The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently ...examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (<10−6). Data were analyzed from a recent clinical trial that evaluated the role of transplantation in newly diagnosed myeloma patients treated with lenalidomide, bortezomib, and dexamethasone (RVD). MRD negativity was achieved at least once during maintenance in 127 patients (25%). At the start of maintenance therapy, MRD was a strong prognostic factor for both progression-free survival (adjusted hazard ratio, 0.22; 95% confidence interval, 0.15-0.34; P < .001) and overall survival (adjusted hazard ratio, 0.24; 95% confidence interval, 0.11-0.54; P = .001). Patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of treatment group (RVD vs transplant), cytogenetic risk profile, or International Staging System disease stage at diagnosis. These results were similar after completion of maintenance therapy. Our findings confirm the value of MRD status, as determined by NGS, as a prognostic biomarker in multiple myeloma, and suggest that this approach could be used to adapt treatment strategies in future clinical trials.
•MRD using NGS-identified patients with an excellent outcome in multiple myeloma.•MRD should be assessed in every prospective trial, and is a candidate to become a primary end point.
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The prognosis of multiple myeloma is mainly dependent upon chromosomal changes. The 2 major abnormalities driving poor outcome are del(17p) and t(4;14). However, the outcome of these high-risk ...patients is not absolutely uniform, with some patients presenting long survival. We hypothesized that these better outcomes might be related to concomitant “good-risk” chromosomal changes exploring hyperdiploidy. We analyzed a large series of 965 myeloma patients, including 168 patients with t(4;14) and 126 patients with del(17p), using high-throughput single-nucleotide polymorphism arrays after plasma cell sorting. As expected, trisomic chromosomes were highly associated. Using the LASSO model, we found that only chromosome 3, when trisomic, was associated with a longer progression-free survival and that 3 trisomies modulated overall survival (OS) in myeloma patients: trisomies 3 and 5 significantly improved OS, whereas trisomy 21 worsened OS. In patients with t(4;14), trisomies 3 and/or 5 seemed to overcome the poor prognosis. For the first time, using a specific modeling approach, we show that not all trisomies display the same prognostic impact. This finding could be important for routine assessment of prognosis in myeloma, and some high-risk patients with a traditional evaluation could in fact be standard-risk patients.
•In myeloma patients, trisomy 3 improved time to progression and trisomies 3 and/or 5 improved overall survival.•In contrast, trisomy 21 significantly worsened overall survival.
The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be ...determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).
•Combination of pomalidomide with dexamethasone is highly active and can salvage end stage myeloma refractory to lenalidomide and bortezomib.•Current data suggest pomalidomide 4 mg/day on days 1 to 21 per 28-days cycle with dexmethasone should be studied in future phase 3 trials.
Aims
In amyloid patients, cardiac involvement dramatically worsens functional capacity and prognosis. We sought to study how the cardiopulmonary exercise test (CPET) could help in functional ...assessment and risk stratification of patients with cardiac amyloidosis (CA).
Methods and results
We carried out a multicentre study including patients with light chain (AL) or transthyretin (TTR) CA. All patients underwent exhaustive examination including CPET and follow‐up. The primary prognostic endpoint was the occurrence of death or heart failure hospitalization. Overall, 150 patients were included (91 AL and 59 TTR CA). Median age, systolic blood pressure, N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) and cardiac troponin T were 70 (64–78) years, 121 interquartile range (IQR) 109–139 mmHg, 2806 (IQR 1218–4638) ng/L and 64 (IQR 33–120) ng/L, respectively. New York Heart Association classes were I–II in 64%. Median peak oxygen consumption (VO2) and circulatory power were low at 13.0 (10.0–16.9) mL/kg/min and 1730 (1318–2614) mmHg/mL/min, respectively. The minute ventilation/carbon dioxide production slope was increased to 37 (IQR 33–45). A total of 77 patients (51%) had chronotropic insufficiency. After a median follow‐up of 20 months, there were 37 deaths and 44 heart failure hospitalizations. At multivariate Cox analysis, peak VO2 ≤13 mL/kg/min hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.6–4.8, circulatory power ≤1730 mmHg/mL/min (HR 2.4, 95% CI 1.2–4.6) and NT‐proBNP ≥1800 ng/L (HR 2.2, 95% CI 1.1–4.3) were found to be associated with the primary outcome. No events occurred in patients with both peak VO2 >13 mL/kg/min and NT‐proBNP <1800 ng/L, while the association of VO2 ≤13 mL/kg/min with NT‐proBNP ≥1800 ng/L identified a very high‐risk subgroup.
Conclusion
In CA, CPET is helpful in assessing functional capacity, circulatory and chronotropic responses as well as the prognosis of patients along with cardiac biomarkers.
Peak oxygen consumption and circulatory power are strong prognostic factors in cardiac amyloidosis.
Refractory immune thrombocytopenia (ITP) was previously defined as lack of a minimum response to splenectomy and the requirement for long-term treatment to reduce the risk of significant bleeding ...events. In this multicenter study, we included 37 patients with multirefractory ITP, defined as no response to splenectomy, rituximab, romiplostim, and eltrombopag. As compared with a historical cohort of 183 ITP patients, matched on the calendar year of ITP diagnosis with a 5:1 ratio, patients with multirefractory ITP were more likely to have secondary ITP (odds ratio OR, 4.84; 95% confidence interval CI, 1.31-17.86; P = .018) and monoclonal gammopathy of undetermined significance (OR, 5.94; 95% CI, 1.08-32.48; P = .04). The median duration of ITP before being recognized as multirefractory was 78 months (range, 6-450). The patients showed failure of a median of 10.5 prior treatment lines for ITP (range, 6-15). At the end of follow-up (median, 84 months; range, 12-455), only 1/14 patients achieved response with immunosuppressant therapy alone. By contrast, 7/10 patients achieved response with a combination of immunosuppressant therapy and thrombopoietin-receptor agonists that lasted for a median of 15 months (range, 6-32). Throughout the course of ITP, 5/37 patients died, 3 with ITP (bleeding, n = 2; sepsis n = 1); 15 (40%) had at least 1 bacterial infection and 9 (24%) at least 1 episode of thrombosis. In conclusion, multirefractory ITP was associated with high morbidity and mortality. Combining an immunosuppressant therapy with thrombopoietin-receptor agonists may be a good strategy for management for these patients with severe disease.
•The baseline characteristics of multirefractory ITP differed from “typical” ITP, outcome was severe, and was associated with high morbidity and mortality.•Combining immunosuppressant therapy with a thrombopoietin-receptor agonist may be a relevant option for these patients.
Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been ...reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.
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.
•Pomalidomide-cyclophosphamide-dexamethasone in first relapse after exposure to lenalidomide and bortezomib is efficacious and safe.•Salvage pomalidomide-cyclophosphamide-dexamethasone can be a bridge for delayed autologous stem cell transplantation.
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