High-risk Cytogenetic Aberrations Research Articles

Identification of Clinical-Biological Features of Newly Diagnosed Early Relapse Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation

Despite many therapeutics advances, Multiple Myeloma (MM) remains an incurable hematological malignancy with a cohort of patients who relapse early or does not respond to first-line therapy, including autologous stem cell transplantation (ASCT). The proportion of patients with early relapse is stable over time at about 30% and they have a median Overall Survival (OS) less than 3 years. Consequently, clinical and/or biological features that identify patient at high risk for early relapse at diagnosis represent a critical unmet medical need. With the aim of identify possible factors of early relapse (ER), we conducted a retrospective, observational, single center study on a cohort of 74 MM patients who received an upfront ASCT between 2011 and 2021 after a novel agent-based induction at the Hematological and BMT Unit of the University Hospital of Parma (Italy). The primary end point of the study was the assessment of possible predictive markers for ER, defined as progressive disease that occurred within 18 months from the time of ASCT. Clinical, biochemical and cytogenetics features of the cohort of MM patients were evaluated (Table 1). Definitions of response and progression were used according to the International Myeloma Working Group (IMWG) response criteria. All statistical analyses were done by SPSS Statistics. The characteristics of cohorts were summarized using the median value for continuous variates and the frequency for categorical ones. The Pearson chi-square test and Student t-test were used to identify differences between groups for categorical and continuous variables, respectively. Kaplan-Meier Curve with log-rank test were used to analyze survival data. The bivariate logistic analysis was conducted to recognize independent factors predicting ER, subsequently Cox regression analysis was performed to confirm the validity of multivariate analysis for survival data. The cohort characteristics were summarized in table 1. Among the 74 MM patients included in the study, a total of 19 patients (25.5) experienced ER, with mean time to relapse of 15.6 (18.0) months. Univariate statistical analysis identified as possible predictive markers for early relapse at diagnosis: IgA MM (p < 0.05), elevated serum LDH level (p < 0.05), C-CRAB criteria (p < 0.05), high risk cytogenetic aberrations (p < 0.05), stage R-ISS III (p < 0.001) and stage R2-ISS III or IV (p < 0.001). Multivariate statistical analysis confirmed IgA isotype (p < 0.05) and higher stage according to R2-ISS (p < 0.001) as effectively independent predictive risk factors for ER. Time-to-event analysis displayed a mean progression free survival (PFS) from transplant of 24.7 (16.0) months and 32.5 (19.0) months for those with IgA MM and stage R2-ISS III or IV, respectively. In the group of patients with IgA isotype the mean OS from transplant was 49.5 (30.0) months, while the mean OS from diagnosis was 58.0 (35.0) months without statistically significant differences compared to counterpart. In the group of patients with stage R2-ISS III or IV the mean OS from transplant was 48.2 (41.0) months, while the mean OS from diagnosis was 56.5 (49.0) months. Finally, in ER cohort the mean OS from diagnosis was 47.1 (35.0) in comparison with the 75.0 (71.0) months of non-ER cohort. In conclusion, this retrospective study was able to identify the main features of newly diagnosed early relapsed MM patients eligible to ASCT identifying the IgA isotype and the R2-ISS score system as the main predictive prognostic factors for early relapse in this cohort of patients.

How Much Have Post-Transplant Outcomes Improved Since 2000 for Older Patients with Acute Myeloid Leukemia? a Study from the EBMT Acute Leukemia Working Party

Acute myeloid leukemia (AML) is a disease of older patients with a median age at diagnosis of 68 years. Patients older than 65 years historically have performed poorly as not being treated with intensive chemotherapy. Biological age is not the only culprit as other factors also play a role in reducing survival, such as performance status, the presence of comorbid conditions, and most importantly the biology of AML that is usually associated with high risk cytogenetic or molecular aberrations. Despite the increasing use of targeted therapies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an important and potentially curative treatment modality for patients with AML. Over time, significant progress in allo-HCT has resulted in decreased non-relapse mortality (NRM) and allowed the delivery of allo-HCT to older patients. However, little information is available about the global impact of the current standard of care for older AML patients after allo-HCT and about the predictive factors for post-transplant outcomes. To address these challenges, we assessed real-world changes over time in transplant characteristics and post-transplant outcomes in older patients with AML (> 65 years), using a large dataset from the European Society for Blood and Marrow Transplantation registry. We identified 7215 adult patients (40% female; median age 68 years, range 65-80) with AML (secondary AML in 25%) allografted between 2000 and 2021 from a matched sibling donor (MSD; 23%), unrelated donor (UD; 63%) or haploidentical donor (Haplo; 14%). Karyotype risk was intermediate in 71% and adverse in 25%. NPM1 mutation and FLT3 ITD were present in 37% and 30% of patients, respectively.At transplant, 64% of patients were in first complete remission (CR1), 14% in CR2+ and 22% had active disease. Comorbidity index was zero in 43% of patients, 1-2 in 26% and >3 in 31%, while the Karnofsky score was <90 in 35%. Conditioning was reduced intensity (RIC) in 82% of patients. In vivo T cell depletion (TCD) and peripheral blood stem cells (PBSCs) were given to 62% and 93% of patients, respectively. Median follow up calculated by reverse Kaplan Meier was 40 months (interquartile range [IQR] 38-42). We compared changes in patient and transplant characteristics over time in 728 (10%) patients transplanted in 2000-2009, 1775 (25%) patients transplanted in 2010-2014, and 4712 (65%) patients transplanted in 2015-2021. Patients transplanted in recent years (65%) were older, were more likely to be in CR1 and to have an adverse-risk karyotype. Patients transplanted more recently were less likely to have had an MSD but more likely to have had a Haplo, PBSCs and TCD. The 3-year cumulative incidence of relapse (CIR) gradually and significantly decreased from 37% to 31%, then to 30% over the 3 time periods (p=0.001) whereas NRM significantly decreased from 31% and 31% to 27% (p=0.003). The 2-year leukemia free survival (LFS) and overall survival (OS) gradually and significantly improved over time from 32% to 38%, and then to 44% (p=0.001) and from 37% to 42%, and then to 49% (p=0.001), respectively, whereas graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) improved from 22% to 29%, and then to 34% (p=0.001). In a Cox regression multivariate analysis (MVA), a significant reduction in CIR and increased LFS, OS and GRFS were noted after 2015. LFS, OS and GRFS were also negatively affected by secondary AML, low Karnofsky score, active disease at transplant, and adverse-risk cytogenetics. GRFS was also negatively affected by older age, and positively affected by TCD. RIC positively affected OS whereas PBSCs positively affected LFS and OS. This improvement of post-transplant outcomes over time was observed for patients in CR1 with LFS and OS increasing from 39% to 44% and then to 47% (p=0.005) and from 43% to 48%, and then to 52% (p=0.006) as well as for patients in CR2 with LFS and OS increasing from 29% to 40% and then to 47% (p=0.001) and from 37% to 44% and then to 52% (p= 0.001), respectively. In conclusion, in older patients with AML, we observed an impressive improvement over time in post-transplant outcomes with decreased CIR and improved LFS, OS and GRFS. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option.

Is t(11;14)(q13;q32) good or bad for newly diagnosed multiple myeloma?

Is t(11;14)(q13;q32) good or bad for newly diagnosed multiple myeloma?

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).

Treatment of double-refractory multiple myeloma

In most publications on relapsed and refractory multiple myeloma, the term double-refractory refers to the loss of response to lenalidomide and proteasome inhibitors. The prognosis in the case of double-refractory multiple myeloma is poor. Usually, these are severely pretreated patients who have accumulated drug toxicity after 2 or more lines of therapy, with limited reserves of bone marrow hematopoiesis and often decompensated comorbidities. A partial solution to the problem was to use certain new drugs that have demonstrated activity as monotherapy or in combination with dexamethasone in this group of patients. This review is aimed to provide a critical review of recent clinical studies addressing this issue. According to the recent European Hematology Association and European Society for Medical Oncology (EHA-ESMO) 2021 guidelines for the diagnosis and treatment of double-refractory multiple myeloma, triple combinations should be considered, including monoclonal antibodies (elotuzumab (Elo), isatuximab (Isa), daratumumab (Dara)), dexamethasone and pomalidomide (Elo-­Pd, Isa-­Pd, Dara-­Pd) or carfilzomib (Isa-Kd, Dara-Kd). In Russia, as of March 2021, the first two regimens were approved (Elo-­Pd, Isa-­Pd). Elotuzumab was tested in combination with pomalidomide in the randomized phase II ELOQUENT-3 trial (Elo-­Pd vs. Pd; n = 177). Median progression-free survival was 10.3 months on Elo-­Pd vs. 4.7 months on Pd (hazard ratio 0.54; 95 % confidence interval 0.34–0.86; р = 0.008). Elo-­Pd superiority was observed in all subgroups, including patients with double-refractory MM, high-risk cytogenetic aberrations del17p, t(4;14), t(14;16), and increased serum LDH. The Isa-­Pd triplet was approved in the randomized phase III ICARIA-MM study (Isa-­Pd vs. Pd; n = 307). The median progression-free survival in this protocol was 11.5 months in the Isa-­Pd group vs. 6.5 months in the Pd group (hazard ratio 0.596; 95 % confidence interval 0.44–0.81; р = 0.001). Isa-­Pd triplet superiority was demonstrated in all unfavorable prognostic subgroups, including lenalidomide-refractory patients, patients with high-risk cytogenetics, and doublerefractory patients. New triplets with monoclonal antibodies represent an important option for the treatment of doublerefractory multiple myeloma.

Clinical Characteristics and Outcomes of Myeloma Patients Exhibiting Translocation (14;16): An Ultra-High-Risk Group of Myeloma Patients

BackgroundImportant advancements in anti-myeloma treatments resulted in significant survival benefits for myeloma patients. While the patients presenting with standard risk cytogenetics have enjoyed these advantages, the outcome of patients exhibiting high-risk cytogenetic abnormalities remains poor. According to IMWG, high risk cytogenetics are defined as the presence of del17p, t(4;14) and t(14;16). The first two abnormalities occur in an appreciable number if patients and have been analyzed in several studies. However, the subgroup of patients harboring t (14;16) has not been well described due to its low incidence, and some prior studies have questioned its prognostic value. We have embarked on describing the clinical presentation and the prognostication of myeloma patients exhibiting t(14;16)MethodsWe performed an IRB-approved outcome analysis of myeloma patients with t(14;16) from the Winship Cancer Institute (WCI) at Emory University, USA and Department of Clinical Therapeutics , National and Kapodistrian University (NKU) of Athens, Greece. The cohort for this analysis consisted of myeloma patients diagnosed with symptomatic myeloma from February 2008 until March 2017. Descriptive information of clinical characteristics and outcomes were analyzed.ResultsIn total 47 patients (29 patients from the WCI and 18 patients from NKU) were included in this analysis. The median age at diagnosis was 64 years (range 37-82), 57% had anemia (hemoglobin < 10 gr/dl), 19% had platelets counts <100x109/L, 35% had hypercalcemia (corrected serum calcium ≥11 mg/dl), 31% had serum creatinine ≥2 mg/dl and 32% had elevated LDH (≥ Upper limit of normal) and per ISS stage, 49% were stage 3. Other cytogenetic abnormalities were also present including del17p in 27%, amp1q21 in 55%, del13q in 67%; importantly in 6% a t(4;14) and in 5% a t(11;14) was also present. Post-induction 81% achieved ≥PR (30% sCR/CR, 28% VGPR and 23% PR) ;44% of the patients received ASCT1 in 1st remission, 21% received post-ASCT consolidation and 48% received maintenance after induction or intensification and the best response for all patients was sCR/CR in 43%, VGPR in 23% and PR in 17%. The use of a PI+IMiD combination was associated with higher and deeper response rates (≥VGPR in 68% vs 43%, p=0.025). After a median follow up of 29 months, the PFS1 was 20 months for the entire cohort and the estimated median OS is 46 months.In univariate analysis, factors associated with poor PFS1 included age >65 years (p=0.024), the presence of amp1q21 (p=0.017), but not of other abnormalities while use of PI+IMiD combination (p=0.043), ASCT at 1st remission (P<0.001) and the use of maintenance therapy after induction (P=0.007) were associated with longer PFS1. In multivariate analysis for PFS1, transplant in 1st remission (HR 3.93, 95% CI1.43-10.83, p=0.008) and maintenance (HR 2.4. 95% CI 0.97-5.95, p=0.059) were identified as independent prognostic factors. Interestingly, among the 13 patients that progressed at WCI, 5 patients progressed as extramedullary relapses (3 with CNS involvement). The aggressiveness of the disease relapses precluded further treatments and most patients at time of death were naïve to a multitude of anti-myeloma therapies. Regarding OS, in univariate analysis, the presence of hypercalcemia at diagnosis (p=0.001) and elevated LDH (p=0.004) were associated with poor OS, while, the presence of additional cytogenetic abnormalities (del17p, or del13q or amp1q21) was not associated with survival in this population of patients with t(14;16).ConclusionThis analysis highlights the poor prognosis of myeloma patients harboring the t (14;16) chromosomal abnormality. Such patients commonly present with poor prognostic features, including hypercalcemia, elevated LDH, increased creatinine, ISS-3 disease and also have increased frequency of other high risk cytogenetic aberrations such as del13q, amp1q21 in more than 50% of patients and del17p in 25% of patients. The use of PI+IMiD regimens probably helps with obtaining deeper responses. The inferior median PFS1 and OS seen in the modern day cohorts and the inability to use the novel regimens in the later course of the disease due to disease aggressiveness prompts us to use active regimens upfront, which can aid in preventing relapse. DisclosuresNooka:Amgen, Novartis, Spectrum, Adaptive tecnologies: Consultancy. Kastritis:Takeda: Honoraria; Amgen: Research Funding; Genesis: Honoraria; Janssen: Honoraria, Research Funding. Kaufman:Amgen, Novartis: Research Funding; Amgen, Roche, BMS, Seattle Genetics, Sutro Biopharma, Pharmacyclics: Consultancy. Boise:Abbvie: Consultancy; Eli Lilly and Company: Research Funding. Terpos:Amgen: Honoraria, Other: SC member, Research Funding; GSK: Honoraria; Janssen: Honoraria, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Abbvie: Honoraria; Takeda: Honoraria, Other: SC member; BMS: Honoraria. Dimopoulos:Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology.

Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma

Cell surface expression levels of GPRC5D, an orphan G protein–coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM.

Asian Population Is More Prone to Develop High-Risk Myelodysplastic Syndrome, Concordantly with Their Propensity to Exhibit High-Risk Cytogenetic Aberrations.

Simple SummaryThe world population is genetically and environmentally diverse. In particular, genetic differences related to an ethnic factor may underlie differences in cancer phenotypic expression. Therefore, we compared the epidemiology, and the clinical, biological and genetic characteristics of myelodysplastic syndrome (MDS) between Asian and Western countries. Our results show substantial differences in the incidence and age of onset between Asian and Western MDS patients. A higher proportion of Asian MDS patients fall into the high- and very-high risk prognostic MDS groups. This finding is supported by the identification of a higher proportion of high-risk cytogenetic aberrations in Asian MDS patients. However, the survival rate is similar for Western and Asian MDS patients. Our findings may impact the clinical management as well as the strategy of clinical trials targeting those genetic aberrations and mutations depending on the world area where they are run.This study explores the hypothesis that genetic differences related to an ethnic factor may underlie differences in phenotypic expression of myelodysplastic syndrome (MDS). First, to identify clear ethnic differences, we systematically compared the epidemiology, and the clinical, biological and genetic characteristics of MDS between Asian and Western countries over the last 20 years. Asian MDS cases show a 2- to 4-fold lower incidence and a 10-year younger age of onset compared to the Western cases. A higher proportion of Western MDS patients fall into the very low- and low-risk categories while the intermediate, high and very high-risk groups are more represented in Asian MDS patients according to the Revised International Prognostic Scoring System. Next, we investigated whether differences in prognostic risk scores could find their origin in differential cytogenetic profiles. We found that 5q deletion (del(5q)) aberrations and mutations in TET2, SF3B1, SRSF2 and IDH1/2 are more frequently reported in Western MDS patients while trisomy 8, del(20q), U2AF1 and ETV6 mutations are more frequent in Asian MDS patients. Treatment approaches differ between Western and Asian countries owing to the above discrepancies, but the overall survival rate within each prognostic group is similar for Western and Asian MDS patients. Altogether, our study highlights greater risk MDS in Asians supported by their cytogenetic profile.

The Prognostic Impact of Dynamic Changes of Genetic Risk Stratification in Multiple Myeloma

Purpose: Most data on the prognostic impact of cytogenetic abnormalities come from the setting of newly diagnosed multiple myeloma, it remains unclear whether the dynamic changes of cytogenetic aberrations affect the prognostic evaluation in multiple myeloma. Methods: We analyzed the prognostic impact of dynamic changes of cytogenetic abnormalities with a cohort consisting of 80 paired patients with consecutive cytogenetic data both at diagnosis and recurrence among 568 patients with newly diagnosed multiple myeloma. Results : Three patterns of recurrence were established from 80 paired patients: Pattern A (40%) consisted of 32 patients without new cytogenetic abnormalities at the time of progression. Pattern B (15%) consisted of 12 patients harboring new standard risk (SR) cytogenetic aberrations. Pattern C (45%) consisted of 36 patients with new high-risk (HR) cytogenetic abnormalities. The median overall survival (mOS; P &amp;lt;0.001) and median progression-free survival (mPFS; P =0.013) differed significantly among three patterns. Four groups including 60 paired patients were further established according to genetic risk stratification changes. There were 15 patients who kept SR in group 1 (25%); 12 SR patients who evolved into HR group in group 2 (20%); 17 HR patients without new HR cytogenetic abnormalities in group 3 (28%); and 16 HR patients harboring new HR cytogenetic aberrations in group 4 (27%). The mOS (P=0.001) also differed significantly among these four groups. Conclusions: Dynamic cytogenetic changes significantly affected prognostic evaluation in multiple myeloma. Patients harboring new HR cytogenetic abnormalities and escalated genetic risk stratification at relapse had worse outcomes. Figure 1 Disclosures Anderson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Higher Expression of Nuclear Cereblon in Bone Marrow Biopsies of Patients with Multiple Myeloma Treated with Imids in the HOVON-87/Nmsg-18 Trial Is Associated with Longer PFS and OS

Introduction Response to treatment in patients with multiple myeloma (MM) is variable. With increasing possibilities of treatment regimens, predictive factors for response are important. Immune modulating agents (IMiDs) require Cereblon (CRBN) for activity. Therefore, the aim of this study was to identify the genes involved in the CRBN pathway which predict the response to therapy with IMiDs. Methods Paraffin embedded bone marrow (BM) biopsies were used from newly diagnosed patients included in HOVON-87/NMSG-18 trial obtained at inclusion. In this trial, elderly patients with MM were randomized between treatment with Melphalan-Prednisone (MP)-Thalidomide (MPT) followed by thalidomide maintenance versus MP-Lenalidomide (MPR) followed by lenalidomide maintenance (Zweegman et al. Blood 2016;127:1109-1116). BM biopsies were stained with a fully automated dual color, bright-field immunohistochemical assay for CRBN, its neosubstrates Ikaros and Aiolos and the downstream targets IRF4 and c-MYC. CD138 was used to identify MM plasma cells in the BM samples. For CRBN, both nuclear and cytoplasmic staining was evaluated. The distribution and intensity of the immunostaining was assessed using the H-score. The H-scores were calculated using the following formula: [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)] and range from 0-300 (0-600 for combined cytoplasmic-nuclear CRBN H-score). For the Cox regression analysis H-scores were corrected by dividing these by a factor 100: hazard rates were considered per 100 points increase of the H-score. Protein levels of the CRBN pathway were compared between patients with complete response (CR) or very good partial response (VGPR) vs partial response (PR) and no change/progressive disease (NC/PD). High-risk cytogenetic aberrations (FISH) were defined as having deletion of 17p, and/or translocation t(4;14) and/or t(14;16). Statistical analysis was done using univariate and multivariate Cox regression analysis for progression free survival (PFS) and overall survival (OS), and the Mann-Whitney test for comparing response groups. Kaplan-Meier survival curves were generated to illustrate survival. Results BM samples obtained at diagnosis from 149 patients were evaluated. Seventy-one patients were treated in the thalidomide arm vs 78 patients in the lenalidomide arm. Median age was 73 years [range 60-90]. Revised ISS stages I/II/III were 12%/80%/8% respectively. At the time of analysis, median follow up of the 45 patients still alive was 83 months [range 23 - 114 months]. Best response on protocol treatment was sCR/CR in 22%, VGPR in 30%, PR in 36% and NC/PD in 12%. Protein expression across the response groups showed higher nuclear CRBN in patients who responded better (sCR/CR/VGPR; median H-score: 178 (49-273)) compared to patients with a worse response (PR/NC/PD; median H-score: 157 (67-251)), albeit not statistically significant (Mann-Whitney p-value=0.06). Higher H-score of nuclear staining of CRBN was associated with a longer PFS and OS, with a hazard ratio (HR) of 0.52 for PFS (95% confidence interval (CI)=0.37-0.86, p&lt;0.001) and a HR of 0.56 for OS (95% CI=0.36-0.78; p&lt;0.01). Patients with the top quartile nuclear CRBN levels had a median PFS of 21 months longer compared to patients with the lowest quartile (38 months vs 17 months). In terms of OS, patients with the highest quartile nuclear CRBN expression demonstrated a median survival that was 2 times as high as found in patients with the lowest quartile (75 months vs 35 months; Figure 1). In addition, cytoplasmic staining of CRBN was associated with improved PFS (HR = 0.66 (95% CI=0.47-0.94; p=0.02), but not with OS (HR = 0.73 (CI=0.48-1.11); p=0.14). None of the other markers were associated with survival. In a multivariate analysis (which included study arm (MPT vs MPR), nuclear CRBN, high-risk cytogenetic aberrations and R-ISS), nuclear CRBN remained independently associated with OS as well as R-ISS and study arm. For PFS, only nuclear CRBN remained statistically significant after backward selection. Despite treatment arm being a statistically significant term in the multivariate Cox model for OS, no relation was found for treatment arm and nuclear CRBN, in terms of OS. Conclusions In this study we demonstrate that higher expression of nuclear CRBN in myeloma cells in BM of patients with MM was associated with a superior PFS and OS. Disclosures Couto: Celgene Corporation: Employment, Equity Ownership, Patents &amp; Royalties. Ren:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding.

Multiple high-risk cytogenetic aberrations confer a progressively negative impact on survivals of newly diagnosed myeloma patients

Cytogenetic aberration detected by fluorescence in situ hybridization is one of the most important prognostic factors for multiple myeloma (MM). Identifying patients with high risk aberrations (HRA) is critical for initial risk stratification as well as follow-up treatment. Although specific HRA has been well discussed, cumulative impact of multiple HRA is still unclear.

Nelfinavir and lenalidomide/dexamethasone in patients with lenalidomide-refractory multiple myeloma. A phase I/II Trial (SAKK 39/10)

The antiretroviral agent nelfinavir has antimyeloma activity and can overcome resistance to bortezomib. Our phase I/II trial investigated whether adding nelfinavir to lenalidomide–dexamethasone can overcome lenalidomide resistance in lenalidomide-refractory multiple myeloma (MM). Twenty-nine patients were included (high-risk cytogenetic aberrations 31%; ≥2 prior therapy lines 93%; lenalidomide–bortezomib double-refractory 34%). Twenty-four patients (83%) had prior bortezomib and 10 (34%) were lenalidomide–bortezomib double-refractory. They received four cycles of nelfinavir 2500 mg/day with standard-dose lenalidomide (25 mg days 1–21) and dexamethasone (40/20 mg days 1, 8, 15, 22). Minor response or better was achieved in 16 patients (55%; 95% CI 36–74%), including 40% of those who were lenalidomide–bortezomib double-refractory, and partial response or better in nine patients (31%; 95% CI 15–51%). Median progression-free survival was 3.4 (95% CI 2.0–4.9) months and median overall survival 21.6 (13.0–50.1) months. Lenalidomide-related pneumonitis, pneumonia, and neutropenic fever occurred, but there were no unexpected adverse events. Peripheral blood mononuclear cells showed a 45% (95% CI 40–51%) reduction in total proteasome activity from baseline and significant induction of unfolded protein response and autophagy. Thus, nelfinavir–lenalidomide–dexamethasone is an active oral combination in lenalidomide-refractory MM.

PS1431 IDENTIFICATION OF THE TRUE HYPERDIPLOID MULTIPLE MYELOMA SUBSET BY COMBINING CONVENTIONAL KARYOTYPING AND FISH ANALYSIS

Background:Prognostic evaluation of Multiple Myeloma (MM) by FISH is focused on high risk (HR) cytogenetic aberrations, namely t(4;14), t(14;16) and deletion of 17p13. Hyperdiploid MM (HRD‐MM), instead, that accounts for about 50% of newly diagnosed MM, is not routinely investigated because multiple probes are required to test over the conventional markers. However, in the era of novel agents, the identification of hyperdiploidy may be helpful in MM prognostication since trisomic MM is responsive to lenalidomide treatment and retains a favourable outcome.Aims:The aim of our study was to elaborate a flow chart of FISH prognostic assessment of MM that, beside the analysis of conventional high risk abnormalities, allows to identify those cases with favourable prognosis within hyperdiploid MM.Methods:Bone marrow of 292 patients affected by newly diagnosed MM was studied by conventional karyotype (CK) and on separated plasmacells by FISH for HR cytogenetic aberrations including t(4;14), t(14;16), 17p13 deletion and 1q21 gain. Patient's characteristics including ISS stage, symptoms at diagnosis, type of treatment and OS were collected.Results:Among our entire cohort, CK was productive in 76 patients and based on the number of chromosome of clone (47–57 chromosomes) 50 patients (66%) were classified as hyperdiploid. All patients received treatment with novel agents, including bortezomib (99%), lenalidomide (70%) or both (70%).Of note, cytogenetic classification of HRD‐MM, beyond the definition of ploidy, includes a heterogeneous group characterized not only by numerical abnormalities, but also by several structural aberrations. Therefore, even the ploidy level was not enough to characterize hyperdiploid MM. As a matter of fact, within HRD‐MM patients, high risk chromosomal changes were detected in 26/50 (52%) cases, including 21 (42%) with gain 1q, one with t(4;14) and 8 (16%) with 17p deletion. Finally, 20 (40%) patients displayed an IgH translocation. Major features associated to decreased OS were trisomy 19 (32 vs 62 months, p = 0.0194), gain 1q (30 vs 56 months, p = 0.0371), and IgH translocations (33 vs 57 months, p = 0.0285) (Figure 1A to C).Provided that definition of HRD‐MM is based on trisomies of odd chromosomes, we further classified our patients according to the number of trisomies in cases with &gt; 5 trisomies (trisomic HRD‐MM, T‐HRD‐MM) and cases with &lt;5 trisomies (non trisomic HRD‐MM, N‐HRD‐MM). The group with &gt; 5 trisomies (n = 26) was characterized by lower rates of overall FISH alterations (&lt;2, 92% vs 31%, p = 0.0001). More in detail, lower frequencies of IgH translocations (23% vs 75%, p = 0.0014) and HR FISH changes (5% vs 50%, p = 0.0023) were detected. Even monosomy 13 was less represented in this subset of patients (15% vs 69%, p = 0.008) as compared to N‐HRD‐MM. Interestingly, concomitant trisomy of 9, 11 and 15 chromosomes was described in 53% of T‐HRD‐MM patients but it was completely absent in N‐HRD MM group (p = 0.0002), indicating that in our cohort these three numerical changes represent the most powerful signature to identify HRD MM. Finally, T‐HRD MM subset displayed better outcome towards N‐HRD MM (57 vs 32 months, p = 0.001, Figure 1D).Summary/Conclusion:In our cohort of patients the combination of banding analysis and FISH for HR aberrations identify some genetic features that correlate with the presence of true hyperdiploid clone. In fact, less than two FISH aberrations, absence of HR aberrations and IgH translocation and the concomitant presence of trisomies of chromosome 9, 11 and 15 identify the hyperdiploid MM subset characterized by a favourable outcome.image

Allogeneic stem cell transplantation using HLA-matched donors for acute myeloid leukemia with deletion 5q or monosomy 5: a study from the Acute Leukemia Working Party of the EBMT.

Deletion 5q or monosomy 5 (-5/5q-) in acute myeloid leukemia (AML) is a common high-risk feature that is referred to allogeneic stem cell transplantation. However, -5/5q- is frequently associated with other high-risk cytogenetic aberrations such as complex karyotype, monosomal karyotype, monosomy 7 (-7), or 17p abnormalities (abn (17p)), the significance of which is unknown. In order to address this question, we studied adult patients with AML harboring -5/5q- having their first allogeneic transplantation between 2000 and 2015. Five hundred and one patients with -5/5q- have been analyzed. Three hundred and thirty-eight patients (67%) were in first remission and 142 (28%) had an active disease at time of allogeneic transplantation. The 2-year probabilities of overall survival and leukemia-free survival were 27% and 20%, respectively. The 2-year probability of treatment-related mortality was 20%. We identified four different cytogenetic groups according to additional abnormalities with prognostic impact: -5/5q- without complex karyotype, monosomal karyotype or abn(17p), -5/5q- within a complex karyotype, -5/5q- within a monosomal karyotype and the combination of -5/5q- with abn(17p). In multivariate analysis, factors associated with worse overall survival and leukemia-free survival across the four groups were active disease, age, monosomal karyotype, and abn(17p). The presence of -5/5q- without monosomal karyotype or abn(17p) was associated with a significantly better survival rate while -5/5q- in conjunction with monosomal karyotype or abn(17p) translated into a worse outcome. The patients harboring the combination of -5/5q- with abn(17p) showed very limited benefit from allogeneic transplantation.

Lenalidomide and dexamethasone in treatment of patients with relapsed and refractory multiple myeloma - analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies.

Lenalidomide (LEN) is an immunomodulator with clinical activity against myeloma cells. Based on the pivotal phase 3 trials MM-009 and MM010, the combination of lenalidomide and dexamethasone(DEX) was approved for patients with multiple myeloma who received at least one prior therapy. Here, we evaluated LEN/DEX therapy in unselected population and subsequently in selected sub-groups of patients with relapsed/refractory multiple myeloma followed in the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. Altogether 858 patients were treated with LEN/DEX in the Czech Republic and Slovakia until end of 2017. The analyzed sub-groups were defined as patients with high risk cytogenetic aberrations and patients with relapsed and refractory MM. The overall response rate (ORR; partial remission or better response, PR) in the whole group of patients was 46.3% for all lines of therapy, 26.4% for high-risk group and 32.1% for relapsed and refractory group. Medians of overall survival (OS) in the same cohorts were as follows: 25.6, 15.7 and 18.5 months, progression free survival (PFS) was: 11.2, 6.4 and 9.0 months respectively. The most common adverse events were hematologic and infectious. In conclusion we found that our results correlated with those found in other studies in terms of response rates, survival measures, and also of treatment toxicity.

Salvage Autologous Transplant and Lenalidomide Maintenance Versus Continuous Lenalidomide/Dexamethasone for Relapsed Multiple Myeloma: Results of the Randomized GMMG Phase III Multicenter Trial Relapse

Salvage Autologous Transplant and Lenalidomide Maintenance Versus Continuous Lenalidomide/Dexamethasone for Relapsed Multiple Myeloma: Results of the Randomized GMMG Phase III Multicenter Trial Relapse

Rola daratumumabu w leczeniu chorych na nawrotowego i opornego szpiczaka plazmocytowego

Despite the significant progress achieved during last two decades, plasma cell myeloma (PCM) remains an incurable disease. The greatest challenge in clinical practice is the optimal treatment of the high-risk group of patients. Numerous clinical trials demonstrated that presence of high-risk cytogenetic aberrations, such as del17p, t(4;14), t(14;16) lub t(14;20), still negatively affects patients’ outcomes in the current era of modern anti-myeloma agents such as proteasome inhibitors (Pi) or immunomodulatory drugs (IMiD). Among other groups of patients with unfavorable prognosis are patients who are refractory to a PIs and IMiD and patients with relapsed disease who had received three or more prior lines of therapy. Improving treatment outcomes in these patients requires novel drugs with different mechanisms of action, which would be able to overcome resistance to standard therapy. In this context, daratumumab i elotuzumab — two novel monoclonal antibodies (MoAbs) directed against myeloma cell surface antigens are of great interest. Daratumumab, a first-in-class anti-CD38 MoAb, has shown significant clinical activity and acceptable toxicity profile in relapsed/refractory PCM, in monotherapy as well as in combination with PI or IMiD. In this review, we discuss the role of daratumumab in the treatment of PCM, with emphasis on the efficacy of this drug in the group of high-risk patients.

Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma

AbstractWe investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)–65/German-Speaking MM Group (GMMG)–HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial.

Efficacy and tolerability of the histone deacetylase inhibitor panobinostat in clinical practice.

The histone deacetylase inhibitor panobinostat has shown efficacy in phase-II and phase-III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n=24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67years (range 49-87) and the median number of prior therapies was 5 (range 2-17). Fourteen patients (58%) had high-risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression-free survival (PFS) and overall survival were 3.5 and 9.8months, respectively. Significant differences between bortezomib-sensitive and -refractory patients were observed. In bortezomib-sensitive patients, median PFS was 6.3months compared to 2.3months in bortezomib-refractory patients (P<.001). Median overall survival was not reached vs 4.8months (P=.046) in bortezomib-sensitive and bortezomib-refractory patients, respectively. The only patient refractory to carfilzomib but sensitive to bortezomib achieved very good partial remission and PFS of 6.3months, suggesting discrete mechanisms of resistance to different PIs. As expected, thrombocytopenia and fatigue/asthenia occurred in nearly all patients (96% and 83%, respectively). Diarrhea was observed in only 19% of patients which compares favorably with the high rates of diarrhea reported in the PANORAMA trials. With panobinostat dose reductions in 67% of patients, FVD was tolerated by the majority of patients. In conclusion, FVD showed efficacy in a heavily pretreated, high-risk multiple myeloma population with a high degree of patients refractory to novel agents including PIs.

Efficacy and Tolerability of the Histone-Deacetylase Inhibitor Panobinostat in Clinical Practice: a Single Center Experience

Efficacy and Tolerability of the Histone-Deacetylase Inhibitor Panobinostat in Clinical Practice: a Single Center Experience