Long-Term Follow-Up of the Gem2010 Trial of Bortezomib-Melphalan-Prednisone and Lenalidomide-Dexamethasone in Elderly, Newly Diagnosed Multiple Myeloma Patients: Impact of Age, High-Risk Cytogenetics and Minimal Residual Disease

2018 ◽  
Author(s):  
María-Victoria Mateos ◽  
Joaquín Martínez-López ◽  
Miguel-Teodoro Hernández ◽  
Enrique-M Ocio ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Long Term Follow Up ◽  
Minimal Residual

Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone (Dara-CVRd): Results of the UK optimum/MUKnine trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8001-8001
Author(s):  
Martin F. Kaiser ◽  
Andrew Hall ◽  
Katrina Walker ◽  
Ruth De Tute ◽  
Sadie Roberts ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Plasma Cell ◽  
Residual Disease ◽  
Cell Leukemia ◽  
Ultra High Risk ◽  
Grade 3 ◽  
Minimal Residual

8001 Background: Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts > 20%) were included in OPTIMUM across 39 UK hospitals. Patients received up to 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference. Results: Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention to treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. MRD status was 41% MRDneg, 40% MRDpos and 19% not evaluable post induction and 64% MRDneg, 14% MRDpos and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% TNR. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was 3.7%. Conclusions: This is to our knowledge the first report on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM. Clinical trial information: NCT03188172.

Eradication of Minimal Residual Disease with Alemtuzumab in Chronic Lymphocytic Leukemia Is Associated with Prolonged Survival and Is an Appropriate Theraputic Endpoint for Relapsed CLL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3114-3114 ◽  
Author(s):  
Hazem A. Sayala ◽  
Paul Moreton ◽  
Ben Kennedy ◽  
Guy Lucas ◽  
Michael Leach ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Median Survival ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
End Point ◽  
Long Term Follow Up ◽  
Minimal Residual

Abstract Eradication of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is emerging as a desirable therapeutic end point predicting for better outcome. The monoclonal antibody alemtuzumab (Mabcampath) is approved for patients with fludarabine refractory CLL. We previously published 91 patients with relapsed CLL (74 men and 17 women, median age 58 years [range, 32 to 75 years]; 44 fludarabine-refractory) who received a median of 9 weeks (range 1 to 16) of alemtuzumab, 30mg 3x a week after dose escalation, between 1996 and 2003. 84 patients had i.v. alemtuzumab and 7 received it subcutaneously. Responses to alemtuzumab according to NCI-WG criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 (19%) and no response (NR) in 42 (46%). Detectable CLL to a level of less than one CLL cell in 10,000 leucocytes, assessed by four-color MRD flow cytometry, was eradicated from the blood and marrow in 18 patients (20%). 8 of these 18 patients were fludarabine refractory. We report here the results of long term follow up of this cohort of patients after a median follow up of 77 months (range 5 to 123 months). Median survival was significantly longer in patients achieving MRD negative responses compared with those with detectable CLL at the end of therapy. The median survival for all 18 MRD negative responders has not been reached but was 87 months for the 8 fludarabine-refractory patients achieving MRD negativity. Overall survival for the 18 patients with MRD-negative remissions was 66% at 72 months (see Figure). MRD positive CR patients had a median survival of 56 months, MRD positive PR patients a median survival of 42 months and non-responders a median survival of 14 months. The median treatment-free interval prior to alemtuzumab for the 18 MRD negative patients was 8 months (range 4 to 35). Excluding planned stem cell transplantation performed in CR, the median time to next treatment for the 18 MRD negative patients was 114 months and 72% (13/18) have required no further therapy. Therefore alemtuzumab can induce MRD negative remissions in CLL resulting in a clear survival advantage with 66% of MRD negative patients alive 6 years after alemtuzumab. The markedly increased treatment-free survival and excellent survival for MRD negative patients strongly suggests that achieving an MRD negative remission is an appropriate therapeutic end-point in relapsed CLL. Figure Figure

Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8010-8010
Author(s):  
Noemi Puig ◽  
Bruno Paiva ◽  
Teresa Contreras ◽  
M. Teresa Cedena ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Prognostic Value ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Time Points ◽  
Minimal Residual

8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to <10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to <10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to <10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p<0,0001), 94% (p=0,034); post-ASCT 86% (p<0,0001), 90% (p=0,022); post-Cons 89% (p<0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

2021 ◽  
pp. JCO.21.01045
Author(s):  
Pieter Sonneveld ◽  
Meletios A. Dimopoulos ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Sara Aquino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Primary Study ◽  
Controlled Clinical Trial ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Minimal Residual

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Long Term Follow-up Data.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 846-846
Author(s):  
Vikram Mathews ◽  
Biju George ◽  
Kavitha M Lakshmi ◽  
Auro Viswabandya ◽  
Ezhilarasi Chendamarai ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Group ◽  
Single Agent ◽  
High Risk Group ◽  
Reproductive Age ◽  
Newly Diagnosed ◽  
Long Term Follow Up ◽  
Good Risk

Abstract Abstract 846 We had previously reported a well tolerated regimen using single agent arsenic trioxide (ATO) (Blood 2006:107; 2627) leading to durable remissions in patients with newly diagnosed acute promyelocytic leukemia (APL). Briefly, the regimen consisted of ATO (10mg/day for adults and 0.15mg/kg/day for pediatric patients) for up to 60 days in induction; this was followed by a 28 day consolidation after a 4 week break. Four weeks after completion of consolidation, patients received ATO for 10 days/month for 6 months. A concern with the previous report was the relatively short duration of follow up. Here we report the long term follow-up data of the same cohort. As previously reported, 72 newly diagnosed cases of APL were enrolled. 62 patients (86.1%) achieved hematological remission. The remaining died prior to achieving remission. There were no primary induction failures. Twenty two (30.6%) of these patients were considered good risk group (WBC count at diagnosis <5×109/L and a platelet count >20×109/L), the rest were considered high risk. Since publication of the last report an additional 7 patients have relapsed to give a total of 13 relapses, 2 were in the good risk group and the remaining 11 in the high risk group. The relapses in the good risk group were salvaged with an autologous SCT and have durable continued second remissions. The median time to relapse was 1.5 years. Five (38.52%) of these relapses occurred beyond 2 years and included both relapses in the good risk group. At a median follow-up of 58 months the 5-year Kaplan-Meier overall survival (OS), event free survival (EFS) and disease free survival (DFS) of the entire cohort was 74.22±5.26%, 68.93±5.52% and 80.00±5.17% respectively. The 5-year OS and EFS of the good risk and high risk group was 100±00% vs. 63.30±6.9% and 90.00±6.71% vs. 59.66±6.99% respectively. Beyond induction, all deaths followed relapse of disease. There were no second malignancies reported. Besides the previously reported toxicities, which were mild and transient in most cases, there were no new toxicities that were reported on continued follow up of these cases. Since completion of therapy, in spite of counseling and advising against pregnancy, 3 males and 4 females in the reproductive age group have had 8 normal children. No abortions, still births or fetal defects were reported among patients in the reproductive age group in this cohort. Hair and nail samples from 5 cases that had completed maintenance therapy more than 24 months earlier have been collected for analysis, the results of which are awaited. At our center the cost of administering this regimen is a quarter of that of a conventional ATRA plus anthracycline based regimen. Additionally, after the initial induction therapy the rest of the treatment did not require hospital admission nor did it result in any Grade III/IV hematological toxicity. Single agent ATO based regimen as reported previously is well tolerated, results in durable remissions and does not have any significant late side effects. In the good risk group it is associated with excellent clinical outcomes while in the high risk group additional interventions are probably required to reduce the risk of late relapses. In a resource constrained environment it is probably the best option. Disclosures: No relevant conflicts of interest to declare.

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