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Large-scale analyses of genomic data from patients with newly diagnosed multiple myeloma (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory MM (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole-genome sequencing (WGS) data from 418 tumors (386 patients) derived from 6 rrMM clinical trials and compared them with WGS from 198 unrelated patients with ndMM in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), noncoding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNAs; 1qGain, 17pLOH), and double-hit events (Amp1q-ISS3, 1qGain-17p loss-of-heterozygosity). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiD)–based therapy. This analysis revealed that TP53, DUOX2, 1qGain, and 17p loss-of-heterozygosity increased in prevalence from ndMM to lenalidomide resistant (LENR) to pomalidomide resistant (POMR) stages, whereas enrichment of MAML3 along with immunoglobulin lambda (IGL) and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be further evaluated in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.

Multiple myeloma embodies the paradigm of the deeper the response, the longer the survival. However, results are conflicting regarding achievement of complete remission (CR) and minimal residual disease (MRD) negativity; some patients with persistent M protein have undetectable MRD. We reviewed the frequency of this discordance and outcomes of these patients. We spotlight possible explanations for and consequences of conflicting response criteria and suggest that MRD be assessed in patients achieving very good partial response or better in clinical trials.

In the era of personalized treatment in multiple myeloma, high-risk patients must be accurately identified. The International Myeloma Working Group recommends using the Revised International Staging System (R-ISS) to pick out high-risk patients. The main purpose of our work was to explore the heterogeneity of outcome among R-ISS stage II patients assessing the impact of International Staging System (ISS) stage, chromosomal abnormalities and lactate dehydrogenase level in this subgroup. Data were collected from 1,343 patients up to 65 years old with newly diagnosed myeloma, enrolled in three clinical trials implemented by the Intergroupe Francophone du Myélome. All patients were eligible for intensive treatment. Patients in R-ISS stage II but ISS stage I had 1.6 times higher risk of death than patients in R-ISS stage I (adjusted hazard ratio=1.6; 95% confidence interval: 1.1-2.2; P=0.01) and patients in R-ISS stage II but with ISS stage III had a better overall survival than patients in R-ISS stage III (adjusted hazard ratio=0.7; 95% confidence interval: 0.4-0.9, P=0.02). However, among patients classified in R-ISS II, ISS stage and chromosomal abnormalities (del[17p] and t[4;14]) were still relevant prognostic factors for death. Dividing R-ISS stage II into three subgroups: ISS I with standard-risk chromosomal abnormalities, ISS II or III with standard-risk chromosomal abnormalities and patients with high-risk chromosomal abnormalities, median overall survival times were, respectively, not reached, 112 months and 71 months (P

Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application. Significance: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501

PDF file - 96K, Characteristics of the patients that were analyzed on the exon arrays.

PDF file - 66K, Table S3 shows CD13 and its splice variant expression patterns in 193 AML patients.

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PDF file - 1538K, Figure S1 illustrates CD13 splice variant protein expression and Figure S2 shows representative electropherograms for DNA fragment analysis and capillary electrophoresis.

PDF file - 162K, Table S2b is a list of spliced oncogenes and tumor suppressors identified in AML patients and Table S2c is a list of genes spliced in both cohorts analyzed.

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Purpose: PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell–mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu.Experimental Design: Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138+ multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti–multiple myeloma immune response and tumor cell growth.Results: Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression.Conclusions: Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti–multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy. Clin Cancer Res; 21(20); 4607–18. ©2015 AACR.

Supplementary Figure and Method. Supplementary Figure: PD-L1 gene expression in MM cells from patients with ND-MM compared to normal plasma cells by Exon Array Analysis. Supplementary Method: Exon Array Dataset and Gene Expression Analysis.

Purpose: Despite new treatments, acute myeloid leukemia (AML) remains an incurable disease. More effective drug design requires an expanded view of the molecular complexity that underlies AML. Alternative splicing of RNA is used by normal cells to generate protein diversity. Growing evidence indicates that aberrant splicing of genes plays a key role in cancer. We investigated genome-wide splicing abnormalities in AML and based on these abnormalities, we aimed to identify novel potential biomarkers and therapeutic targets.Experimental Design: We used genome-wide alternative splicing screening to investigate alternative splicing abnormalities in two independent AML patient cohorts [Dana-Farber Cancer Institute (DFCI) (Boston, MA) and University Hospital de Nantes (UHN) (Nantes, France)] and normal donors. Selected splicing events were confirmed through cloning and sequencing analysis, and than validated in 193 patients with AML.Results: Our results show that approximately 29% of expressed genes genome-wide were differentially and recurrently spliced in patients with AML compared with normal donors bone marrow CD34+ cells. Results were reproducible in two independent AML cohorts. In both cohorts, annotation analyses indicated similar proportions of differentially spliced genes encoding several oncogenes, tumor suppressor proteins, splicing factors, and heterogeneous-nuclear-ribonucleoproteins, proteins involved in apoptosis, cell proliferation, and spliceosome assembly. Our findings are consistent with reports for other malignances and indicate that AML-specific aberrations in splicing mechanisms are a hallmark of AML pathogenesis.Conclusions: Overall, our results suggest that aberrant splicing is a common characteristic for AML. Our findings also suggest that splice variant transcripts that are the result of splicing aberrations create novel disease markers and provide potential targets for small molecules or antibody therapeutics for this disease. Clin Cancer Res; 20(5); 1135–45. ©2013 AACR.

PDF file - 68K, Table summarize results of annotation analyses of aberrantly spliced transcripts detected in AML patients as compared to normal donors.

Bei der Impfung handelt es sich um eine der erfolgreichsten medizinischen Maßnahmen, die bereits Millionen von Menschen das Leben gerettet hat. Die Impfung ist besonders wichtig bei Patienten mit einem Multiplen Myelom, deren Infektionsrisiko aufgrund der krankheitsinhärenten Immunsuppression sowie der immunsuppressiven Wirkung der Therapie erhöht ist. Daher sollten alle geeigneten Maßnahmen ergriffen werden, um eine wirksame Immunantwort gegen weitverbreitete Krankheitserreger wie Influenza, Pneumokokken, das Varicella-Zoster-Virus sowie gegen Bakterien und Viren (Haemophilus influenzae, Meningokokken und Hepatitis), die häufig ein erhebliches Risiko für Patienten mit einem Multiplen Myelom darstellen, anzuregen. Patienten nach autologer und insbesondere nach allogener Transplantation haben stark reduzierte Antikörpertiter und benötigen daher ein breiteres Impfspektrum. Die Impfreaktion ist bei Myelom-Patienten oft weniger stark ausgeprägt als in der Allgemeinbevölkerung, sodass entweder die Messung der Antikörpertiter nach der Impfung und/oder eine Wiederholungsimpfung erforderlich ist. In dieser Arbeit stellen wir die Daten zusammen, die zur Impfung von Patienten mit Multiplem Myelom existieren, und geben Empfehlungen für die klinische Praxis.

International audience; The International Myeloma Working Group recently fully incorporated 18F-FDG PET into multiple myeloma (MM) diagnosis and response evaluation. Moreover, a few studies demonstrated the prognostic value of several biomarkers extracted from this imaging at baseline. Before these 18F-FDG PET biomarkers could be fully endorsed as risk classifiers by the hematologist community, further characterization of underlying molecular aspects was necessary. Methods: Reported prognostic biomarkers (18F-FDG avidity, SUVmax, number of focal lesions, presence of paramedullary disease [PMD] or extramedullary disease) were extracted from 18F-FDG PET imaging at baseline in a group of 139 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov identifier NCT02541383). Transcriptomic analyses using RNA sequencing were realized on sorted bone marrow plasma cells from the same patients. An association with a high-risk gene expression signature (IFM15), molecular classification, progression-free survival, a stringent clinical response, and minimal residual disease negativity were explored. Results:18F-FDG PET results were positive in 79.4% of patients; 14% and 11% of them had PMD and extramedullary disease, respectively. Negative 18F-FDG PET results were associated with lower levels of expression of hexokinase 2 (HK2) (fold change, 2.1; adjusted P = 0.04) and showed enrichment for a subgroup of patients with a low level of bone disease. Positive 18F-FDG PET results displayed 2 distinct signatures: either high levels of expression of proliferation genes or high levels of expression of GLUT5 and lymphocyte antigens. PMD and IFM15 were independently associated with a lower level of progression-free survival, and the presence of both biomarkers defined a group of "double-positive" patients at very high risk of progression. PMD and IFM15 were related neither to minimal residual disease assessment nor to a stringent clinical response. Conclusion: Our study confirmed and extended the association between imaging biomarkers and transcriptomic programs in MM. The combined prognostic value of PMD and a high-risk IFM15 signature may help define MM patients with a very high risk of progression.

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.

In the era of personalized treatment in multiple myeloma, high-risk patients must be accurately defined. The International Myeloma Working Group recommends using the Revised International Staging System (R-ISS) to identify high-risk patients. The main purpose of our work was to explore the heterogeneity of outcome among R-ISS stage II patients assessing the impact of ISS, chromosomal abnormalities (CA) and LDH level in this subgroup. Data were issued from 1,343 newly diagnosed myeloma patients up to 65 years, enrolled in 3 clinical trials implemented by the Intergroupe Francophone du Myelome. All patients were eligible to an intensive treatment. Patients R-ISS stage II but ISS stage I had 1.6 times more risk of death than patients R-ISS stage I (adjusted HR 1.6; 95% CI, 1.1 to 2.2; P = .01) and patients R-ISS stage II but ISS stage III had a better overall survival than patients R-ISS stage III (adjusted HR 0.7; 95% CI, 0.4 to 0.9, P = .02). However, among patients classified in R-ISS II, ISS stage and CA (del(17p) and t(4;14)) were still relevant prognostic factors for death. Dividing R-ISS stage II into 3 subgroups: ISS I with standard risk CA, ISS II or III with standard risk CA and, high risk CA patients, median overall survivals were respectively not reached, 112 and 71 months (P0.001). In conclusion, stratification of patients in the R-ISS stage II group can be improved by taking into account CA and ISS. However, this does not improve predictive performance of survival models.

The International Myeloma Working Group recently fully incorporated (18)F-FDG PET into multiple myeloma (MM) diagnosis and response evaluation. Moreover, a few studies demonstrated the prognostic value of several biomarkers extracted from this imaging at baseline. Before these (18)F-FDG PET biomarkers could be fully endorsed as risk classifiers by the hematologist community, further characterization of underlying molecular aspects was necessary. Methods: Reported prognostic biomarkers ((18)F-FDG avidity, SUV(max), number of focal lesions, presence of paramedullary disease [PMD] or extramedullary disease) were extracted from (18)F-FDG PET imaging at baseline in a group of 139 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov identifier NCT02541383). Transcriptomic analyses using RNA sequencing were realized on sorted bone marrow plasma cells from the same patients. An association with a high-risk gene expression signature (IFM15), molecular classification, progression-free survival, a stringent clinical response, and minimal residual disease negativity were explored. Results: (18)F-FDG PET results were positive in 79.4% of patients; 14% and 11% of them had PMD and extramedullary disease, respectively. Negative (18)F-FDG PET results were associated with lower levels of expression of hexokinase 2 (HK2) (fold change, 2.1; adjusted P = 0.04) and showed enrichment for a subgroup of patients with a low level of bone disease. Positive (18)F-FDG PET results displayed 2 distinct signatures: either high levels of expression of proliferation genes or high levels of expression of GLUT5 and lymphocyte antigens. PMD and IFM15 were independently associated with a lower level of progression-free survival, and the presence of both biomarkers defined a group of “double-positive” patients at very high risk of progression. PMD and IFM15 were related neither to minimal residual disease assessment nor to a stringent clinical response. Conclusion: Our study confirmed and extended the association between imaging biomarkers and transcriptomic programs in MM. The combined prognostic value of PMD and a high-risk IFM15 signature may help define MM patients with a very high risk of progression.

LBA4 Background: Optimal use of triplet/quadruplet induction, ASCT, and R-based maintenance in patients (pts) with NDMM who are eligible for transplant continues to evolve. The IFM 2009 trial, which used R maintenance for 1 year (y), showed progression-free survival (PFS; median, 35.0 vs. 47.3 months [mos]) but no overall survival benefit (OS; 60 vs. 62% at 8 y; median follow-up, 89.8 mos) with RVd + ASCT vs. RVd alone in the setting of multiple effective options at relapse, including ASCT at first relapse in 77% of pts (Attal M et al, N Engl J Med 2017; Perrot A et al, ASH 2020). We report primary data from our US DETERMINATION trial, which used R maintenance until progression. Methods: Pts with NDMM aged 18-65 y were randomly assigned to receive 3 RVd cycles, stem cell mobilization, and then 5 more RVd cycles (Arm A) or IV melphalan 200 mg/m2 + ASCT and 2 RVd cycles (Arm B). Each 21-d RVd cycle comprised PO R 25 mg (d 1-14), IV/SC bortezomib 1.3 mg/m2 (d 1, 4, 8, 11), and PO dexamethasone 20/10 mg (cycles 1-3/≥ 4; d 1, 2, 4, 5, 8, 9, 11, 12). Both arms received R 10-15 mg/d maintenance until progression or intolerance. The primary endpoint was PFS (90% power to detect PFS hazard ratio [HR] of 1.43 [Arm A vs. B] with α = 0.05 on stratified two-sided log-rank test; full information: 329 events in 720 pts). Data cut-off was Dec 10, 2021. Results: 357 and 365 pts were randomly assigned to Arms A and B, respectively; median age was 57 and 55 y, 14% and 13% had ISS stage III MM, and 18% each had high-risk cytogenetics [t(4;14), t(14;16), del17p]. In the respective arms, 291 and 290 pts received R maintenance for a median duration of 36 and 41 mos. After median follow-up of 76 mos and 328 events, median PFS was 46.2 vs. 67.6 mos in Arm A vs. B (HR 1.53; 95% CI, 1.23–1.91; p < .0001). Best responses in pts assessed to date were 52 vs. 62% ≥ CR (p = .006), 79 vs. 83% ≥ VGPR and 94 vs. 96% ≥ PR; in 251 evaluable pts, rate of MRD negativity (10-5) was 37.3 vs. 52.1% (p = .021) within 1 y of maintenance. 63 vs. 53% of pts have received subsequent treatment; of Arm A, 22% had ASCT as first non-protocol therapy. With 90 vs. 88 pts having died in Arm A vs. B, 4-y OS was 84% (95% CI, 80–88%) vs. 85% (95% CI, 81–88%); HR 1.10 (95% CI, 0.81–1.47; p = .274). Grade ≥ 3 related adverse events were less common in Arm A vs. B (78 vs. 94%; hematologic: 61 vs. 90%, p < .0001); 10 vs. 11% had secondary malignancies (ALL, 7 vs. 3 pts, p = .22; AML/MDS, 0 vs. 10 pts, p = .002). Difference in mean change from baseline in EORTC QLQ-C30 global health status score was < 10 points throughout treatment except at RVd cycle 5 vs. post-ASCT (compliance rate, 75% vs. 55%; mean change +3.0 vs. –11.1; p < .0001). Whole-genome sequencing, additional QOL, and correlative analyses are ongoing. Conclusions: RVd ± ASCT and R maintenance to progression resulted in the longest median PFS reported for each approach, and a highly significant 21.4-mo gain in median PFS benefit using RVd + ASCT. No OS advantage has been observed to date. Clinical trial information: NCT01208662.

8002 Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 20, 40%), t(4;14) (n = 26, 52%) or t(14;16) (n = 10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n = 1 ; drug-induced hepatitis, n = 1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event ( > 5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % > very good partial response. Among 37 (/46) evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10-5) was 62%. Conclusions: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients. Clinical trial information: NCT03606577.

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy., Relapse following BCMA targeted CAR T-cell therapy is frequently observed in patients with multiple myeloma (MM). Here, by single cell transcriptome profiling on serially collected bone marrow samples, the authors report biallelic loss of BCMA as the mechanism of resistance underlying both relapse and lack of response to a second CAR T infusion in a patient with MM.

The most recent update to the International Myeloma Working Group consensus criteria places a strong emphasis on the need for more sensitive haematological markers of response driven by the success of novel therapies. One such marker is serum free light chain (sFLC) analysis, which was first incorporated into the definition of stringent complete response in 2006. However, over the past decade there has been some reluctance to extend the role of the sFLC assays to replace 24 h urine electrophoresis for monitoring multiple myeloma (MM). In this review, we lay out the evidence in favour of serum over urine for monoclonal FLC measurements and propose modified criteria for response assignment in myeloma.

Recent studies have shown that Dickkopf-related protein (DKK1) and sclerostin decrease when a complete response (CR) is obtained after chemotherapy in myeloma multiple (MM). To study variations in DKK1, sclerostin and P1NP in patients treated for MM, between complete response (CR) and relapse, we carried out a prospective study ancillary to the IFM 2009 protocol (IFM). The aim of IFM was to compare progression-free survival between patients treated with chemotherapy with or without transplantation. We selected 69 patients who reached CR and relapsed. We assayed by ELISA: DKK1, sclerostin and P1NP at 3 end points T1: CR, T2: 4 months before relapse and T3: relapse. There was a significant increase in DKK1 and sclerostin between T1, T2 and T3. (DKK1 medians (IQR): T1 = 30 pmol/l (20.4-41.1), T2 = 37.4 pmol/l (29.8-49.4), p 0.0001, T3 = 42 pmol/l (33.8-55.5), p 0.0001 sclerostin medians (IQR): T1 = 0.57 (0.47-0.69), T2 = 0.62 ng/ml (0.53-0.79), p 0.0001, T3 = n0.64 ng/ml (0.56-0.79), p = 0.005). No significant variation was detected in the levels of P1NP. No association was observed between the characteristics of the MM, or the treatment received and the variation between T1-T3 for DKK1, sclerostin or P1NP. A significant increase in DKK1 and sclerostin was observed four months before relapse.

Introduction: The 2-part phase 3 CASSIOPEIA study (NCT02541383) investigated the combination of DARA with VTd (D-VTd) in transplant-eligible NDMM pts. D-VTd induction/consolidation (ind/cons) led to increased rates of MRD negativity and prolonged progression-free survival (PFS) compared with VTd (Moreau P, et al. Lancet. 2019;394(10192):29-38). In Part 2, DARA as post-autologous stem cell therapy (ASCT) maintenance significantly improved PFS in pts who received VTd ind/cons. Most common (≥2.5%) grade 3/4 adverse events included pneumonia (DARA: 2.5%; observation [OBS]: 1.4%), lymphopenia (3.6%; 1.8%), and hypertension (3.0%; 1.6%; Moreau P, et al. J Clin Oncol. 2021;39(no. 15_suppl):8004). Here, we present results from a detailed analysis of MRD negativity. Methods: Eligible pts were 18-65 years of age, had NDMM and were ASCT eligible. Pts were randomized 1:1 to 4 (28-day) cycles of pre-ASCT induction and 2 (28-day) cycles of post-ASCT consolidation with D-VTd or VTd (bortezomib, 1.3 mg/m 2 SC on Days 1, 4, 8, 11; thalidomide, 100 mg PO daily; dexamethasone, 20-40 mg IV/PO; ± DARA, 16 mg/kg IV weekly (QW) in Cycles 1-2, Q2W in Cycles 3-6). Pts who completed consolidation and achieved partial response or better were re-randomized 1:1 to maintenance DARA at reduced intensity (DARA, 16 mg/kg Q8W) for a maximum of 2 years, or OBS. Samples were collected for MRD analysis at predefined timepoints from all pts regardless of response to ind/cons and in pts with very good partial response or better during maintenance. The primary MRD assessment methodology was multiparametric flow cytometry during ind/cons and next-generation sequencing during maintenance, each at the 10 -5 threshold. MRD negativity is reported here for pts who achieved complete response or better. Results: 1,085 pts were randomized to ind/cons (D-VTd, n=543 or VTd, n=542) and 886 pts were re-randomized for post-ASCT maintenance (DARA, n=442 or OBS, n=444). The rate of MRD negativity was higher with D-VTd than with VTd following induction (9.2% vs 5.4%; odds ratio [OR], 1.79; P=0.0150) and consolidation (33.7% vs 19.9%; OR, 2.06; P During maintenance, the rate of MRD negativity significantly favored DARA over OBS (58.6% vs 47.1%; OR, 1.80; P=0.0001). In pts who received D-VTd ind/cons, the MRD-negativity rates with DARA and OBS were 64.2% and 57.6% respectively (OR, 1.43; P=0.1037). In contrast, pts who had received VTd ind/cons showed significantly higher MRD-negativity rates during DARA maintenance vs OBS (52.6% vs 35.8%; OR, 2.26; P=0.0002). The rates of sustained MRD negativity in the D-VTd group were not significantly different with DARA vs OBS (1yr sustained: 48.5% vs 41.0%; OR, 1.41; P=0.0885; 2yr sustained: 28.8% vs 21.8%; OR, 1.47; P=0.0789). In the VTd group, the 1-year sustained MRD-negativity rate was significantly higher with DARA vs OBS (35.7% vs 21.4%; OR, 2.22; P=0.0006) but no difference was observed in the 2-year sustained MRD rate (11.3% vs 13.0%; OR, 0.83; P=0.5481). Conclusion: In CASSIOPEIA, the highest and most durable rates of MRD negativity were achieved after D-VTd ind/ASCT/cons and DARA maintenance. Reduced intensity (Q8W) DARA maintenance did not significantly improve MRD negativity compared to OBS in patients treated with D-VTd. In patients treated with VTd, DARA maintenance did improve MRD negativity, but this effect was not long lasting. Longer follow-up is required to assess the potential long-term benefits of sustained MRD negativity for DARA vs OBS after D-VTd. Figure 1 Figure 1. Disclosures Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Moreau: Amgen: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. van der Velden: Janssen: Other: Service Level Agreement; BD Biosciences: Other: Service Level Agreement; Navigate: Other: Service Level Agreement; Agilent: Research Funding; EuroFlow: Other: Service Level Agreement, Patents & Royalties: for network, not personally. Hulin: abbvie: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Arnulf: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Karlin: Janssen: Honoraria, Other: member of advisory board, travel support; Abbvie: Honoraria; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; GSK: Honoraria, Other: member of advisory board; oncopeptide: Honoraria. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Perrot: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: 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: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van De Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Krevvata: Janssen: Current Employment. Rigat: Janssen: Current Employment, Current equity holder in publicly-traded company. Yang: Janssen: Current Employment. Vanquickelberghe: Janssen: Current Employment. de Boer: Janssen: Current Employment. Kampfenkel: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria; Sanofi: Honoraria; Bristol-Meyer Squibb: Honoraria; Amgen: Honoraria. OffLabel Disclosure: The specific regimen combination is not yet approved in the maintenance setting.

Background Focal amplifications and rearrangements drive tumor growth and evolution in cancer. Focally amplified regions often involve the juxtaposition of rearranged segments of DNA from distinct chromosomal loci into a single amplified region and nearly half of these regions can be explained by circular, extrachromosomal DNA (ecDNA) formation. Cancer-associated ecDNA shows a unique circular placing ecDNA at the interface of cancer genomics and epigenetics. As formation of ecDNA represents a manifestation of genomic instability, we have investigated presence and prognostic impact of ecDNA in multiple myeloma (MM). Methods Whole genome (WGS) and transcriptome (RNAseq) sequencing data from CD138 purified MM cells from 191 uniformly-treated newly diagnosed MM patients were used for this analysis. Copy number variants (CNV), single nucleotide variants (SNV) and structural variants (SV) were identified on all WGS samples using Facets, Mutect2 and Manta. Seed data from these CNV results was passed to the AmpliconArchitect tool to determine presence of focally amplified and rearranged segments of DNA. Seed CNV thresholds were set for a minimum CNV size of 100kb and a copy number of equal or greater to 5. Extrachromosomal calls were then annotated using the Amplicon Classifier to determine the presence of ecDNA. Multivariate survival analysis was performed after segregating samples into the conventional myeloma risk classifications including translocations, copy number alterations, ISS, age and mutations associated with risk. Differential expression analysis was performed on transcriptomic data using DEseq2. Results We identified 6.8% of the newly diagnosed patients with ecDNA, 12.5% with complex non-cyclic DNA amplifications and 10.1% with linear amplifications. ecDNA and complex events were targeting MM dependent genes, including MYC/PVT1, IRF4 as well as known driver genes such as CDYL and TRAF2. We further evaluated association between ecDNA, complex rearrangements, linear amplification and patients with none of these amplification types and found that patients with ecDNA had significantly poor PFS (median PFS 22 months vs. 41 months) and OS (median OS 41 months vs. 105 months). Patients having ecDNA in their MM cells did not show any significant enrichment for known translocations, double hit or TP53 mutations. In a multivariate model including ecDNA and all other known MM risk features, ecDNA was found to be an independent predictor of progression free survival.(HR 2.6, CI: 1.26 -5.6, p=0.0082) and overall survival (HR 7.94 CI:3.5-17.9 p < 0.0001). Patients with ecDNA have higher mutational load probability(8798 vs 6982, effect size = 0.64 , probability is 91.1). However, this was not reflected in heterogeneity by using MATH score. We found that patients with ecDNA are likely to have BRAF mutations (OR= 25.07 [2.57 - 330 95% CI], p value = 0.002), however overall RAS/RAF pathway mutations were similar to other patients. Patients with ecDNA showed fragile DNA with more breaks (median segments 197 vs. 125.5, p value = 0.001). Although ecDNA is defined as copy number gain with fragments having 5 or more copies, overall genomic gain between ecDNA and other patients were similar. However, overall genomic loss in patients with ecDNA were higher than others (7% vs. 4.2%, p = 0.06). By differential gene expression analysis we noted 98 differentially expressed genes in MM cells with ecDNA. The downregulated geneset involved pathways responsible for cell death as well as the RAS pathway. Interestingly, CD38 was upregulated in the ecDNA dataset suggesting greater potential for CD38 targeting therapies in these patients. Conclusions ecDNA, as an unique marker of perturbed genomic integrity, is observed in a subset of patients and is an independent prognostic marker in newly diagnosed MM patients. As patients with ecDNA are not fully captured by other risk features its incorporation in an expanded definition of a high risk group of multiple myeloma should be investigated. Future studies will endeavor to explore the biological mechanism through which ecDNA are formed and influences outcomes in myeloma. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Secura Bio: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Thakurta: Oxford University: Other: Visiting Professor; BMS: Current Employment, Current equity holder in publicly-traded company. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Celgene: Consultancy; Pfizer: Consultancy.

Background: The role of maintenance lenalidomide in myeloma, following autologous stem cell transplantation (ASCT) or not, is well established. However, 29% of patients discontinue the treatment with a median duration of less than 2 years with an increased rate of secondary primary malignancies (SPM). Pomalidomide could provide alternative maintenance therapy. Methods: This was a single arm phase II study of pomalidomide/dex (PD) maintenance therapy for MM patients (pts) in first relapse after treatment in the IFM 2009 trial. At first relapse, 100 pts received pomalidomide/cyclophosphamide/dex (PCD) for 4 cycles, after which half underwent ASCT (if no first line transplant) followed by 2 cycles of PCD consolidation (Arm A), or 5 cycles of PCD (if previously transplanted) (Arm B). All pts then received maintenance therapy consisting of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dex 20 mg once a week until progression (Blood 2018). The primary objective was to establish the safety and efficacy of PD as maintenance therapy. Results: A total of 75 pts were enrolled in the maintenance phase from January 2015 to November 2017 (Table 1) and the database was locked on 07/07/2021. The median age was 60 (range 39-70); 67% (50/75) were male. 53 pts had ISS stage I, 10 stage II and 3 stage III disease (9 missing). Infectious prophylaxis was antiviral in 94%, sulfamethoxazole/trimethoprim in 76%, penicillin in 69% and fluoroquinolone in 38%. A granulocyte colony stimulating factor was administered in 15 (20%) pts and immunoglobulins in 13 (17%). One quarter had thromboprophylaxis. The median follow-up was 73 months (95% CI: 68-75). Among the 75 pts, 63 (84%) left the study, 34 (54%) due to progressive disease, 19 (30%) due to AE/SAE, 7 (11%) on investigator (PI) discretion and 3 (5%) after consent withdrawal. 12 (16%) remained on therapy in July 2021.The median duration of maintenance was 23.7 months (IQR: 14.5-44). Pts received a median of 26 cycles (range 1-80) and 17 (23%) had 50 or more cycles. The reasons for pomalidomide discontinuation were progression or death in 54%, AE/SAE in 30%, PI decisions in 11% and patient decisions in 5%. 56 (75%) pts required a reduction in the dose of pomalidomide due to AE/SAE in 50%, omission in 19%, resumption of treatment in 11%, PI decisions in 16% and patient decisions in 2.7%. The reasons for dex discontinuation were progression or death in 30%, AE/SAE in 43%, PI decisions in 22% and patient decisions in 3%. 57 (76%) pts required a reduction in the dose of dex due to AE/SAE in 54%, omission in 3.4%, resumption of treatment in 0.3%, PI decisions in 38.7% and patient decisions in 3.1%. 31 SAE were reported in 22 pts: 13 (42%) infections, 5 tumors, 1 case of thrombosis, 1 diabetic ketoacidosis and 12 others. Grade 3/4 hematologic AE included neutropenia (51%), lymphopenia (35%), anemia and thrombocytopenia (0%). G3/4 drug-related non-hematologic AE (>5%) comprised 13% infections (5% pneumonia). G1/2 AE included 69% infections (49% bronchitis), 49.3% gastrointestinal disorders (20% diarrhea, 20% constipation), 48% fatigue, 31% skin disorders, 25% muscle spasms, 24% insomnia and 14.7% eye disorders (6.7% cataracts, 4% dry eyes). Concerning peripheral neuropathy, one patient had G3/4 and 45% G1/2. Eight pts developed SPM: 4 basocellular carcinoma, 1 epidermoid carcinoma, 1 melanoma, 1 colon carcinoma and 1 non small cell bronchial carcinoma. We observed an improvement in the response from the initiation of treatment: PR: 32.4 to 17.4%, VGPR: 56.8 to 49.3%, CR: 9.5 to 28%, sCR: 0 to 5.3% (at initiation to best response, respectively). A total of 33.4% of pts improved their response. The median PFS was 33.2 months (95% CI: 25.6-53.3). 41 pts died and the median OS was not reached (95% CI: 70.7-NR). All deaths were related to myeloma progression except 2 due to pulmonary infection, 1 lung carcinoma and 1 colorectal cancer. Conclusions: In the first relapse PCD trial, 75% initiated maintenance therapy. Long term administration of pomalidomide/dexamethasone as maintenance therapy is feasible. Thirty percent stopped pomalidomide because of SAE/AE, mostly related to hematologic AE, but this could be managed with dose reductions. There was generally G1/2 neuropathy, rare SPM and no other unexpected toxicity. One third of the pts improved their depth of response. The combination is safe, feasible and well tolerated and experience to date supports its further exploration with monoclonal antibodies. Figure 1 Figure 1. Disclosures Garderet: Amgen: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Roussel: Amgen: Consultancy; BMS: Honoraria; GSK: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Leleu: Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Karlin: Takeda: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Abbvie: Honoraria; oncopeptide: Honoraria; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Celgene-BMS: Honoraria, Other: member of advisory board. Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Macro: abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; takeda: Honoraria; janssen: Honoraria. Jourdan: Novartis: Consultancy; Abbvie: Consultancy; bms/celgene: Consultancy. Jaccard: Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Mohty: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria. Hulin: Celgene/BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. OffLabel Disclosure: pomalidomide as maintenance treatment

Additional file 2. Supplementary material on running CNVkit, CoNIFER, ExomeDepth and CopywriteR.

Additional file 1. Dendrogram of 141 normal samples based on clustering by read depth at all capture regions. Distance between samples was defined as 1 – Pearson correlation of read depth at capture regions.

Additional file 3. Sensitivity of CNV Radar (blue) and CNVkit (pink).

Additional file 4. Sample SRR2128693 was called more accurately by CNVkit than CNV Radar. Top panel of horizontal bars indicates CNV calls by CNV Radar and CNVkit as well as the true CNV status defined by WGS.

The wealth of data recently generated highlights that minimal residual disease (MRD)–negative status can be achieved in a large proportion of patients. These studies, in addition to a meta-analysis, clearly suggest significant improvement in both event-free survival (EFS) and overall survival (OS) among those patients achieving MRD–negative status, especially with sensitivity of one cell in 1 million bone marrow cells. There is an evolving consensus that achieving MRD–negative status should become the ultimate goal of therapeutic intervention. Further future efforts should now be directed at determining how MRD status can be used to guide and personalize further therapy including type of consolidation and maintenance therapy.

It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.

Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable response to treatment and outcome. With the recent increase in treatment armamentarium and the projected further increase in approved therapeutic agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and rationally apply treatment is coming to the fore. A number of robustly validated prognostic markers have been identified and the use of these markers in stratifying patients into different risk groups has been proposed. In this consensus statement, the International Myeloma Working Group propose well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic factors. At the same time, these risk categories serve as a framework to rationalize the use of therapies.

The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen. We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure. Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH. This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.

The authors describe a family with a high penetrance of plasma cell dyscrasias, suggesting inheritance of an autosomal dominant risk allele.The authors performed whole-exome sequencing and reported on a combined approach aimed at the identification of causative variants and risk loci, using the wealth of data provided by this approach.The authors identified gene mutations and single-nucleotide polymorphisms of potential significance, and pinpointed a known risk locus for myeloma as a potential area of transmissible risk in the family.To the authors' knowledge, the current study is the first to provide a whole-exome sequencing approach to such cases, and a framework analysis that could be applied to further understanding of the inherited risk of developing plasma cell dyscrasias. Cancer 2017;123:3701-3708. © 2017 American Cancer Society.