scholarly journals Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis

2020 ◽  
Vol 20 (1) ◽  
pp. e30-e37 ◽  
Author(s):  
Hervé Avet-Loiseau ◽  
Heinz Ludwig ◽  
Ola Landgren ◽  
Bruno Paiva ◽  
Chris Morris ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Disease Status ◽  
Surrogate Endpoint ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Minimal Residual

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.

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma

2021 ◽  
Author(s):  
Luciano J. Costa ◽  
Saurabh Chhabra ◽  
Eva Medvedova ◽  
Bhagirathbhai R. Dholaria ◽  
Timothy M. Schmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Progression Free Survival ◽  
High Rate ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
Disease Response ◽  
Minimal Residual

PURPOSE The MASTER trial combined daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) in newly diagnosed multiple myeloma (NDMM), using minimal residual disease (MRD) by next-generation sequencing (NGS) to inform the use and duration of Dara-KRd post-autologous hematopoietic cell transplantation (AHCT) and treatment cessation in patients with two consecutive MRD-negative assessments. METHODS This multicenter, single-arm, phase II trial enrolled patients with NDMM with planed enrichment for high-risk cytogenetic abnormalities (HRCAs). Patients received Dara-KRd induction, AHCT, and Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS at the end of induction, post-AHCT, and every four cycles (maximum of eight cycles) of consolidation. Primary end point was achievement of MRD negativity (< 10–5). Patients with two consecutive MRD-negative assessments entered treatment-free MRD surveillance. RESULTS Among 123 participants, 43% had none, 37% had 1, and 20% had 2+ HRCA. Median age was 60 years (range, 36-79 years), and 96% had MRD trackable by NGS. Median follow-up was 25.1 months. Overall, 80% of patients reached MRD negativity (78%, 82%, and 79% for patients with 0, 1, and 2+ HRCA, respectively), 66% reached MRD < 10–6, and 71% reached two consecutive MRD-negative assessments during therapy, entering treatment-free surveillance. Two-year progression-free survival was 87% (91%, 97%, and 58% for patients with 0, 1, and 2+ HRCA, respectively). Cumulative incidence of MRD resurgence or progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2+ HRCA, respectively. Most common serious adverse events were pneumonia (6%) and venous thromboembolism (3%). CONCLUSION Dara-KRd, AHCT, and MRD response-adapted consolidation leads to high rate of MRD negativity in NDMM. For patients with 0 or 1 HRCA, this strategy creates the opportunity of MRD surveillance as an alternative to indefinite maintenance.

Minimal Residual Disease in Multiple Myeloma Patients: Influence on Indicators of Progression Free Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5705-5705
Author(s):  
Andrei Garifullin ◽  
Sergei Voloshin ◽  
Irina Martynkevich ◽  
Alexey Kuvshinov ◽  
Elizaveta Kleina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Negative Group ◽  
Free Survival ◽  
Positive Group ◽  
Genetic Abnormalities ◽  
Minimal Residual

Abstract Background. Induction, consolidation of response and maintenance therapy are very effective approaches in the treatment of patients with multiple myeloma (MM). However, the majority of patients will inevitably relapse despite achieving progressively higher complete response (CR) rates. Activation of residual clonal plasmatic cells is a cause of relapse disease. Therefore, the assessment of minimal residual disease (MRD) is a strong prognostic factor for progression-free survival (PFS). Aim. To estimate influence of MRD on PFS indicators in MM patients. Methods. We analyzed 28 patients with MM (median age 56 years, male/female - 1.8:1). 5-color flow cytometry was used for immunophenotyping of bone morrow cells as well as definition of primary tumor cells phenotype and detection of MRD. Such markers as CD38, CD138, CD45, CD19, CD20, CD27, CD56 and CD117 were used to identify clonal plasma cells. In addition, MRD was assessed by FISH analysis in patients with genetic abnormalities; CT-PET carried out to patients with the MRD-negative CR. Results. Patients had bortezomib- or lenalidomide-based programs of therapy. Autologous stem cell transplantation (ASCT) was carried out in 18 patients. Performing ASCT statistically significantly increased frequency of MRD-negative CR (p<.01). Before ASCT MRD-negative CR was reached in 3/28 (10,7%) patients. After ASCT 9/18 (50,0%) patients were transferred to the MRD-negative group (6/9 patients before ASCT had MRD-positive CR, 1/9 - MRD status did not change, 2/9 - stringent CR was reached). One patient with MRD-negative CR had CT-PET positive specific lesions. 19/28 (67,8%) patients were transferred to the MRD-positive group (9/19 patients had CR, 5/19 - VGPR, 5/19 - PR). The median PFS didn't correlate with ASCT in general and the MRD-positive groups (р>.05). PFS in the MRD-negative group was better than in the MRD-positive group with CR (median was not reached vs median of 63.9 months, respectively; 2-year PFS was 100% vs 77%, respectively) (p=.0048). In addition, we analyzed the influence of CR in the MRD-positive group on PFS. Absence of CR is an inferior prognostic factor and is characterized by decrease of PFS in patients with MRD-positive status. The median PFS in the MRD-positive group with CR was 63.9 months and 26.0 months in the MRD-positive group without CR (VGPR and PR) (p=.049). Genetic abnormalities were detected in 7/26 (26.9%) patients before antimyeloma therapy: t(11;14) - in 5/26 (19.2%), del(13q) - in 3/26 (11.5%), t(4;14) - in 1/26 (3.8%), del(1p) - in 1/26 (3.8%). After treatment patients with CR (MRD-positive and MRD-negative) had normal genetic status by FISH. Only 1/7 patients with MRD-positive PR had residual clone with del(13q). Conclusion . Performing ASCT influences frequency of MRD-negative CR. The PFS indicators (median and 2-year PFS) were higher in the group of MM patients, who had MRD-negative status of the disease compared to than in the MRD-positive group. The FISH method had low sensitivity in detection of residual clone with genetic abnormalities, especially in patients with CR. Disclosures Shuvaev: BMS: Honoraria; Pfizer: Honoraria; Novartis pharma: Honoraria.

scholarly journals Sustained Minimal Residual Disease Negativity With Daratumumab in Newly Diagnosed Multiple Myeloma: MAIA and ALCYONE

Blood ◽  
2021 ◽  
Author(s):  
Jesus F. San-Miguel ◽  
Hervé Avet-Loiseau ◽  
Bruno Paiva ◽  
Shaji K Kumar ◽  
Meletios A A Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Pooled Analysis ◽  
Response To Therapy ◽  
Newly Diagnosed ◽  
Intent To Treat ◽  
Minimal Residual

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone; D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone; D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better, and after ≥CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving ≥CR. In MAIA, (D-Rd, n=368; Rd, n=369), and ALCYONE (D-VMP, n=350; VMP, n=356), the median duration of follow-up was 36.4 months and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS versus control groups. In a pooled analysis, patients who were MRD negative had improved PFS versus patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. ClinicalTrials.gov identifier NCT02252172 (MAIA); NCT02195479 (ALCYONE).

scholarly journals Minimal Residual Disease in Multiple Myeloma: State of the Art and Future Perspectives

2020 ◽  
Vol 9 (7) ◽  
pp. 2142 ◽  
Author(s):  
Roberto Mina ◽  
Stefania Oliva ◽  
Mario Boccadoro
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Complete Response ◽  
Therapeutic Decisions ◽  
Patient Prognosis ◽  
Definition Of ◽  
Minimal Residual

Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure the response obtained with therapies for multiple myeloma (MM). The achievement of MRD negativity has superseded the conventional complete response (CR) and has been proposed as a surrogate endpoint for progression-free survival and overall survival. Several techniques are available for the detection of MRD inside (next-generation sequencing, flow cytometry) and outside (PET/CT, magnetic resonance) the bone marrow, and their complementary use allows a precise definition of the efficacy of anti-myeloma treatments. This review summarizes MRD data and results from previous clinical trials, highlights open issues related to the role of MRD in MM and discusses how MRD could be implemented in clinical practice to inform on patient prognosis and drive therapeutic decisions.

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]

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