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 Ofatumumab Plus Hypercvad/MA Induction Leads to High Rates of Minimal Residual Disease (MRD) Negativity in Patients with Newly Diagnosed Mantle Cell Lymphoma, Results of a Phase 2 Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2817-2817
Author(s):  
Pallawi Torka ◽  
Nishitha Reddy ◽  
Adrienne Groman ◽  
Angela Kader ◽  
Jenna Nichols ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Survival Outcomes ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Mantle Cell ◽  
Minimal Residual

Background: Minimal residual disease (MRD) status is an independent prognostic marker for response duration in patients with mantle cell lymphoma (MCL). Rituximab-based therapy led to a molecular remission (MR) in 48% young MCL patients treated with intense chemo-immunotherapy. More recently, 4 courses of R-DHAP were reported to yield a 66% MRD negativity rate prior to high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Ofatumumab is a humanized type 1 anti-CD20 mAb that binds to a unique, more membrane-proximal epitope on the CD20 antigen. Pre-clinical studies have demonstrated that ofatumumab (O) is more active than rituximab in eliciting complement-mediated cytotoxicity (CMC) in MCL cell lines, primary tumor cells and murine lymphoma xenograft models. Hence, we evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL (NCT01527149). Study design: This was a single-arm, open-label, multi-center (2 centers), prospective, phase 2 clinical trial. Thirty-seven transplant-eligible patients with newly diagnosed MCL were enrolled. Ofatumumab (1000mg) was given every 3 weeks on day 1, followed by standard doses of alternating HyperCVAD and MA starting on day 3. A total of 6 cycles were given at 3-week intervals followed by HDC-ASCT. Maintenance rituximab 375 mg/m2 every 2 months for 3 years post-ASCT was added after protocol amendment following publication of the LyMa study. Primary objectives were to determine the overall response rate (ORR) and CR rate (CRR) at the end of therapy. Secondary objectives included MRD negativity, progression free survival (PFS), overall survival (OS), feasibility of successful mobilization of autologous stem cells and safety assessment. MRD assessment was performed in peripheral blood (PB) and bone marrow (BM) using high sensitivity multiparametric flowcytometry at baseline, after 2 cycles, after 4 cycles, pre-ASCT, post-ASCT and 6 months post-ASCT. Exploratory endpoints included correlation of MRD with survival, correlation of surface CD20 levels with response and to compare differences in ORR according to Cheson and modified Cheson (MC) criteria. Results: Median age was 60yrs; 73% of patients were male, 92% had an ECOG PS 0-1, majority (81%) had stage 4 disease with 86% having bone marrow involvement; 22% had low risk, 43% had intermediate risk and 35% had high risk MIPI score; 11% had blastoid and 11% had pleiomorphic variants of MCL; 25% harbored p53 deletion. MRD was assessed in 28 of 37 patients; 9 patients from partner site were excluded due to time lag in sample delivery for flowcytometry. MRD positivity was noted in 75% patients in PB and 71.4% patients in BM at baseline. Subsequent samples showed an MRD negativity rate of 82.1% and 64.3% after 2 cycles and 76% and 96% pre-ASCT in PB and BM respectively. Post-ASCT, MRD in BM and PB was found negative in 58% and 90%, respectively. Attainment of early MRD negativity (after 2 cycles) was associated with improved PFS (p=0.04) and OS (p=0.03). Since majority of patients were MRD negative pre-ASCT, we could not demonstrate correlation between pre-ASCT MRD and survival outcomes. The ORR and CRR were 95% and 62% by Cheson and 97% and 84% respectively by modified Cheson criteria. At the end of induction therapy, ORR was 86% and CRR was 62% by Cheson criteria. 73% pts underwent HDC-ASCT. Only one patient failed stem cell collection. The median PFS and OS were 45.5 months and 56 months respectively. There were 3 deaths while on therapy- 2 from sepsis and one from acute myeloid leukemia. Grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients, most of them were hematological AEs related to the chemotherapy regimen. Correlation of surface CD20 expression using mean fluorescent intensity (MFI) and response rates is currently under analysis and will be reported at the meeting. Conclusion: The addition of ofatumumab to HyperCVAD/MA led to high rates of MRD negativity by flowcytometry in patients with newly diagnosed MCL. Early MRD negativity (after 2 cycles) was associated with better PFS and OS. Despite higher ORR, CR and MRD negativity rates, survival outcomes were similar to historical cohorts using rituximab-HypeCVAD/MA. This may be in part due to increased number of patients with high-risk disease in our study. Disclosures Reddy: KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding. Sait:Celgene: Consultancy. OffLabel Disclosure: Ofatumumab was investigated in combination with chemotherapy in newly diagnosed mantle cell lymphoma in this clinical trial.

Dynamics of minimal residual disease in patients with multiple myeloma on continuous lenalidomide maintenance: a single-arm, single-centre, phase 2 trial

2021 ◽  
Vol 8 (6) ◽  
pp. e422-e432
Author(s):  
Benjamin Diamond ◽  
Neha Korde ◽  
Alexander M Lesokhin ◽  
Eric L Smith ◽  
Urvi Shah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Phase 2 ◽  
Single Centre ◽  
Phase 2 Trial ◽  
Minimal Residual

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 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.

Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 688-688 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Asselberg-Hacker ◽  
Sonja Zweegman ◽  
Bronno van der Holt ◽  
Marie Jose Kersten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Phase 2 Trial ◽  
Cell Harvest

Abstract Background A proteasome inhibitor (PI) combined with an immune-modulatory dexamethasone has significant activity in replapse and newly diagnosed Multiple Myeloma (MM). Carfilzomib is an effective 2nd generation PI. We report an update of a Phase 2 trial using Carfilzomib combined with Thalidomide and Dexamethasone in newly diagnosed MM. Introduction This investigator sponsored, dose escalation phase 2 trial was designed to investigate Carfilzomib © combined with Thalidomide (T) and Dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Fifty patients in cohort 1 received 4 cycles of Carfilzomib at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, Thalidomide 200 mg p.o. days 1 through 28 of a 28 day cycle and Dexamethasone 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 (20 patients) the dose of Carfilzomib was escalated from 27 mg/m2 to 36 mg/m2 in the same schedule. In cohort 3 (20 patients) the dose of Carfilzomib increased to 45 mg/m2 in the same schedule. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and autologous stem cell transplantation (ASCT), followed by consolidation therapy: 4 cycles of Carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), Thalidomide 50 mg days 1-28 of a 28 day cycle and Dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was very good partial response (VGPR) after 4 CTD cycles: secondary endpoints were complete response (CR), stringent CR (sCR), VGPR and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS). Results 90 patients were included as of 1st April 2013. We here report the response of cohorts 1+2 (n=70) with a median follow-up of 22 and 7 months respectively. Median age was 58 yrs and ISS stages I/II/III were 27%/40%/27%, respectively. Six (9%) patients had renal failure with serum creatinine > 2 mg/dL. Of 70 patients in cohorts 1 and 2, 8 patients stopped treatment during/after induction and 4 patients after HDM because of refusal (n=2), toxicity (n=4) non-eligibility (n=2) or progression (n=4). 39 patients completed protocol treatment with 19 still on treatment. Overall response rate on protocol treatment was 96%. After induction therapy response was 19% (CR/sCR), 60% (≥ VGPR) and 93% (≥ PR), respectively. The CR/sCR rate increased to 30% after HDM and to 49% after consolidation. CR/sCR rate was not different across ISS staged I/II/III. In addition, response was similar in poor risk FISH (gain 1q or t(4;14) or del17p: 26% of patients) and standard risk FISH (all other). Progression-free survival (PFS) f 70 patients is 74%, overall survival (OS) is 7%. Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 60/60 patients and HDM/ASCT was performed with complete hematologic recovery in 53/53 patients. This regimen was well tolerated. Safety analysis for all 3 cohorts showed non-hematological toxicity CTC Grade 3+4 in < 5%, mainly infections and skin lesions. Other toxicities were Grade 2 ≤ or less than 5% including cardiac symptoms. Purified myeloma plasma cells, obtained in 39 patients at diagnosis were used for gene expression profiling and exome sequencing. The prognostic impact of the EMC-92 gene classifier on outcome with CTd will be presented. Conclusion Carfilzomib combined with thalidomide and dexamethasone is a safe and rapidly effective regimen for newly diagnosed MM. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals. Disclosures: Sonneveld: Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.

Subcutaneous PAD As Induction Therapy for Patients with Newly Diagnosed Myeloma: A Phase 2 Trial Assessing the Impact of Minimal Residual Disease (MRD) in Patients with Deferred Autologous Stem Cell Transplantation (PADIMAC)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4745-4745
Author(s):  
Rakesh Popat ◽  
James D Cavenagh ◽  
Roger G Owen ◽  
Matthew Streetly ◽  
Stephen A Schey ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Stem Cell ◽  
Genetic Risk ◽  
Research Funding ◽  
Residual Disease ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Disease Response ◽  
Grade 3 ◽  
Minimal Residual

Abstract Introduction: The role of autologous stem cell transplantation (ASCT) as first line treatment for newly diagnosed patients with myeloma is currently under evaluation given the high response rates to novel induction treatment. The outcomes for patients that do not proceed to ASCT following induction remain unclear and are likely to be determined by genetic risk and response to therapy. In order to evaluate this further, this single arm phase 2 clinical trial conducted at 13 sites in the UK was designed to determine the 2 year progression free survival for patients that achieved ≥ very good partial response (VGPR) following induction therapy without ASCT. Those achieving partial response (PR) were consolidated with ASCT according to routine practice. In this first analysis we report secondary endpoints: disease response and regimen-related toxicity in patients completing induction, including minimal residual disease (MRD) negativity by multiparameter flow cytometry. Methods: Patients with newly diagnosed myeloma eligible for ASCT received PAD (bortezomib 1.3mg/m2 days 1, 4, 8, 11; doxorubicin 9mg/m2 days 1-4 and dexamethasone 40mg days 1-4 (and days 8-11 and 15-18 for the first cycle only)) for up to 6 cycles (minimum of 4). Bortezomib was initially given intravenously (IV), but once approved this was switched to sub-cutaneous (SC). Those failing to achieve PR were offered salvage therapy off protocol. All others had peripheral blood stem cell (PBSC) mobilisation using cyclophosphamide + GCSF, followed by MRD assessment on bone marrow aspirates using multi-parameter flow cytometry. Depending on disease response, patients were then stratified to ASCT (PR) or no further treatment (≥VGPR). Responses were assessed using International uniform response criteria (Durie 2006) by intent-to-treat and toxicity scored according to CTCAE version 4.0. High risk disease was defined by the presence of one or more adverse FISH lesions (t(4;14), t(14;16), t(14;20), del(17p13), +1q21) as described in the MRC Myeloma IX trial. Results: Between March 2011 and January 2014, 153 patients were enrolled (median age of 55, range 28-71 years). 139 (91%) received between 4-6 cycles of PAD. The majority (135, 88%) received SC only bortezomib and 18 (12%) received at least 1 cycle IV. The overall response rate to PAD was 81% with 46% achieving ≥VGPR (sCR: 6 (4%), CR: 13 (8%), VGPR: 51 (33%), PR: 54 (35%)). FISH data was available for 122 patients, 91 (75%) patients were standard risk and 31 (25%) were adverse. Responses were similar irrespective of ISS or genetic risk (standard, ≥VGPR 44%, PR 34%; adverse, ≥VGPR 55%, PR 29%). MRD results are currently available in 70 of the 124 patients achieving PR post PBSC harvest. Of this group 41 achieved ≥VGPR post-harvest (22 MRD+ and 19 MRD-) and hence did not proceed to ASCT, 13 patients achieved CR of which 8 were MRD negative. Toxicity was as expected for PAD and predominantly haematological. Notably the incidence of neuropathy was lower than that previously reported with IV bortezomib. Grade 3-4 events were: neutropenia: 18%; thrombocytopenia 7%. Grade 2-4 peripheral neuropathy was reported in 27% compared to 40% in the HOVON-65/ GMMG-HD4 Trial using IV bortezomib. Grade 1-2 neuropathy was similar for patients who received IV (55.6%) or SC (60%) bortezomib; however only 7% of patients receiving SC bortezomib developed grade 3 neuropathy compared to 28% with the IV route. Conclusions: SC PAD is a highly effective induction regimen for patients with newly diagnosed myeloma achieving a ≥VGPR of 46%. Of the 41 patients achieving ≥VGPR post-harvest with MRD result available, 46% were MRD negative. Response rates were similar across ISS and with adverse FISH. The use of SC bortezomib improved tolerability and substantially reduced neurotoxicity. ISRCTN no: 03381785. Disclosures Popat: Janssen: Honoraria. Cavenagh:Janssen: Honoraria. Schey:Janssen: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cook:Janssen: Honoraria, Research Funding. Yong:Janssen: Honoraria.

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.

Sign in / Sign up

Export Citation Format

Share Document