scholarly journals Consolidation with Carfilzomib, Lenalidomide and Dexamethasone (KRd) Following ASCT Results in High Rates of Minimal Residual Disease Negativity and Improves Bone Metabolism, in the Absence of Bisphosphonates, Among Newly Diagnosed Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3118-3118 ◽  
Author(s):  
Maria Gavriatopoulou ◽  
Evangelos Terpos ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Panagiotis Malandrakis ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Metabolism ◽  
Research Funding ◽  
Residual Disease ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Tracp 5B ◽  
Stage 1 ◽  
Minimal Residual

Consolidation therapy post autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) seems to deepen disease responses. MRD negativity represents a strong prognostic factor for prolonged remission. Carfilzomib is a second-generation proteasome inhibitor, which in combination with lenalidomide has been associated with high rates of deep responses before ASCT in phase 2 studies. In this context, we prospectively evaluated the role of carfilzomib, lenalidomide and dexamethasone (KRd) as consolidation therapy post-ASCT in newly diagnosed MM pts who have not achieved MRD negative complete remission (CR). The primary endpoint was to assess KRd efficacy in terms of improving disease response, whereas secondary endpoints included percentage of minimal residual disease (MRD) (performed by Next Generation Flow Cytometry) negativity post KRd, safety, time to progression (TTP), time to next treatment (TtNT), overall survival (OS) and the effects of KRd on bone metabolism in the absence of bisphosphonate administration. All pts achieving at least partial response and less than MRD negativity post-ASCT were eligible for inclusion in the study. Consolidation consisted of 4 cycles of KRd, starting on day 100 post-ASCT: carfilzomib was given at a dose of 20 mg/m2 iv on day 1 cycle 1 and 56 mg/m2, on days 1, 8, 15 thereafter; lenalidomide was given at 25 mg daily on days 1-21 and dexamethasone at 40mg weekly every 28-days. All pts continued lenalidomide maintenance 10 mg following consolidation until progressive disease. Pts did not receive bisphosphonates during or post-ASCT as well as throughout the period of KRd consolidation. Bone remodeling was evaluated by the following serum indices before and after KRd (2 measurements for each pt): i) osteoclast regulators (soluble receptor activator of nuclear factor kappaB ligand and osteoprotegerin), ii) osteoblast inhibitors (dickkopf-1 and sclerostin) iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers (bone-specific alkaline phosphatase and osteocalcin). Between January 2018 and May 2019, 39 consecutive pts all MRD positive (20M/19F, median age 56 years, range 44-67 years) entered the study. The distribution per revised ISS was 36.1% stage 1, 52.8% stage 2 and 11.1% respectively. After a median follow-up of 16 months (range 1-17) following KRd initiation, 35 (89.7%) pts had received 4 cycles of KRD, whereas two pts continue on treatment and two discontinued treatment due to toxicity. Following ASCT, one (2.6%) pt had achieved stringent CR (sCR), 4 (10.3%) were in CR, 29 (74.4%) were in very good partial remission (VGPR) and 5 pts (12.8%) were in PR. Post KRd consolidation, 30 out of 37 evaluable pts (81%) pts improved their response status with KRd. Overall, 28 (75.7%) pts achieved a sCR, one (2.7%) CR and 8 (21.6%) VGPR, while 25 (67.6%) pts achieved MRD negativity at 10-5. Among the 25 MRD negative pts, 11 (44%) were R-ISS stage 1, 13 (52%) stage 2 and one (4%) stage 3. Positron emission tomography-computed tomography (PET/CT) scans that were performed in 14 MRD (-) pts were negative for all pts except one. The markers of bone metabolism were measured in 22 pts. Only TRACP-5b levels showed a significant reduction (p=0.011) post KRd consolidation, which suggests a beneficial effect on bone resorption that must be further investigated. No new skeletal-related events (SREs) were reported. No patient has progressed whereas 37/39 (95%) are alive. One patient died due to staphylococcal pneumonia and another due to refractory thrombotic thrombocytopenic purpura complicated by brain hemorrhage and in-hospital infection during KRD. 7 (18%) pts experienced ≥grade 3 toxicities (mainly infections, TTP, fatigue, neutropenia, pneumonitis, hypocalcemia and increase of γGT and ALP). There were no new cases of peripheral neuropathy. In conclusion, KRd consolidation with weekly carfilzomib, post ASCT, is highly effective and improves the quality of response by increasing MRD negativity rates. Although it is given for four cycles only, KRD consolidation reduces bone resorption and correlates with no SREs in the absence of bisphosphonates. Infections prophylaxis is strongly encouraged. This triplet combination should be further investigated as a potential consolidation regimen both for standard and high-risk pts. Disclosures Gavriatopoulou: Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses. Terpos:Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Medison: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.

scholarly journals The Combination of Bortezomib and Lenalidomide (VR) Consolidation Post-ASCT, in the Absence of Dexamethasone and Bisphosphonates, Improves Response Rates and Bone Metabolism in Newly Diagnosed Patients with Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3462-3462
Author(s):  
Evangelos Terpos ◽  
Efstathios Kastritis ◽  
Dimitrios Christoulas ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Bone Resorption ◽  
Bone Metabolism ◽  
Stable Disease ◽  
Newly Diagnosed ◽  
Infectious Episode ◽  
Short Period ◽  
Tracp 5B ◽  
Grade 3

Abstract Consolidation therapy post autologous stem cell transplantation (ASCT) with combinations of bortezomib with an IMiD (thalidomide or lenalidomide) and dexamethasone has been evaluated in patients with multiple myeloma (MM) in an attempt to deepen responses and to improve survival. Bortezomib, IMiDs and steroids have been usually administered in various combinations. However, it is not clear if the use of dexamethasone is needed in consolidation regimens. The primary endpoint of this prospective study was to explore the efficacy of VR consolidation without dexamethasone in newly-diagnosed MM patients who received bortezomib-based induction treatment and then underwent high dose melphalan (HDM) and ASCT. Secondary endpoints included: safety, time to progression (TTP), time to next treatment (TtNT), OS and the effects of VR on bone metabolism in the absence of bisphosphonates administration. Between January 2010 and November 2013, 59 consecutive patients (30M/29F, median age 54 year, range 37-68 years) who achieved at least stable disease post-ASCT were entered into this study. Consolidation consisted of 4 cycles of VR, which started on day 100 post-ASCT. Bortezomib was given at a dose of 1.3 mg/m2, iv (or sc when it was available), on days 1, 4, 8 and 11 of a 21-day cycle, while lenalidomide was given at a dose of 25 mg, p.o., daily on days 1-14. Patients did not receive any bisphosphonate during or post-ASCT as well as throughout the period of VR consolidation. Bone remodeling was studied by the measurement of the following serum indices on the day of stem cell collection prior to ASCT and then before and after VR consolidation (3 measurements for each patient): i) osteoclast regulators [soluble receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin], ii) osteoblast inhibitors dickkopf-1 (Dkk-1) and sclerostin, iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Before HDM, one (1.7%) patient had achieved a stringent complete remission (sCR), one (1.7%) was in CR, 30 (50.8%) were in very good partial remission (vgPR), 22 (37.3%) were in PR, while 5 (8.5%) patients had stable disease. After ASCT, 34 (57.6%) patients improved their status of response; in total, 14 (23.7%) patients achieved a sCR, one (1.7%) CR, 35 (59.3%) vgPR and 9 (15.3%) PR. After VR consolidation, 23/59 (39%) patients further improved their status of response; overall, 30 (50.8%) patients achieved a sCR, one (1.7%) CR, 26 (44.1%) vgPR and two (3.4%) PR. The most important adverse events (>10% of the patients) included neutropenia (68%, grade 3/4 23%), thrombocytopenia (59%, grade 3/4 7%), peripheral neuropathy (56%, grade 3/4 2%), anemia (50%, grade 3/4 4.5%), skin rash (34%, grade 3/4 9%), infections (34%, no grade 3/4), fatigue (20%, no grade 3/4), diarrhea (16%, no grade 3/4) and constipation (14%, 2% grade 3/4). No patient developed deep vein thrombosis. Fifteen patients (34.1%) experienced at least one infectious episode (grade 1 and 2); the majority included viral or bacterial infections of the upper respiratory tract. Post-VR consolidation there was a reduction of sRANKL/OPG ratio and of sclerostin (p<0.001) in all patients. Patients who achieved at least vgPR showed higher reductions of sRANKL/OPG and sclerostin compared to patients who achieved a PR (p<0.01). There was no reduction of markers of bone resorption (CTX and TRACP-5b) during the study period, possibly due to the dramatic reduction of these markers during induction therapy when zoledronic acid was given. Furthermore, there were no alterations in Dkk-1, bALP and OC, despite the use of bortezomib which has bone anabolic effects. This may be due to the enhanced expression of Dkk-1 caused by lenalidomide and the short period of observation. No skeletal-related events (SREs) were observed during the study period. The median follow-up after the ASCT was 31 months (range: 7-49 months) and 14 of 44 (31.8%) patients have progressed. The median TTP and TtNT after the ASCT have not been reached yet. The probability of 4-year without progression was 55%. We conclude that 4 cycles of VR consolidation without dexamethasone is an effective regimen which improves the quality of response in approximately 40% of patients and produces long TTP. In the absence of bisphosphonates, VR consolidation has beneficial effects on bone metabolism and is related with no SREs. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Phase 2 Study with Minimal Residual Disease (MRD) Driven Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma with Upfront Daratumumab-Based Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3191-3191
Author(s):  
J Christine Ye ◽  
Philip S Boonstra ◽  
Daniel F. Boyer ◽  
Larry D. Anderson ◽  
Brea C. Lipe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Residual Disease ◽  
Adaptive Strategy ◽  
Response Criteria ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Trial ◽  
Patient Will ◽  
Minimal Residual

Background: Minimal Residual Disease (MRD) was clearly demonstrated as a prognostic marker for prognosis in multiple myeloma and has been integrated into IMWG clinical guidelines as one of the response criteria. There is however no consensus yet when and how to use MRD data in clinical practice throughout treatment course. Daratumumab was approved by FDA in different settings after it had been shown as a highly effective agent with a reasonable safety profile in myeloma treatment. It also showed impressive data to achieve MRD negativity. We plan to use the combination of daratumumab, lenalidomide, and dexamethasone upfront, with the addition of Velcade for consolidation if needed, in newly diagnosed multiple myeloma (NDMM) patients. We propose to use an MRD driven adaptive strategy for decision making in myeloma treatment and use daratumumab-based frontline therapy. Trial Design and Methods: We designed this prospective, single-arm, multi-center, phase 2 trial. The primary objective is to determine the rate of MRD negativity after daratumumab-based induction and consolidation therapy if necessary in both transplant eligible and ineligible NDMM patients. The secondary objective is to describe the overall survival, progression free survival, MRD conversion rate after consolidation, quality of life for patients, safety and tolerability of daratumumab-based combination regimens in both transplant eligible and ineligible patient populations, estimation of a successful stem cell mobilization after receiving daratumumab-based induction therapy. The primary endpoint will be MRD-negativity after six cycles of induction, followed by three cycles of consolidation therapy if MRD is positive after induction. We will seek to establish evidence that the true proportion of patients who can achieve MRD negativity after induction + consolidation (if still MRD+ after induction) is high, which we define as any response rate that is at least 23%. Patients with NDMM meeting IMWG diagnostic criteria are eligible for this trial, regardless of transplant candidacy. Patient will have stem cell collection after induction therapy. We will follow the patients' treatment response using IMWG response criteria including MRD status through induction, consolidation, transplant (if applied) and maintenance. Patient will come off the study if disease progression per IMWG response criteria. We plan for MRD testing by next generation sequencing and flow cytometry. This study will enroll 50 eligible patients. A two-stage design will be conducted, with an interim futility analysis after the primary endpoint is available on the first 20 enrolled patients. We will proceed to a final analysis with all 50 patients if at least 2/20 (10%) of patients achieve MRD negativity after consolidation. This trial is anticipated to be open at four academic centers. Conclusion: This multicenter phase 2 trial will apply a novel clinical trial design with an adaptive strategy to treat newly diagnosed myeloma patients based on MRD results. Therapeutic advance with Daratumumab-based combination regimen as frontline therapy may help myeloma patients to achieve higher rate of MRD negativity. Figure Disclosures Ye: AbbVie: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; MingSight: Research Funding; Portola Pharmaceuticals: Research Funding. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. Lipe:amgen: Research Funding; amgen: Consultancy; Celgene: Consultancy. Talpaz:Samus Therapeutics: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding.

scholarly journals A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5043-5043
Author(s):  
Elizabeth K. O'Donnell ◽  
Clifton C. Mo ◽  
Andrew J. Yee ◽  
Omar Nadeem ◽  
Andrew R. Branagan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Stem Cell Collection ◽  
Minimal Residual

Abstract Background: Clinical data support the combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). Recently, the GRIFFIN study evaluated the addition of the CD38 antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated improved efficacy with an acceptable safety profile. Isatuximab is a newer CD38 monoclonal antibody that binds to a specific epitope of the CD38 receptor. In addition to antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, isatuximab eliminates MM cells via direct apoptosis without the need for crosslinking. Isatuximab enhances immune function by boosting the activation and cytotoxic activity of natural killer cells and by depleting CD38+ immune suppressor cells such as regulatory T cells and inducing clonal expansion of T cells. Isatuximab is approved in combination with carfilzomib and dexamethasone for relapsed, refractory MM based on the results of the IKEMA study. The MANHATTAN study evaluated the 4-drug combination of daratumumab, lenalidomide, carfilzomib, and dexamethasone. The primary end point, minimal residual disease negativity was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%). Building upon these data, our study evaluates the addition of isatuximab to weekly carfilzomib, lenalidomide, and dexamethasone. Study Design and Methods: A phase II, open-label clinical trial is being conducted to evaluate the efficacy of once weekly carfilzomib, lenalidomide, dexamethasone, and isatuximab (Isa-KRd) in 50 patients with newly diagnosed, transplant-eligible MM (NCT04430894). Eligible patients will have NDMM, age ≥18 years, ECOG PS of 0-2, and are deemed eligible for stem cell transplantation (SCT). All patients will receive 4 cycles of induction therapy with Isa-KRd followed by stem cell collection with the option to either proceed to upfront SCT versus deferred SCT. Patients undergoing upfront SCT will receive 4 cycles of therapy followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy then maintenance. Patients deferring SCT following collection will receive 4 cycles of therapy followed by stem cell collection followed by 4 additional cycles of therapy then maintenance. Each 28-day cycle will consist of isatuximab 10 mg/kg IV Q1 week for 8 weeks, then Q2 weeks for 16 weeks, thereafter Q4 weeks; carfilzomib (20 mg/m 2 Day 1 only) 56 mg/m 2 IV on Days 1, 8, 15; lenalidomide 25 mg po on Days 1-21; and dexamethasone 20 mg po day of and day after all doses of carfilzomib (Days 1, 2, 8, 9, 15, and 16) and isatuximab (Cycles 1 and 2 Days 22 and 23). For maintenance, patients will be stratified based on cytogenetics (high-risk cytogenetics include deletion (del) 17p, translocation t(4:14), t(14;16), t(14;20)). Patients with standard-risk cytogenetics will receive lenalidomide 10 mg po Days 1-21. Patients with high-risk cytogenetics will receive carfilzomib 56 mg/m 2 Days 1, 15; lenalidomide 10 mg po Days 1-21; and isatuximab 10 mg/kg IV Day 1. Dexamethasone, 20 mg orally or IV will be administered to patients as a pre-infusion medication prior to isatuximab dosing. Main Outcomes and Measures: The primary end point is complete response (CR + stringent CR) rate after 4 cycles of Isa-KRd as assessed by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include determining safety and tolerability of Isa-KRd, minimal residual disease (MRD) after 4 cycles, at completion of consolidation (post-transplant) or induction (transplant-deferred), and sustained MRD at 24 months, progression-free survival, overall survival rates, and quality of life. Efficacy analysis will be performed both in the intent-to-treat (ITT) population and efficacy evaluable (EE) population. The ITT population will include all treated patients, and the EE population will include all patients who receive at least 1 cycle of study drug. The primary analysis will be based on the EE population, and will use the investigator-assessed response data evaluated according to consensus recommendations based on the IMWG criteria. CR (CR+sCR) rate after 4 cycles of Isa-KRd will be reported with 90% confidence interval. Support: Amgen and Sanofi Figure 1 Figure 1. Disclosures O'Donnell: Oncopeptide: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Mo: Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol Myer Squibb: Consultancy. Branagan: Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; CSL Behring: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

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.

scholarly journals Comparison of Minimal Residual Disease Detection between the Manual and Automated Gating Strategies of Euroflow Next-Generation Flow in Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3083-3083
Author(s):  
Hiroyuki Takamatsu ◽  
Takeshi Yoroidaka ◽  
Takeshi Yamashita ◽  
Ryoichi Murata ◽  
Mikio Ueda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Pharmaceutical Company ◽  
Research Funding ◽  
Plasma Cells ◽  
Residual Disease ◽  
Next Generation ◽  
Chugai Pharmaceutical ◽  
Company Limited ◽  
Minimal Residual

Background: The rate of complete response (CR) in multiple myeloma (MM) has dramatically increased because of the development of novel agents. In addition, the development of methods for measuring minimal residual disease (MRD), such as multiparameter flow cytometry and next-generation sequencing, has made it possible to stratify CR patients according to the MRD extent. EuroFlow next-generation flow (EuroFlow-NGF) is considered one of the gold standard methods for evaluating the negative status of MRD in MM. The automated gating strategy of EuroFlow-NGF has been shown to detect MRD as accurately as the manual gating strategy by experts. Oberle et al. (Haematologica, 2017) have found that daratumumab persisted on the surface of myeloma cells treated with it and that the anti-CD38 multi-epitope antibody used in EuroFlow-NGF has partial cross-reactivity with daratumumab, leading to generally lower mean fluorescence intensities of CD38. Therefore, MRD levels may have been underestimated in patients who were treated with anti-CD38 monoclonal antibodies (mAbs) using the automated gating strategy, leading to inappropriate management of the patients. Because no studies have examined the correlation of MRD extent between the manual and automated gating strategies in patients with MM who have received anti-CD38 mAbs, we compared MRD detection between the two gating strategies of EuroFlow-NGF in patients with MM. Methods: The study included bone marrow samples from 51 patients with MM (27 male and 24 female patients), including 13 patients treated with anti-CD38 mAb (12 treated with daratumumab and 1 treated with isatuximab). The median patient age was 70 years (range, 32-92 years) at MRD assessment. The disease statuses at MRD assessment were stringent CR in 26 patients (51%), CR in 7 (14%), very good partial response in 13 (26%), partial response in 1 (2%), and progressive disease in 4 (8%). The sample preparation protocol, Ab panel, and automated gating strategy of EuroFlow-NGF have been reported previously (Flores-Montero et al. Leukemia 2017). Briefly, we performed the EuroFlow-NGF method, which involved ammonium chloride-based bulk lysis, followed by surface staining using antibodies against CD138-BV421, CD27-BV510, CD38 multiepitope (ME)-FITC, CD56-PE, CD45-PerCP Cy5.5, CD19-PECy7, CD117-APC, and CD81-APC C750 in tube 1 and surface/intracellular staining using antibodies against CD138-BV421, CD27-BV510, CD38 ME-FITC, CD56-PE, CD45-PerCP Cy5.5, CD19-PECy7, CD117-APC, CD81-APC C750, cytoplasmic (cy) Igκ-APC, and cyIgλ-APC C750 after permeabilization in tube 2. For data analysis, events from both eight-color tubes (tubes 1 and 2) were merged, and the values of all parameters per tube were mathematically calculated using the merge and calculation functions of Infinicyt software (Cytognos SL, Salamanca, Spain). Automatic identification and enumeration of total plasma cells (tPCs) and abnormal plasma cells (MRD) were performed using the automatic gating function of Infinicyt software as described previously (Flores-Montero et al. Leukemia 2017). We compared the total nucleated cell number, tPC ratio, and MRD ratio between the manual (by experts) and automated gating strategies of EuroFlow-NGF. Results: In patients with MM who did not receive any anti-CD38 mAb therapy, we observed high correlations for both the tPC (r = 0.959, P < 0.0001) (Figure A) and MRD (r = 0.974, P < 0.0001) (Figure B) ratios between the manual and automated gating strategies of EuroFlow-NGF. On the other hand, in patients with MM who received anti-CD38 mAb therapy, we did not observe good correlations for both the tPC (r = 0.349, P = 0.2) (Figure A) and MRD (r = 0.292, P = 0.3) (Figure B) ratios between the two strategies owing to a lower fluorescence intensity of CD38 on PCs. In addition, when the MRD threshold was set to 10-5, the discordance of MRD positivity/negativity between the two strategies was significantly higher in patients who received anti-CD38 mAb therapy than in those who did not receive anti-CD38 mAb therapy [4/13 (31%) vs. 1/38 (3%), P = 0.012]. Conclusion: Although the automated gating strategy of EuroFlow-NGF could be a viable alternative to the manual strategy for the assessment of MRD in MM, we may have to utilize the manual strategy to obtain precise MRD results for patients with MM who received anti-CD38 mAbs. Figure Disclosures Takamatsu: Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; CSL Behring: Research Funding; SRL: Consultancy, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Fujimoto Pharmaceutical: Honoraria; Becton, Dickinson and Company: Honoraria; Abbvie: Consultancy; Daiichi-Sankyo Company: Honoraria. Yoroidaka:Ono Pharmaceutical: Honoraria. Yamashita:Janssen Pharmaceutical K.K.: Honoraria; Daiichi-Sankyo Company: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd: Honoraria; TEIJIN PHARMA LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Celgene: Honoraria. Murata:Celgene: Honoraria; Ono pharmaceutical: Honoraria. Nakao:Daiichi-Sankyo Company, Limited: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; SynBio Pharmaceuticals: Consultancy; Ohtsuka Pharmaceutical: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co.,Ltd: Honoraria; Kyowa Kirin: Honoraria; Alaxion Pharmaceuticals: Honoraria. Matsue:Novartis Pharma K.K: Honoraria; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical K.K.: Honoraria.

Real-World Experience with Minimal Residual Disease Testing with Next Generation Flow Cytometry and Functional Imaging in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
David Böckle ◽  
Paula Tabares Gaviria ◽  
Xiang Zhou ◽  
Janin Messerschmidt ◽  
Lukas Scheller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
High Risk ◽  
Functional Imaging ◽  
Real World ◽  
Research Funding ◽  
Residual Disease ◽  
Focal Lesions ◽  
High Risk Disease ◽  
Minimal Residual

Background: Minimal residual disease (MRD) diagnostics in multiple myeloma (MM) are gaining increasing importance to determine response depth beyond complete remission (CR) since novel agents have shown to induce high rates of deep clinical responses. Moreover, recent reports indicated combining functional imaging with next generation flow cytometry (NGF) could be beneficial in predicting clinical outcome. This applies in particular to the subset of patients suffering from relapsed/refractory multiple myeloma (RRMM) who tend to show a higher incidence of residual focal lesions despite serological response. Here, we report our institutions experience with implementing both functional imaging and NGF-guided MRD diagnostics in clinical practice. Methods: Our study included patients with newly diagnosed multiple myeloma (NDMM) and RRMM achieving VGPR, CR or sCR. Bone marrow aspirates were obtained for MRD-testing according to IMWG 2016 criteria. Samples were collected between July 2019 and July 2020 and analyzed with NGF (according to EuroFlowTM guidelines) at a sensitivity level of 10-5. Results were compared to functional imaging obtained with positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). High-risk disease was defined as presence of deletion 17p, translocation (14;16) or (4;14). Results: We included 66 patients with NDMM (n=39) and RRMM (n=27) who achieved VGPR or better. In patients with RRMM the median number of treatment lines was 2 (range 2-11). Fifteen patients suffered from high-risk disease. Median age at NGF diagnostics was 64 years (range 31-83). Among patients achieving VGPR (n=27), CR (n=10) and sCR (n=29) seventeen (26%) were MRD-negative by NGF testing. CR or better was significantly associated NGF MRD-negativity (p=0.04). Notably, rates of NGF MRD-negativity were similar among patients with NDMM (28%) and RRMM (26%). Even some heavily pretreated patients who underwent ≥ 4 lines of therapy achieved MRD-negativity on NGF (2 of 9). Functional imaging was performed in 46 (70%) patients with DW-MRI (n=22) and PET (n=26). Median time between NGF and imaging assessment was 2 days (range 0-147). Combining results from imaging and NGF, 12 out of 46 (26%) patients were MRD-negative with both methods (neg/neg). Three patients displayed disease activity as measured with both, imaging and NGF (pos/pos). Twenty-nine of the remaining patients were MRD-positive only according to NGF (pos/neg), while two patients were positive on imaging only (neg/pos). More patients demonstrated combined MRD-negativity on NGF and imaging (neg/neg) in the NDMM setting than in RRMM (32% versus 19%). We also observed that 30% of the patients with high-risk genetics showed MRD-negativity on both imaging and NGF. Of note, none of the patients with very advanced disease (≥4 previous lines) was MRD-negative on both techniques. Conclusion In the clinical routine, MRD diagnostics could be used to tailor maintenance and consolidation approaches for patients achieving deep responses by traditional IMWG criteria. Our real-world experience highlights that MRD-negativity can be achieved in patients suffering from high-risk disease and also in late treatment lines, supporting its value as endpoint for clinical trials. However, our data also support MRD diagnostics to be combined with functional imaging at least in the RRMM setting to rule out residual focal lesions. Future studies using MRD for clinical decision-making are highly warranted. Disclosures Einsele: Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rasche:Celgene/BMS: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; Sanofi: Honoraria.

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