Erratum: A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control

Abstract Abstract 3949 Although in MM an optimal response to front-line therapy is a surrogate for extended survival, two class of patients fall outside this paradigm: those that after treatment show unsustained complete remission (CR) and those that not achieving CR, return into an MGUS-like signature and experience nevertheless long term disease control (LTDC). The prospective identification of the later group remains to be accomplished. Herein, we hypothesized that whole BM immunophenotypic profiling by multiparameter flow cytometry (MFC) would help to identify upfront, symptomatic MM patients with an occult MGUS-like signature (from here on named MGUS-like-MM). For this purpose, the relative frequency of plasma cells (plus the balance between clonal and normal PC), precursor and mature B-cells, T- and NK-cells, erythroblasts, monocytes, neutrophils and eosinophils was determined in 698 newly diagnosed, transplant eligible MM patients included in two consecutive GEM/PETHEMA trials: GEM2000 (VBMCP/VBAD; n=486) and GEM2005<65y (randomized induction with the same chemotherapy plus bortezomib in the last two cycles or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; n=212). In addition, we extended this analysis to 114 high-risk smoldering MM patients included in the Quiredex trial. Median follow-up was 63 months for symptomatic MM patients. Unsupervised hierarchical cluster analysis was used on the log2 transformed values of the 11 variables described above. Whole BM immunophenotypic profiling identified a cluster of 176 (25%) symptomatic MM patients “assigned as MGUS-like-MM” based on the following phenotypic features: significantly decreased median numbers of myelomatous PC together with a significant increment of eosinophils, neutrophils, monocytes, T- and NK -cells, mature B-cells and particularly normal PC. This subgroup was characterized by a favorable clinical presentation with increased (P<.005) frequency of ISS stage I or II (88%), high baseline hemoglobin (116 g/L) and albumin (3.8 g/dL) values. MGUS-like-MM patients showed an increased frequency of hyperdiploid DNA content (63%; P=.001) and a lower incidence of t(4;14) (3%; P=.05). When compared to the overall population, MGUS-like-MM patients showed a markedly superior median TTP (88 vs 40 months; P<.001) and OS (141 vs 61 months; P<.001). Moreover, the MGUS-like signature was a strong predictor for LTDC, with 16% of these patients being disease-free at 10 years as compared to 3.5% in the overall MM population (P<.001). Interestingly, while the depth of response achieved after HDT/ASCT translated into superior TTP (P=.032) and OS (P=.005) in the overall population, MGUS-like-MM patients failing to achieve CR showed non significantly different median TTP (80m vs 105m; P=.167) and OS (not reached vs 141m; P=.438) as compared to those attaining CR, respectively. Finally, it should be pointed out that this MGUS-like signature was not restricted to symptomatic MM, since we have also found a subset of high-risk smoldering MM patients with the same signature. These later patients showed a significantly lower risk of progression into symptomatic MM as compared to the rest of high-risk smoldering MM patients (data not shown). In summary, whole BM immunophenotypic profiling by MFC is capable to identify a subset of symptomatic MM patients with an occult MGUS-like signature associated with prolonged survival. Given that in this subgroup of patients the value of CR is not as important as in the rest of MM patients, the prospective identification of this signature may contribute to discriminate a sub-optimal response that require additional treatment from a residual “MGUS-like component” that may remain stable without further treatment. Disclosures: Paiva: Celgene: Honoraria; Miellenium: Honoraria; Janssen: Honoraria. Martínez-López:Celgene: Honoraria. Mateos:Celgene: Honoraria; Miellenium: Honoraria; Janssen: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Lahuerta:Celgene: Honoraria; Millenium: Honoraria. Blade:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria.

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Multidimensional Flow Cytometric (MFC) Analysis of the Immune System of Multiple Myeloma (MM) Patients Achieving Long Term Disease Control

Blood ◽

10.1182/blood.v118.21.810.810 ◽

2011 ◽

Vol 118 (21) ◽

pp. 810-810

Author(s):

Roberto J. Pessoa Magalhaes ◽

María-Belén Vidriales ◽

Bruno Paiva ◽

Maria-Victoria Mateos ◽

Norma C. Gutierrez ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

B Cells ◽

Disease Control ◽

B Cell ◽

Nk Cells ◽

Cell Populations ◽

High Dose ◽

Newly Diagnosed

Abstract Abstract 810FN2 Increasing evidence shows that a small fraction of MM patients (pts) treated with high-dose therapy followed by autologous stem cell transplantation achieve long-term remission. Interestingly, this is not restricted to pts in complete response (CR), since those that revert to a monoclonal gammopathy of undetermined significance (MGUS) profile may also achieve long-term remission, despite the persistence of residual myeloma plasma cells (PCs). These results suggest that in addition to the anti-myeloma therapy, other factors may play a role in the control of the disease. Herein, we used 8-color MFC for detailed characterization of the structural components of the immune system and hematopoietic precursor cells (HPC) in paired bone marrow (BM) and peripheral blood (PB) samples from 26 MM patients in long-term disease control (LTDC): 9 in continuous CR and 17 who reverted to an MGUS profile and that subsequently showed stable disease without treatment for ≥5 years (median of 9 years; range, 5–19). As controls, paired BM and PB samples from 23 newly-diagnosed MGUS and 16 MM pts, together with 10 healthy adults (HA), were studied in parallel. In all BM and PB samples the distribution of the major T- (CD4, CD8, Tregs and γδ), NK- (CD56dim and CD56bright) and B-cell subsets (Pro-B, Pre-B, naïve and memory), in addition to normal PCs, dendritic cell (DC) subsets (plasmacytoid, myeloid and monocytic), monocytes, and CD34+ HPC (myeloid and lymphoid), were studied. The percentage and absolute count of each cell population was analysed in the BM and PB, respectively. Comparison of the two groups of MM pts with LTDC (9 CR vs. 17 MGUS-like) showed similar (p>.05) cellular profiles in PB and BM, except for an increased number of BM and PB normal PCs in CR patients (P≤.04). Consequently, for all subsequent analyses, LTDC myeloma pts were pooled together. When compared to HA, patients with LTDC had increased numbers of CD8 T-cells and CD56dim NK-cells in both the BM and PB (p≤.03 and p≤.01, respectively). Despite this, the distribution of BM and PB CD4, CD8 and γδ T-cells among LTDC patients was similar (p>.05) to that of both newly-diagnosed MM and MGUS cases; in contrast, BM and PB Tregs were significantly decreased vs newly-diagnosed MM (P=.03) and MGUS (P=.04). Regarding B-cells and normal PCs, LTDC patients showed increased numbers of BM B-cell precursors (both Pro-B and Pre-B cells) and normal PCs vs. newly diagnosed MM (P≤.05), but not MGUS, together with increased numbers of naïve B-cells vs. both MM and MGUS pts (P≤.01); all such cell populations returned to levels similar (p>.05) to those of HA. As expected, this also included the number of CD34+ B-cell HPC which was increased among patients who achieved LTDC vs MM (p=.02), at levels similar (p>.05) to those of MGUS and HA. Regarding DC, LTDC patients showed normal DC numbers in PB (but with higher PB myeloid-DC numbers vs. MM; p=.02), in association with decreased numbers of plasmacytoid DC and increased monocytic-DC in the BM vs. HA (p≤.04). No differences were found for the numbers of BM and PB monocytes. In summary, here we investigated for the first time the immune cell profile of MM patients who achieve long-term disease control. Our results show that, as newly-diagnosed MM, patients that achieve long-term disease control also show increased numbers of cytotoxic T-cells and CD56dim NK-cells; however, in contrast to newly-diagnosed MM, among LTDC patients such increase is associated with lower numbers of T-regs and an almost complete recovery of the normal PC, B-cell precursor and naïve B-cell compartments both in BM and PB. Further investigations on the activation and functional status of these cell populations are warranted.MO (%)/SP (cels./μl)HA N= 10MGUS N= 23MM N= 16LTDC-MM N= 26T cells9.588110.6117313113711926 CD4+4.85004.6624^6*5085463 CD8+3.7∼216∼4.63865.32645.3431 TCR γδ.2426.3230.2428.3421 Treg.4137.4141^.54*38.3432NK cells.7∼87∼1.51982.11721.6212 CD56 dim.65∼79∼1.41922.21681.6202B cells2.81471.8104.97*68*1.9160 Pro B.11—.06—.02*—.07— Pre B.6—.4—.08—.23— Naive SP—80—57^—36*—118 Normal-PCS.18.9.11.7.008.72*.11.84DCs.3449.3653.6848.558 Monocytes2.22472.42853.43023.1315 m-DC SP—11—14—8*—12 MO-DC.11∼29.2036.434.2837 p-DC.2∼4.1.145.112.8.123.8CD34+.9∼1.46.61.1.261.4.431.4 Mie-HPC.8∼—.53—.26—.36— Linfo-HPC.1—.07—.03*—.05—*p≤.05 LTDC vs MM: ^ p≤.05 LTDC vs MGUS; ∼ p≤.05 LTDC vs HA Disclosures: Paiva: Jansen-Cillag: Honoraria; Celgene: Honoraria. Martinez:Janssen: Honoraria; Celgene: Honoraria. Maiolino:Centocor Ortho Biotech Research & Development: Research Funding.

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Bone Marrow Interaction in Multiple Myeloma Pathogenesis: Phenotypical Analysis, Kinetics and Novel Therapy Approaches Based On CXCR4 Inhibition.

Blood ◽

10.1182/blood.v120.21.2450.2450 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2450-2450

Author(s):

Johannes Waldschmidt ◽

Dagmar Wider ◽

Marie Follo ◽

Josefina Udi ◽

Martina Kleber ◽

...

Keyword(s):

Flow Cytometry ◽

Adhesion Molecules ◽

Cell Lines ◽

Cxcr4 Expression ◽

Cell Trafficking ◽

Newly Diagnosed ◽

Infiltration Rates ◽

Dependent Cell ◽

And Migration

Abstract Abstract 2450 Introduction: The interaction between malignant plasma cells and their microenvironment is central in multiple myeloma (MM) pathogenesis. Binding of MM cells to bone marrow (BM) stroma cells triggers the expression of adhesion molecules and secretion of chemo- and cytokines, promoting MM cell growth, drug resistance and migration. Stromal-derived factor-1 (SDF-1) and its receptor CXCR4 are essential for normal hematopoietic progenitor cell movement and adherence within the BM microenvironment. In leukemia and lymphoma, oncoproteins may inhibit SDF-1-dependent cell trafficking within the BM through a mechanism that is not fully understood. For that reason, understanding SDF-1-dependent cell trafficking within the BM and targeting MM-cell - host-BM interactions display a promising approach for the development of novel therapeutic strategies. Methods: BM samples of MM patients (n=59) were analysed using flow cytometry and compared to MGUS patients (n=3) and healthy volunteers (n=7). We compared patient samples with low BM infiltration (≤5%; n=13) intermediate (5–30%; n=29) and high infiltration rates (≥30%; n=17). We also assessed expression of adhesion molecules in MM patients with long-term disease control (n=20) vs. both newly diagnosed (n=16) and symptomatic MM patients (n=23) as previously grouped by San Miguel et al. (Haematologica July 6,2012). We also sought to elucidate in vitro, whether specific anti-MM agents (bortezomib, vorinostat, pomalidomide, EGCG), with and without M210B4 stroma support, and with and without the CXCR4 inhibitor AMD3100, target the interaction of MM cells. Experiments were performed using MM cell lines (U266, RPMI8226, L363, NCI-H929), the control T-cell line MOLT-4 and MM-patient BM samples. Cell viability was assessed via Trypan Blue- and AnnexinV/PI-staining. CD138, CXCR4 (SDF1-receptor), CD49d (VLA-4), CD11a (LFA-1) and CD44 (HERMES antigen) expression was evaluated by flow cytometry and ScanR microscopy. Results: In BM samples of MM patients as compared to MGUS and healthy volunteers, the CXCR4/CD138- (p=.036), CD49d/CD138- (p=.0013) and CD44/CD138-expression (p=.0072) was significantly amplified and correlated with increasing BM infiltration rates (p=.001). Both newly diagnosed and symptomatic MM patients confirmed significantly increased CXCR4/CD138-, CD49d/CD138- (p=.0013) and CD44/CD138-expression as compared to patients with long-term disease control. Of note, in newly diagnosed patients, the expression of adhesion molecules was even more enhanced than in symptomatic myeloma patients, underlining their critical and future potential role as targets for novel therapeutics. Comparison of MM cell lines' adhesion and migration markers with that of MM-patient BM specimens revealed U266 as the cell line most closely resembling human specimens. Cytotoxic effects with use of MM cell lines and bortezomib, vorinostat and pomalidomide confirmed prior cytotoxic concentrations. Cocultivation with stroma substantially reduced apoptosis and induced tumor protective effects. Additional AMD3100 treatment restored sensitivity to bortezomib, vorinostat and pomalidomide. CXCR4 expression was substantially reduced after AMD3100 treatment, while that of CD49d, CD44 and CD11a remained widely unchanged. Toxic or therapeutic effects of AMD3100 monotherapy were excluded for used doses of 50μM. Additional use of ScanR microscopy visualized co-localisation of CXCR4 expression both on the cell surface and within the cytoplasm of MM cells. ScanR microscopy results correlated with flow cytometry-determined CXCR4 expression. Ongoing analyses of both ScanR microscopy and flow cytometry will allow the detailed assessment of treatment studies with and without anti-MM agents and AMD3100. Conclusions: Our findings underline the critical role of adhesion and migration molecules in MM and may pave the way for novel therapeutic approaches targeting these microenvironmental mediators. Disclosures: No relevant conflicts of interest to declare.

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Analysis of Immunophenotypic Response (IR) by Multiparameter Flow Cytometry In 516 Myeloma Patients Included In Three Consecutive Spanish Trials

Blood ◽

10.1182/blood.v116.21.1910.1910 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1910-1910 ◽

Cited By ~ 2

Author(s):

Bruno Paiva ◽

María-Belén Vidriales ◽

María-Angeles Montalbán ◽

María-Victoria Mateos ◽

Laura Rosiñol ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Residual Disease ◽

Young Patients ◽

Novel Agents ◽

Multiparameter Flow Cytometry ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

The Impact

Abstract Abstract 1910 The outcome of multiple myeloma (MM) patients has markedly improved in the last decade. Thus, overall response rates between 85%-95%, with 30%-50% complete remission (CR) rates are now being reported in young patients treated with novel agents plus high-dose therapy/autologous stem cell transplantation (HDT/ASCT). A similar scenario is also emerging in the elderly (non-transplant candidates) population. Accordingly, more sensitive techniques are needed to assess patients’ response; these may contribute to compare the efficacy of different treatment schemas, to monitor minimal residual disease (MRD) and for prognostication. In the present study we have assessed the frequency and the prognostic value of IR by multiparameter flow cytometry in a total of 516 newly diagnosed MM patients included in three consecutive PETHEMA/GEM Spanish trials: two designed for transplant candidate patients - GEM 2000 (n=157) and GEM2005<65y (n=206) - and one for elderly patients - GEM2005>65y (n=153). The GEM2000 trial was based on 6 induction cycles of VBMCP/VBAD followed by HDT/ASCT; the GEM2005<65y included three arms with 6 cycles each (Thalidomide/Dexamethasone -TD-, Bortezomib/Thalidomide/Dexamethasone -VTD- and, VBMCP/VBAD with Bortezomib in the two final cycles -VBMCP/VBAD/Bortezomib) followed by HDT/ASCT; and the GEM2005>65y compared 6 cycles of Bortezomib/Melphalan/Prednisone -VMP- vs. Bortezomib/Thalidomide/Prednisone -VTP-. All three trials had in common that patients received 6 induction cycles and IR was evaluated at this time point. In addition, IR was assessed on day +100 after HDT/ASCT in the first two trials. Patients were defined to be in IR when myelomatous plasma cells (MM-PCs) were undetectable by MFC or when less than one phenotypically aberrant PC was detected among 104 cells analyzed. Patients were referred for MRD studies if they were mainly in CR or VGPR. The IR rates reported here were calculated on intention to treat analysis. Figure 1 summarizes the IR rates after induction. The lowest IR rates corresponded to the VBMCP/VBAD and TD schemes (5% and 6%, respectively) while with the bortezomib-based regimens an approximately 3-fold increment in the IR rates was observed: VTP (12%), VBMCP/VBAD/Bortezomib (15%), VMP (16%) and VTD (17%). After HDT/ASCT, IR rates were found to be significantly increased (p<.001) in the GEM2000 protocol (14%) and in all arms of the GEM2005<65y trial: TD (18%), VBMCP/VBAD/Bortezomib (30%) and VTD (34%). Thus, a minimum 2-fold increment of IR rates was further achieved after HDT/ASCT. In addition, IR rates achieved after HDT/ASCT in patients included in all three arms of the GEM2005<65y trial were significantly superior (p≤.008) to cases treated according to the GEM2000 protocol, indicating that induction regimens with novel agents improved post-transplantation rates of IR. Moreover, bortezomib-based regimens vs. TD were associated with increased IR rates not only before but also after HDT/ACSCT (p=.06 and p=.02 for VBMCP/VBAD/Bortezomib and VTD, respectively). We further compared the impact of achieving an IR after induction and at day+100 after HDT/ASCT in the progression-free (PFS) and overall survival (OS) within the three protocols. Patients in IR status after an induction regimen according to the GEM2000, GEM2005<65y and GEM2005>65y protocols showed significantly longer (p<.001) 3-year PFS rates (100%, 100% and 90%, respectively) compared to patients in a no-IR status (61%, 59% and 35%, respectively). Similarly, 3-year OS rates were significantly longer (p=.01) in IR vs. no-IR patients status (100%, 100% and 94% vs. 84%, 90% and 76% for the GEM2000, GEM2005<65y and GEM05>65y protocols, respectively). Likewise, an IR vs. no-IR status after HDT/ASCT in both the GEM2000 and GEM05<65y trials was also associated with significantly increased 3-year PFS (p<.001) and OS (p=.007) rates. In summary, this study demonstrates that the achievement of an IR is a strong prognostic factor regardless of the type of treatment; thus, higher IR rates may help to identify optimal therapeutical schemes. In this sense, HDT/ASCT is able to markedly increase IR rates after induction even in the era of novel agents, and this translates into extended survival. Disclosures: Off Label Use: VTP is not approved for the treatment of newly diagnosed myeloma patients and VT and VP are not approved for maintenance therapy. None of the combinations proposed, VBCMP/VBAD plus bortezomib, VT and VTD are approved as induction therapy in newly diagnosed myeloma patients. Mateos:Janssen Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen Cilag: Honoraria. De La Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria; Celgene: Honoraria. Garcia-Laraña:Janssen Cilag: Honoraria; Celgene: Honoraria. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Long Term Response To Lenalidomide With and Without Continuous Therapy Among Patients With Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3209.3209 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3209-3209

Author(s):

Taxiarchis Kourelis ◽

Shaji K Kumar ◽

Geetika Srivastava ◽

Morie A Gertz ◽

Martha Q Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Control ◽

Median Time ◽

Research Funding ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Newly Diagnosed ◽

Best Response ◽

Standard Risk

Abstract Introduction Lenalidomide is an immunomodulatory drug that is active in newly diagnosed as well as relapsed multiple myeloma (MM). The goal of this study is to describe patients with newly diagnosed MM remaining on lenalidomide for more than 3 years (long term responders) as well as patients that after discontinuing lenalidomide were able to maintain disease control while only on observation (LenO group). Methods We retrospectively reviewed 283 patients with newly diagnosed MM that were treated with lenalidomide between January 2003 and January 2011. We excluded patients that underwent early autologous stem cell transplant (n=102) or had less than 3 years of follow-up (n=6), leaving 175 patients for the current analysis. Results Long term responders Thirty-three patients (19%) received lenalidomide for more than 3 years. When compared to patients receiving lenalidomide for less than 3 years, at baseline, long term responders were more likely to have standard risk disease (64% versus 44%, p=0.03) and less likely to have high risk disease (18% versus 4%, p=0.04). They were more likely to have achieved a deeper response (VGPR versus PR, p<0.001) and had a longer median time to best response (6 versus 4 months, p<0.001). When considering the 12 patients who received lenalidomide for more than 5 years, this group was more likely to have achieved a deeper response (CR versus PR, p<0.0001) and had a longer median time to achieving best response (9 versus 4 months, p<0.0001) than those 163 patients who remained on lenalidomide for fewer than 5 years. Observation group Thirty-three patients (19%) discontinued lenalidomide for reasons other than progression and were observed without receiving further treatment (LenO group). Prior to moving to observation, five patients had received lenalidomide for more than three years. Indications for stopping in the LenO group included: prolonged disease stability (n= 20); and toxicity (n=13). The only differences in baseline characteristics between the LenO group and patients that were not observed off any treatment was depth of response, with 61% (n=20) of LenO in VGPR or better versus 23% (n=23) in the remainder, p=0.0003. Median PFS from the time of discontinuing lenalidomide was significantly longer in those patients who took lenalidomide for more than 1 year (n=24) when compared to patients taking it for less than one year (n=9) (median PFS off therapy was 38.5 months versus, 14.9 months log rank 0.08; Wilcoxon p<0.05), figure 1a; PFS for those treated for 1-2 years (n=11) as compared to 2 years or greater (n= 13) were comparable to each other (data not shown). Among those taking lenalidomide for at least a year, PFS from time of discontinuing lenalidomide was superior in patients who had achieved a VGPR/CR (n=20) as compared to those who achieved only a PR (n=13) (Median 48.4 months versus 14.8 months, log-rank p<0.05; Wilcoxon p=0.01), figure 1b. Conclusion Approximately one out of five patients with newly diagnosed MM can achieve responses lasting more than three years while on treatment with lenalidomide. Patients with standard risk FISH and those achieving at least VGPR are more likely be long-term responders. Furthermore, long-term responders were more likely to be slow responders. We also demonstrate that suspension of lenalidomide therapy after 1 year among those patients achieving a VGPR or better can result in long-term disease control and can be considered as a therapeutic strategy. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Gertz:Celgene: Honoraria. Lacy:Celgene: Honoraria. Dispenzieri:Celgene: Research dollars Other.

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Multiparameter flow cytometry (MFC) and next generation sequencing (NGS) for minimal residual disease (MRD) evaluation: Results of the FORTE trial in newly diagnosed multiple myeloma (MM).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8533 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8533-8533 ◽

Cited By ~ 1

Author(s):

Stefania Oliva ◽

Elisa Genuardi ◽

Angelo Belotti ◽

Pio Manlio Mirko Frascione ◽

Monica Galli ◽

...

Keyword(s):

Flow Cytometry ◽

Residual Disease ◽

Staging System ◽

Similar Rate ◽

Autologous Stem Cell Transplant ◽

Multiparameter Flow Cytometry ◽

Cell Transplant ◽

Newly Diagnosed ◽

Next Generation ◽

Few Data

8533 Background: The role of MRD by MFC and NGS is well known in MM, with few data on the concordance of the two techniques. We analyzed and compared MRD data from the FORTE trial both by MFC and NGS. Methods: Newly diagnosed MM patients (pts) ≤65 years were randomized to: carfilzomib, lenalidomide, dexamethasone (KRd) induction-autologous stem cell transplant (ASCT) - KRd consolidation (KRd_ASCT); 12 KRd cycles (KRd12); carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT-KCd consolidation (KCd_ASCT). Pts were then randomized to maintenance: lenalidomide alone or plus carfilzomib. MRD was assessed by 8-color second generation flow cytometry (sensitivity 10−5) in pts with ≥very good partial response (VGPR) before maintenance. In a subgroup of these pts, next generation flow (NGF; sensitivity 10−5-10−6) was performed. In ≥CR pts, MRD pre-maintenance was also assessed by NGS (Adaptive Biotechnologies; sensitivity 10−5-10−6). Thus, both MFC and NGS evaluations were available only in ≥CR pts. 1-year sustained MRD negativity by MFC and NGS was also analyzed in pts with at least one sample available at least 1 year apart. Results: MFC and NGS data were available in 184/233 (79%) CR pts (66 KRd_ASCT, 67 KRd12 and 51 KCd_ASCT). Median age of this ≥CR population was 57 years (IQR 52-62), 13% had International Staging System (ISS) III and 27% high risk cytogenetics by FISH [either del(17p) or t(4;14) or t(14;16)]. Table reports MRD negativity rate by MFC and NGS at a cut-off of 10−5 and 10−6 among ≥CR negative pts in the 3 arms. NGS negativity at a cut-off 10−6 was found in 36/133 (27%) ≥CR pts (for 51/184 CR pts 10−6 sensitivity was not reached). In evaluable pts, 1-year sustained 10−5 MRD negativity by MFC and NGS was superimposable (83%). We evaluated concordance of MRD results by the two techniques and observed agreement was 86% for MFC and NGS at 10−5 evaluable samples (n: 335; r: 0.61) and 78% for MFC and NGS at 10−6 evaluable samples (n: 56; r: 0.77). Conclusions: In pts who achieved ≥CR, similar rate of pre-maintenance 10−5 negativity by MFC and NGS has been reached in each arm, with 83% pts maintaining 1-year MFC or NGS 10−5 sustained MRD negativity. Concordance between MFC and NGS was good, particularly when the same sensitivity was reached. Longer follow up is needed to draw definitive conclusions. Clinical trial information: NCT02203643 . [Table: see text]

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