We introduce a secure data-independent priority queue which supports polylogarithmic-time insertion operations and constant-time deletions and read-front (aka peek) operations as opposed to the ...originally introduced queue by Toft (PODC '11). Moreover, we minimize the number of comparisons required to perform different operations on Toft's priority queue. Data-independent data structures—first identified explicitly by Toft, and further elaborated by Mitchell and Zimmerman (STACS '14)—serve the purpose of computing on encrypted data without executing branching code which can be used to avoid prohibitively expensive operations in secure computation applications. Focusing on the costly sorting operations, we show significant asymptotic improvements over prior privacy preserving dark pool applications. Dark pools are securities-trading venues which attain ad-hoc order privacy, by matching orders outside of publicly visible exchanges via the so-called dark pool operators. In this paper, we describe an efficient and secure dark pool (implementing a full continuous double auction) based on our new priority queue. Our construction's security guarantees are cryptographic based on secure multiparty computation (MPC), and do not require that the dark pool operators are trusted. Our construction improves upon the asymptotic efficiency attained by previous efforts. Existing cryptographic dark pools process new orders in time which grows linearly in the size of the standing order book; ours does so in polylogarithmic time. We describe a concrete implementation of our MPC protocol with malicious security in the honest majority setting. We also report benchmarks of our implementation and compare them to prior works. Our protocol reduces the total running time by several orders of magnitude over prior secure dark pool solutions.
Anemia, neutropenia, and thrombocytopenia are expected complications of autologous hematopoietic cell transplant (AHCT) for multiple myeloma (MM). However, prolonged cytopenias may predispose ...patients to other infectious, cardiovascular, and/or hematological toxicities. Various factors have been implicated in the length of post-AHCT cytopenias including stem cell dose, marrow microenvironment, and clonal hematopoiesis. We hypothesize that the length of post-transplant anemia, neutropenia, and thrombocytopenia may negatively impact hospital length-of-stay (LOS) and in-hospital complications.
This is a single-center observational study of MM patients who underwent AHCT. Patients were part of a larger cohort with detailed single nucleotide polymorphism (SNP) array cytogenetic data. Exclusion criteria were concurrent amyloidosis and tandem transplant. Demographic data, comorbidities, cytogenetic features (presence of TP53 deletion, and translocation status of MMSET, CCDN3, CCDN1, MAF, and MAFB), therapy line, peri-transplant laboratory values, and clinical outcome were collected retrospectively. LOS was calculated from transplant day -2 to hospital discharge. Predictive factors for LOS were calculated with multiple linear regression. Multiple logistic regression was then used to calculate associating factors for in-hospital complications. Grade III and IV post-transplant cardiovascular, infectious, and hematological complications were collected following the Common Terminology Criteria for Adverse Events (CTCAE). Post-transplant anemia was defined as sustained hemoglobin (Hb) <8 g/dL despite transfusions. The cutoffs for neutropenia and thrombocytopenia were absolute neutrophil count (ANC) <1.5 K/uL, and platelet (PLT) count <50 K/uL, respectively.
158 AHCT cases of MM patients were identified. 95 patients received AHCT as frontline treatment, 35 patients were transplanted in the salvage setting, and 14 patients received both frontline and subsequent-line transplant. The most commonly used conditioning regimen was melphalan 200 mg/m2 in 123 cases, followed by melphalan 140 mg/m2 in 23 patients. 50.6% (80/158) developed grade III anemia with a median onset of 9 days after transplant (IQR 5-11 days) and median length of 2 days (IQR 1-6 days). Neutropenia had higher incidence of 96.8% (153/158) with an earlier onset of 5 days (IQR 5-6 days) and median length of 5 days (IQR 2-7 days). Grade III thrombocytopenia occurred in 98.1% (155/158), with median onset of 7 days (IQR 5-7 days) and a median duration of 8 days (IQR 6-10 days). When comparing patients who received frontline transplant vs subsequent line transplants, no statistical significance was observed between onset or length of cytopenias (p=0.40). Median LOS was 16 days (IQR 15-19 days). The most frequent post-AHCT complications in our cohort were neutropenic fever (N=27), followed by engraftment syndrome (N=12), pneumonia (N=4), urinary tract infection (N=2), cellulitis (N=2), and bacteremia (N=1). Cardiovascular events were uncommon (N=3) and included pericarditis, new onset atrial fibrillation, and new onset supraventricular tachycardia. Pulmonary embolism (N=1) and deep vein thrombosis (N=3) were recorded. No major bleeding was observed. Longer LOS was independently associated with post-AHCT anemia (p=0.03) and thrombocytopenia (p=0.0005). Notably, LOS and in-hospital complication rates were not significantly associated with demographic data, pre-existing comorbidities, pre-transplant cytopenias, or cytogenetic abnormalities.
In our cohort, longer duration of post-transplant anemia and thrombocytopenia were statistically associated with longer hospital LOS, but not with post-transplant complications. Prospective validation in an independent cohort is warranted.
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Landgren:Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Merck: Other; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding. Chung:Genentech: Research Funding.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
INTRODUCTION: Multiple myeloma (MM) evolution is shaped by the acquisition and selection of distinct genomic events over time. While various temporal patterns have been identified, the precise ...chronological order in which key clonal genomic defining events are acquired, and their specific impact on clinical outcomes remain to be fully elucidated. METHODS: To decipher the genomic life history of MM and its impact on clinical outcomes, we interrogated the high coverage (80X) whole genome sequencing (WGS) of 378 MM patients. Overall, 319 and 59 WGS were generated from samples collected at diagnosis and at relapse, respectively. Newly diagnosed MM (NDMM) patients were treated upfront with proteosome inhibitors, lenalidomide, dexamethasone, +/- monoclonal antibodies. To estimate the relative and absolute temporal relationship among clonal events, we leveraged the molecular time approach, based on the corrected ratio between duplicated and non-duplicated single nucleotide variants (SNV). RESULTS: Overall, 300/378 (79%) patients had at least one large chromosomal gain defined as >1Mb with >50 clonal SNV eligible for molecular time analysis, for a total of 1493 events tested. Consistent with recent findings, using clock-like mutational signatures SBS1-SBS5, we estimated that the first gain in MM is typically acquired around the second or third decade of life, with a median time lag of approximately 33 years between acquisition and diagnosis. In 158/178 (89%) of hyperdiploid (HRD) patients, all trisomies of odd-numbered chromosomes were acquired simultaneously. Among patients with canonical IGH translocations and HRD, the molecular time when trisomies were acquired was usually late compared to HRD without canonical IGH translocations (p<0.0001). Next, we examined the temporal relationship between IGH canonical translocations and gains linked to the same IGH canonical translocation in 29 patients. We consistently observed that when IGH canonical translocations co-occurred with HRD (n=7), and/or 1q gain (n=8) in the same patient, the canonical IGH translocation was always found to be the initiating event, occurring earlier than the chromosomal gains. Interestingly, in 104/178 (58.4%) HRD patients, the earliest multi-gain event was not always restricted to odd chromosomes, but in involved other non-HRD chromosomes such as: 6p (n=43) and 1q (n=32), demonstrating that gain 1q, which is assumed to occur at progression, can also be acquired very early in disease life history. A total of 92 and 21 patients with 1q gain and 1q amp (>3 copies) were identified, respectively. In 14/21 (66%) with 1q amp, the first and second 1q extra copies were acquired in two distinct and independent time windows. Interestingly, patients with early 1q gain showed the same clinical outcomes as 1q amp, and inferior progression free survival outcomes compared to late 1q gain (p=0.01; Figure 1). In 18/21 1q amp the first 1q duplication was acquired early, suggesting that the adverse prognostic effect of 1q gain/amp in NDMM may be more dependent on the timing of its acquisition rather than the number of extra copies gained. To investigate late temporal patterns and differentiate selection versus acquisition of large gains at relapse after autologous stem cell transplant (ASCT), we interrogated 25/59 (42%) RRMM patients exposed to melphalan with detectable SBS-MM1. To establish the temporal order of events, we employed the melphalan mutational signature, SBS-MM1, as a unique temporal barcode (Diamond et al. Blood 2023). Overall, we observed that 21% of all loss of heterozygosity (LOH) events and 15% of all gains were acquired after ASCT (i.e., SBS-MM1 mutations were only detectable in the pre-gain/duplicated SNV). Notably, among these events, 1q gain was acquired after ASCT in 3/4 patients, indicating that the acquisition of 1q gain can occur even after administration of first-line therapy. CONCLUSIONS: In our study, we have uncovered distinct temporal patterns in the acquisition of early genomic drivers in MM. These patterns contribute to the reconstruction and better understanding of the life history of MM and may hold potential clinical and prognostic implications.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Chimeric antigen receptor T cells (CAR T) or bispecific T cell engagers (TCE) targeting multiple myeloma (MM) antigens result in deep responses in relapsed patients. Nevertheless, resistance ...invariably emerges requiring salvage treatments. Sequential therapies with CAR T or TCE, in patients with or without prior anti-BCMA therapy exposure, reported durable responses. However the genomic and molecular determinants of response to sequential immunotherapies are poorly defined. To define the molecular determinants of response to sequential immunotherapies we identified patients treated with more than one anti-BCMA or -GPRC5D (n=8) regimens. Bone marrow (BM) and peripheral blood (PB) mononuclear cells from these patients were collected prior to each therapy and at the time of progression. Sorted CD138+ cells were subjected to whole genome sequencing (WGS) or single cell CNV (scCNV) and single cell RNA (scRNA) analysis. CD3+ T cells were subjected to CITEseq and functional in vitro cytotoxicity assays. Patient 1 received anti-BCMA CAR T (Ide-cel) with VGPR lasting 7 months (mos) (Figure 1). He subsequently received elranatamab with no response. CITEseq profiling of T cells at progression post CAR T did not reveal expansion of exhausted cytotoxic or regulatory T cells. However, WGS and scCNV of MM cells identified biallelic TNFRSF17 deletion consistent with antigenic escape as cause of resistance. Patient 2 received Ide-cel (DOR = 3.5 mos) followed by elranatamab with no response. CD138+ MM cells retained BCMA expression and in vitro studies with in-house manufactured anti-BCMA CAR T efficiently eliminated his MM cells. Profiling of T cells showed terminal T cells exhaustion (CD45RA +, TOX +, TIGIT +, PDCD1 + and LAG3 +). In contrast to recipients of CAR T, antigenic loss was commonly observed post TCE therapy. Patient 3 received 3 sequential therapies with Ide-cel (DOR = 3 mos), teclistamab (DOR = 6 mos), and then talquetamab with daratumumab with an ongoing response of 11 mos. While T cell exhaustion was not observed, functional loss of BCMA on MM cells was detected post teclistamab, with 2 coexisting clones harboring TNFRSF17 extracellular domain mutations (p.Pro34del, or p.Ser30del) that abrogated teclistamab binding. Similarly in patient 4 progressing on elranatamab (DOR = 21 mos), there was no evidence of T cell exhaustion but rather acquired BCMA mutation (p.Pro34del) in MM cells. Consistent with fit T cells profile, he has an ongoing response (13+ mos) to talquetamab and daratumumab in his next line of therapy. Patient 5 with penta-refractory disease and high disease burden (> 90% BM infiltration) had no response to elranatamab, however achieved an ongoing sCR (DOR = 30 mos) with talquetamab, daratumumab and pomalidomide (Tal-DP). PB T cells did not show exhaustion at the time of progression on elranatamab. A similar pattern was observed in patient 6 with high disease burden and no response to teclistamab but achieved lasting VGPR to Tal-DP (DOR=24 mos) in the next line followed by an acquired biallelic loss of GPRC5D at progression. Patient 7 had a 17 mos remission to talquetamab and daratumumab and similarly to patient 6, he acquired biallelic loss of GPRC5D at progression. He subsequently received elranatamab with no response with elevated serum soluble BCMA (sBCMA=638 ng/ml) level and phenotypic and functional evidence of T cell exhaustion. Patients 5, 6 and 7 illustrate the impact of disease burden and the ensuing sBCMA sink effect on the efficacy of anti-BCMA TCEs. Lastly patient 8 had lasting remissions to elranatamab (DOR 13 mos) and subsequently to talquetamab (DOR 13 mos) with no evidence of T cells exhaustion but rather antigenic escape with acquired functional antigenic losses with clonal BCMA (p.Arg27Pro) and subsequently GPRC5D (p.Asp239Asn) mutation. Highlighting the lack of cross resistance between anti-BCMA therapies, our in vitro studies showed that while mutant BCMA (p.Ser30del or p.Pro34del) abrogated teclistamab mediated T cell killing, T cells transduced with teclistamab based scFv CAR retained cytolytic activity. Therefore, TCE resistance derived from BCMA mutations does not preclude retreatment with another anti-BCMA TCE or CAR T. We here describe variable non-overlapping mechanisms mediating resistance to sequential TCE and CAR T therapies. Dynamic surveillance for antigenic escape and functional evaluation of T cell fitness will optimize immunotherapy sequencing.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
INTRODUCTION: Anti-CD38 monoclonal antibody (MoAb)-based treatment (e.g. daratumumab), especially when used in combination, have significantly improved the outcomes in patients with multiple myeloma ...(MM). However, despite the good results with this combination, a notable fraction of patients inevitably experiences relapse. METHODS: To characterize the genomic and immune microenvironment factors associated with resistance to daratumumab, lenalidomide and dexamethasone (dara-Rd), we integrated whole genome sequencing (WGS) and flowcytometry data generated from a longitudinally cohort (N=32) of relapsed/refractory MM (RRMM) patients (NCT03848676). WGS was performed in 28 patients, with 6 patients having samples collected before treatment and at the time of progression. To explore the impact of pretreatment bone marrow (BM) and peripheral blood (PB) immune composition, samples from both compartments were captured at baseline for each patient and investigated by flowcytometry (N=64). Additionally, to characterize the dara-Rd-induced immune modulation over time, flowcytometry was used to profile PB samples collected every 3 months after treatment start until progression for each patient (N=170). This project was funded and supported by Associazione Italiana per la Ricerca sul Cancro (AIRC IG 20541). RESULTS: Single base substitutions (SBS) signature APOBEC (SBS2 and SBS13), and SBS18 (oxygen radical stress) were significantly associated with shorter progression free survival (PFS; p=0.047, p=0.03 respectively). Furthermore, shorter PFS was also observed in patients harboring del1p22.1 ( RPL5, p=0.031), del17p13.1 ( TP53, p=0.015), del16p13.3 ( CREBBP, p=0.034) and del10p15.3 (p=0.006). Of note, all patients with TP53 deleted progressed. Moreover, 6/7 of patients with structural variants involving MYC progressed (p=0.00016). Chromothripsis was detected in 10/28 (36%) patients, with 7 experiencing early progression (p=0.05). Reconstructing the genomic evolution between baseline and progression, patterns of branching evolution were observed in all 6 patients, without any recurrent genomic events positively selected or acquired at relapse. The BM and PB immune cell composition at baseline showed high concordance (p<0.001). In both PB and BM baseline samples, patients that progressed were characterized by higher levels of exhausted T cells (T cytotoxic TIM3+), lower presence of T helper cells, and higher proportion of CD38+ NK cells compared to the progressors (p<0.05). Investigating dynamic PB immune changes during treatment with dara-Rd; we detected a significant depletion and CD38+ down-modulation of NK cells (p<0.0001). This observation combined with the impact of NK cells at baseline reflects a scenario where dara bind both myeloma cells and NK cells, promoting NK fratricide, potentially limiting the immune activity against the myeloma cells. In line with this model, proliferative NK cells were characterized by a higher expansion at 3 months compared to cytotoxic NK cells (p<0.0001), in particular among non-progressed patients (p=0.046). Similar to NK cells, CD38+ T regs drastically decreased (p=0.003) between baseline and 3 months. Finally, our immune longitudinal analysis revealed relevant findings such as enrichment of exhausted T helper and T cytotoxic cells, as well as T regs and granulocytic myeloid-derived suppressor cells (MDSC) in progressive patients (p<0.05). By integrating WGS and flowcytometry data we were able to define associations between unfavorable genomic features and immune environment patterns. Specifically, patients with high APOBEC contribution and MYC SV were characterized by increased T cell exhaustion (T helper and T cytotoxic TIM3+ cells; p<0.05). MYC SV were also associated with a low number of naïve and central memory T cells (p=0.018, p=0.048). Furthermore, patients with del_1p22.1 exhibited a low number of T regs CD38+ and a high presence of monocyte-MDSC (p<0.05). Finally, low numbers of cytotoxic NK cells at baseline were observed among patients with any of the high-risk genomic feature listed above (p=0.009). CONCLUSION: Overall our data revealed that the MM resistance and progression to dara-Rd in RRMM patients is driven by a complex interplay between high genomic complexity and an immune-exhausted microenvironment.
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B cell maturation antigen (BCMA) targeting chimeric antigen receptor T cells (CAR T) and bispecific T cell engagers (TCE) have remarkable efficacy in multiple myeloma (MM). While BCMA antigen escape, ...driven by TNFRSF17 deletions or mutations, is a mediator of anti-BCMA CAR T/ TCE resistance, the majority of patients retain BCMA surface expression at progression. Furthermore, patients with high disease burden and extramedullary disease associated with poorer response to anti-BCMA therapies, have high levels of soluble BCMA (sBCMA). The mechanisms mediating this resistance, and in particular the contribution of sBCMA, have not been fully elucidated. In order to assess the effect of sBCMA on anti-BCMA CAR T function, we measured CAR T cells activation with an in-house manufactured anti-BCMA CAR transduced with an NFAT-GFP reporter gene after co-culture with increasing concentrations of sBCMA (0-2500 ng/mL). sBCMA bound to CAR scFv in a dose dependent manner, effectively competing with the fluorophore tagged BCMA peptide binding. Despite their stable engagement, sBCMA failed to induce the expression of GFP, CD69, CD25, or 41BB on CAR T cells. To further examine the functional effect of sBCMA on CAR T cytotoxicity, we generated isogenic OPM2 cell lines with distinct BCMA expression profiles: OPM2 over-expressing BCMA (OPM2_BCMA high) generated by lentiviral transduction of TNFRSF17, and Cas9 BCMA knockout OPM2 (OPM2_BCMA -/-). OPM2_BCMA high cells exhibited one-log-fold increase in surface BCMA expression and 10-fold increase in sBCMA and were more resistant to CAR T mediated lysis. In addition, in co-culture assays, elevated sBCMA impaired OPM2 target cell lysis by anti-BCMA CAR T in a dose dependent-manner. To gain insight into the effect of chronic sBCMA exposure on CAR T, we exposed anti-BCMA CAR T to OPM2 cells secretome in the absence of direct cell to cell contact in a trans-well co-culture system. On day 24, CAR T in co-culture with OPM2_BCMA high (sBCMA levels of 2343 ng/mL) significantly contracted with no viable cells, while CAR T in culture with parental OPM2 (sBCMA level of 267 ng/mL) did persist with up-regulated TIM3 and TIGIT. In contrast CAR T cultured with OPM2_BCMA -/- remained viable with no expression of exhaustion markers. In examining the impact of sBCMA on TCE activity, sBCMA level as low as 50 ng/mL in vitro impaired anti-BCMA TCE binding to K562 cells transduced to stably express BCMA (K562_wtBCMA) . Consistent results were found in cytotoxicity assays wherein the addition of 2 ng/mL of sBCMA was sufficient to induce a reduction in anti-BCMA TCE mediated cytotoxicity of K562_wtBCMA cells by healthy donor peripheral blood mononuclear cells. To identify genomic events that lead to elevated sBCMA expression and subsequent resistance to CAR T/TCE, we conducted bulk whole genome sequencing (100X) on CD138+ bone marrow MM cells obtained from 40 MM patients treated with anti-BCMA CAR T/ TCE. Structural variants (SVs) at or adjacent to TNFRSF17 locus were identified in four patients. These included i) focal copy number gain of TNFRSF17 (3 copies) in a patient who progressed within 3 months post anti-BCMA TCE, ii) subclonal duplication of TNFRSF17 locus in another patient (n=1), as well as iii) focal copy number losses 5‘ or 3‘ to the TNFRSF17 gene locus (n=2). In addition to SVs affecting TNFRSF17 locus, we also identified mutations involving TNFRSF17 transcriptional regulators. Notably, MM clones at progression 4 months post anti-BCMA TCE (n=1) harboured copy number gains (3 copies) of POU2AF1 gene on chr11q23. POU2AF1 encodes a key transcriptional regulator of TNFRSF17 expression. Indeed, sBCMA level from this patient was significantly elevated at relapse at a level (638 ng/mL) correlated with resistance to anti-BCMA TCE. In addition, we identified translocation involving MAP3K14 encoding the NF-kB regulator NIK in a patient with short remission post anti-BCMA CAR T. Of interest, analysis of the CoMMpass dataset revealed significantly higher BCMA transcripts in patients with translocations involving MAP3K14 locus. Our findings highlight the impact of sBCMA levels and its chronicity of exposure on anti-BCMA TCE and CAR T activities in MM. We further identified structural genomic events driving TNFRSF17 over-expression and their correlation to sBCMA levels facilitating tumoral immunotherapeutic escape.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years.
To decipher and predict the molecular and ...clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data.
Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p,
loss,
translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited.
Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.
Objectives
The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM).
Methods
We ...identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26 627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis.
Results
The cumulative melphalan exposure was significantly higher (OR = 2.8, 95% CI 1.7‐5.2; P < .001) among cases (median 988 mg; IQR 644‐1640) compared with controls (median 578 mg; IQR 360‐967). Median time to AML/MDS development was 3.8 years (IQR 2.8‐5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy.
Conclusion
In this nationwide population‐based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long‐term risks.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
