Prognostic value of minimal residual disease and polyclonal plasma cells in myeloma patients achieving a complete response to therapy.

The International Myeloma Working Group (IMWG) recently introduced the evaluation of minimal residual disease (MRD) within the multiple myeloma (MM) response criteria, and MRD negativity assessed inside and outside the bone marrow is currently considered the most powerful predictor of favorable long-term outcomes. However, MRD evaluation has thus far relied on flow-cytometry or molecular-based methods, despite the limitations associated with the patchy infiltration of bone marrow (BM) plasma cells and the presence of extra-medullary (EMD). On the contrary, imaging-based sensitive response assessment through the use of functional rather than morphological whole-body (WB) imaging techniques, such as positron emission tomography with computed tomography (PET/CT) and magnetic resonance imaging (MRI), likely is a promising strategy to overcome these limitations in evaluating response to therapy and in the assessment of the MRD status in MM patients. However, despite the significant advances in the development and availability of novel functional imaging techniques for MRD evaluation, a worldwide standardization of imaging criteria for acquisition, interpretation, and reporting is yet to be determined and will be object of future investigations.

Download Full-text

Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma

Blood ◽

10.1182/blood-2014-01-550020 ◽

2014 ◽

Vol 123 (20) ◽

pp. 3073-3079 ◽

Cited By ~ 249

Author(s):

Joaquin Martinez-Lopez ◽

Juan J. Lahuerta ◽

François Pepin ◽

Marcos González ◽

Santiago Barrio ◽

...

Keyword(s):

Multiple Myeloma ◽

Minimal Residual Disease ◽

Deep Sequencing ◽

Prognostic Value ◽

Residual Disease ◽

Complete Response ◽

Disease Detection ◽

Sequencing Method ◽

Key Points ◽

Minimal Residual

Key Points MRD assessment by sequencing is prognostic of TTP and OS in multiple myeloma patients. Among patients in complete response, MRD assessment by sequencing enables identification of 2 distinct subgroups with different TTP.

Download Full-text

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

Blood ◽

10.1182/blood.2020010439 ◽

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).

Download Full-text

Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽

10.1182/blood-2007-09-114082 ◽

2008 ◽

Vol 111 (6) ◽

pp. 2984-2990 ◽

Cited By ~ 33

Author(s):

Stella M. Davies ◽

Michael J. Borowitz ◽

Gary L. Rosner ◽

Kristin Ritz ◽

Meenakshi Devidas ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Response To Therapy ◽

Oncology Group ◽

Risk Status ◽

Prognostic Features ◽

Minimal Residual

Abstract Minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not known. We measured MRD by flow cytometry at day 8 (in blood) and at day 28 (in bone marrow) of induction therapy in more than 1000 children enrolled in Pediatric Oncology Group therapy protocols 9904, 9905, and 9906. We classified patients as “best risk” if they had cleared MRD by day 8 of therapy and as “worst risk” if they had MRD remaining in bone marrow at day 28, and tested whether MRD was related to polymorphisms in 16 loci in genes hypothesized to influence response to therapy in acute lymphoblastic leukemia (ALL). After adjusting for known prognostic features such as presence of the TEL-AML1 rearrangement, National Cancer Institute (NCI) risk status, ploidy, and race, the G allele of a common polymorphism in chemokine receptor 5 (CCR5) was associated with more favorable MRD status than the A allele (P = .009, logistic regression), when comparing “best” and “worst” risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy.

Download Full-text

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.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8010 ◽

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]

Download Full-text

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.21.01045 ◽

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.

Download Full-text

Prognostic impact of incomplete hematologic count recovery and minimal residual disease on outcome in adult acute lymphoblastic leukemia at the time of second complete response

Leukemia & Lymphoma ◽

10.1080/10428194.2017.1344842 ◽

2017 ◽

Vol 59 (2) ◽

pp. 363-371 ◽

Cited By ~ 2

Author(s):

Caner Saygin ◽

Nikolaos Papadantonakis ◽

Ryan D. Cassaday ◽

Michaela Liedtke ◽

Katrina Fischer ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Complete Response ◽

Prognostic Impact ◽

Adult Acute Lymphoblastic Leukemia ◽

Minimal Residual ◽

Count Recovery

Download Full-text

Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma

Blood ◽

10.1182/blood.2019000241 ◽

2019 ◽

Vol 134 (16) ◽

pp. 1337-1345 ◽

Cited By ~ 34

Author(s):

Laura Rosiñol ◽

Albert Oriol ◽

Rafael Rios ◽

Anna Sureda ◽

María Jesús Blanchard ◽

...

Keyword(s):

Multiple Myeloma ◽

Minimal Residual Disease ◽

Induction Therapy ◽

Residual Disease ◽

Complete Response ◽

Autologous Transplant ◽

Key Points ◽

Minimal Residual

Key PointsVRD was effective and well tolerated before ASCT; 33.4% complete response/28.8% minimal residual disease–negative after 6 induction cycles. Responses deepened with VRD throughout induction and over the course of treatment with few discontinuations due to toxicity.

Download Full-text