: Other: Clinical study sponsorship, Research Funding; GSK: Other: Clinical study sponsorship, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Participation in congresses. Tacchetti:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Bristol-Myers Squibb: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Gay:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

Subcutaneous (SC) bortezomib-based regimens represent the standard induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma patients. Published data are based principally on intravenous (IV) administration: this retrospective observational study aimed to define patients’ outcomes upon SC bortezomib administration, before and after ASCT. Of 131 enrolled patients, 86% received bortezomib-dexamethasone plus thalidomide (VTD), 5% plus cyclophosphamide (VCD), and 9% alone (VD), for a median of 4 cycles induction therapy, followed by single (52%) or double (48%) ASCT. 48 patients received consolidation with the same induction regimen. 35% had at least one adverse event, mainly gastrointestinal disorders and peripheral neuropathy (PN). ORR was 93.1%, 97.7% and 100%, after induction, ASCT(s) and consolidation, respectively. Median PFS and PFS2 were 55.8 months and 72 months, respectively, (median follow-up 45.3 months), while median OS was unreached. Concluding, SC bortezomib has similar efficacy with reduced PN than IV administration.

Background Immune therapies have had a major impact in multiple myeloma (MM). Responses induced in relapsed and/or refractory MM (RRMM) patients (pts) are unprecedented; however the key challenge is their durability. Most immunotherapeutic approaches rely on the fitness of pts’ T cells but exposure to multiple therapies may alter immune cell numbers and function. Here we analyzed and compared the transcriptome and phenotype of T cells from healthy donors (HD), newly diagnosed MM (NDMM) and RRMM pts. Methods Peripheral Blood Mononuclear Cells (PBMCs) from age-matched HD, NDMM and RRMM pts were collected before the start of a new line of treatment. Single cell RNA sequencing (scRNAseq) was performed and proportion of cell types were inferred using a reference PBMC dataset with Seurat. Cell type proportions were also estimated with CyTOF and conventional flow cytometry Results PBMCs from 10 HDs (median age 69, range 53-79), 20 NDMM pts (median age 71, range 54-88), 20 RRMM pts (median age 71, range 54-80) were analyzed. RRMM pts were exposed to 1 (n=8), 2 (n=6) or 3 (n=6) lines of treatment. All RRMM pts were exposed to a proteasome inhibitor, 75% were exposed to an immunomodulatory drug, and 65% received autologous stem cell transplantation. 48 out of 50 samples were processed by scRNAseq, 45 by CyTOF and 33 by flow cytometry. NDMM pts demonstrated a trend towards lower frequency of CD4 T cells compared to HD. This decreased number was accompanied by a decrease in the expression of genes involved in mitochondrial oxidative phosphorylation and an increase in expression of immediate early response genes (e.g. FOS, JUN, JUNB). In the CD8 compartment, CD8 naive cells were lower in NDMM compared to HD. No differences were found on CD8 central memory, effector memory and/or terminal effector populations In RRMM, the proportion of naive CD4 cells was significantly lower compared to NDMM (p Conclusion T cell phenotypes in MM pts are altered, especially after treatment. These findings may provide the rationale for the investigation of immunotherapy in NDMM and less heavily pretreated MM. Ongoing functional studies will demonstrate whether these phenotypic and transcriptomic changes lead to less fit T cells with consequent impact on effectiveness of T cell directed therapies.