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.

scholarly journals Sustained Minimal Residual Disease Negativity in Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated with Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (DEX) Followed By 2 Years of Lenalidomide Maintenance (CRd-R): Updated Results of a Phase 2 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4527-4527 ◽  
Author(s):  
Dickran Kazandjian ◽  
Neha S Korde ◽  
Mark Roschewski ◽  
Sham Mailankody ◽  
Candis Morrison ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
Lung Infection ◽  
Risk Profile ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Minimal Residual

Abstract Background: State of the art treatment for patients with NDMM involves induction with triplet regimens utilizing newer therapies including combinations of immunomodulatory (IMiD) drugs and proteasome inhibitors (PI) which improve progression-free survival (PFS) over doublet regimens. CFZ is a selective PI that inhibits the chymotrypsin-like activity of the 20S proteasome and has been approved in combination with LEN and DEX for the treatment of patients with relapsed or refractory MM who have received 1-3 lines of therapy. Furthermore, it has been associated with decreased neuropathy and increased clinical benefit over bortezomib-based combinations. This phase 2 study of 45 patients demonstrated that deep and durable responses with CRd-R can be achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing minimal residual disease negativity (MRDneg) at complete response (CR) and after 1 and 2 years of LEN maintenance. We also characterize depth of response by age and cytogenetic risk profile. Methods: Treatment-na•ve patients with MM were treated for 8 cycles (28-day cycles) with CFZ 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; LEN 25 mg PO days 1-21, and DEX 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles of CRd and then continued CRd treatment (i.e. by-default-delayed high-dose melphalan with autologous stem cell transplant; HDM-ASCT). After 8 cycles of combination therapy, patients with SD or better received 2 years of LEN 10 mg PO maintenance. The primary objective of the study was to estimate the rate of ³ Grade 3 peripheral neuropathy with secondary objectives of response (ORR), MRDneg, PFS, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, and 1 and 2 years of LEN maintenance. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; median age 60, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda). The proportion of patients who obtained a complete response (CR) with MRDneg after 8 cycles of induction, 1 year of maintenance and 2 years of maintenance was 44%, 54% and 46%, respectively (Table 1). These deep responses of MRDneg CR were observed regardless of age group or cytogenetic-based risk profile (Table 2). ORR was 98% with a DoR at 48 months of 81%. PFS at 48 months was 82% and overall survival at 58 months was 86% with a median duration of follow-up of 31 months. Toxicities, in general, were manageable, with Grade 3-4 events occurring in >1 patient including lymphopenia (69%), neutropenia (27%), thrombocytopenia (20%) anemia (18%), hypophosphatemia (18%), leukopenia (16%), maculo-papular rash (13%), alanine aminotransferase elevation (11%), fatigue (9%), dyspnea (9%), hyponatremia 7%, thromboembolism (7%), lung infection (4%), hypoalbuminemia (4%). Serious adverse events included thromboembolism (13%), dyspnea (9%), anemia (7%), lung infection (4%), thrombocytopenia (4%), hyponatremia (4%), and pleural effusion (4%). Conclusions: Upfront treatment of NDMM with modern, highly efficacious CRd-R therapy with by-default-delayed HDM-ASCT led to high rates of sustained MRDneg CR (as defined by the updated 2016 IMWG response criteria) which is correlated with longer PFS and OS. Clinically important, these deep responses were observed regardless of the age of patients or cytogenetic risk. Our findings stress the importance of utilizing highly efficacious triplet-based regimens for the treatment of patients with NDMM regardless of age or cytogenetic risk. Updated results will be presented at the Annual Meeting. Disclosures Korde: Medscape: Honoraria. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Landgren:Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; Merck: Honoraria; BMS: Honoraria.

WT1 Monitoring of Minimal Residual Disease (MRD) in Patients with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3695-3695 ◽  
Author(s):  
Michele Malagola ◽  
Crisitina Skert ◽  
Enrico Morello ◽  
Francesca Antoniazzi ◽  
Erika Borlenghi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
End Of Treatment ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: Although a complete remission (CR) can be achieved in 70-80% of newly diagnosed acute myeloid leukemia (AML) patients, relapses occur in up to the 50% of cases. Thus, minimal residual disease (MRD) monitoring is a major issue for early detection of patients at high-risk of treatment failure and relapse. Aim: to dynamically evaluate WT1 pan-leukemic molecular marker of MRD in patients with AML. Matherial and methods: 107 newly diagnosed AML patients consecutively treated between 2010 and 2013 were monitored with quantitative WT-1 from bone marrow (BM) and peripheral blood (PB) at baseline, after induction, after the first consolidation course, before allogeneic stem cell transplantation (allo-SCT), at the 3rd and the 6th month after transplantation Results: At diagnosis, 104/107 (97%) had increased PB and BM WT1 levels assessed according to the ELN assay. Eighty-eight out of 107 patients (82%) achieved a complete remission (CR) after induction, 30/88 (34%) relapsed during follow up and 24/107 (22%) were addressed to allogeneic stem cell transplantation (allo-SCT). By univariate analysis, PB-WT > 50x10^4/ABL and BM-WT1 > 250x10^4/ABL after induction (PB: p=0.02; BM: p=0.04), after consolidation (PB: p=0.003), at the end of treatment (PB and BM: p=0.001), at 3rd month of follow up (PB and BM: p=0.005) and at 6th month of follow up (PB: p=0.005) were associated with a reduced overall survival (OS). By multivariate analysis, a BM-WT1 > 250 x 10^4/ABL at the end of treatment was significantly associated with a reduced OS. In order to adapt the cut-off of WT1 in our series of patients, we considered WT1 levels as continuous variables and categorized them at approximately the 25th, 50th, and 75th percentile. A cut-off of PB-WT1 > 25x10^4/ABL and BM-WT1 > 125x10^4/ABL at the end of the treatment program was identified as correlated with reduced leukemia-free survival (LFS) and OS (p=0.001). Similarly, and restricting the analysis on the 24 patients allo-transplanted in CR, 8/11 (73%) with pre-transplant PB-WT1 ≥ 5 and 4/13 (31%) with PB-WT1 < 5 relapsed, respectively (p=0.04). The incidence of relapse was higher in AML patients with PB-WT1 ≥ 5 measured at 3rd (56% vs 38%; p=0.43) and 6th month (71% vs 20%; p=0.03) after allo-SCT. Interestingly, 5/5 (100%) patients with pre-transplant PB-WT1 ≥ 5 who never reduced this level at 3rd or 6th month after allo-SCT experienced a disease recurrence. Conclusions: our data, although retrospectively collected, show that WT1 monitoring may be useful to predict the relapse in AML patients. Acknowledgments: This work was supported in part by Banca di Credito Cooperativo di Pompiano e Franciacorta and Lions Club Bassa Bresciana Association. Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy.

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.

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.

scholarly journals A Prospective Phase 2 Study to Assess Minimal Residual Disease after Ixazomib, Lenalidomide and Dexamethasone Treatment for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Raija Helena Silvennoinen ◽  
Anders Waage ◽  
Valdas Peceliunas ◽  
Fredrik Schjesvold ◽  
Pekka Anttila ◽  
...  
Keyword(s):  
Research Funding ◽  
Residual Disease ◽  
Median Number ◽  
Tumor Burden ◽  
Advisory Board ◽  
Phase 2 ◽  
Board Meeting ◽  
Cd34 Cells ◽  
Grade 3 ◽  
Minimal Residual

Introduction Autologous stem cell transplantation (ASCT) combined with novel agents is considered as the standard treatment for eligible patients &lt; 70(-75) years of age with multiple myeloma (MM). The number of induction cycles is usually 4-6 followed by ASCT, consolidation and maintenance. The role of consolidation is still under debate especially if complete response has been achieved and maintenance will follow. To improve the quality of life and avoid the frequent visits at hospital an all-oral treatment would be a preferred choice. Despite novel drugs, the outcome of high-risk (HR) patients is poor. We designed a phase 2 Nordic Myeloma Study Group (NMSG) trial (NCT03376672) to explore the response of ixazomib, lenalidomide and dexamethasone (IRd) induction, followed by single ASCT, IRd consolidation and risk-based maintenance either with IR or R. Here we present the response rates and safety after IRd x 4 induction in all patients and in 87% of patients before consolidation. Patients and methods This study included 120 patients in 22 NMSG sites. Patients received 4 IRd cycles as induction, ixazomib 4 mg on days 1, 8, 15, lenalidomide 25 mg on days 1-21, dexamethasone 40 mg weekly in 28-day cycles. Mobilization and ASCT were performed according to standard practice. Three months post-ASCT all patients will receive 2 IRd as consolidation followed by maintenance. Thereafter patients will be stratified to HR if any of the following FISH aberrations were found at inclusion: del17p at least 60%, t(4;14), t(14;16), t(14;20) or +1q and they receive ixazomib 4 mg on days 1, 8, 15 and lenalidomide 10 mg on days 1-21. Non-HR patients receive lenalidomide 10 mg on days 1-21. Maintenance will continue until progression (PD). Lenalidomide dose will increase to 15 mg after 3 cycles. The primary endpoint of the study is minimal residual disease (MRD) by 8-color Euroflow &lt; 0.01%. The secondary endpoints include flow-MRD negativity by 10-5, overall response, safety and progression-free survival. Serological responses were assessed before cycles and if sCR or CR is achieved flow-MRD sampling will be performed and repeated every 6 months. Samples were taken concomitantly for later comparison with BM- molecular-MRD, blood cell-free DNA, blood heavy-light chain assay and blood mass spectrometry. Results Within 21 months 120 patients were included, 46 % of them belong to the HR group. Mobilization is by July 2020 performed for 101 (84%) patients with cyclophosphamide (Cy) + G-CSF in 74% and G-CSF alone in 26%. Plerixafor was needed in 32 (32%) patients. The median number of harvesting days was 2 (0-4) and the median number of collected CD34+ cells was 6.4 (0-19.2) x 106/kg. Four patients (4%) failed to mobilize during 1st attempt. Eighty-six (72%) patients have so far received ASCT with the median number of 3.4 x 106/kg CD34+ cells in graft. Overall response rate is 93%. The responses after IRD x 4 induction and before consolidation are presented in Table 1. Before consolidation 10 patients (8%) are out of study due to PD and 4 (3%) have been withdrawn due to toxicity. Toxicity events included hypersensitivity with hepatorenal failure, grade 3 cytopenia with liver toxicity and one unexplained encephalitis. One patient was withdrawn due to Cy toxicity. Eight additional patients are withdrawn from study, 7 by physician´s decision and 1 by patient´s decision. All these 7 patients had high tumor burden based on paraprotein level either in serum (53 - 102 g/L) or in 24h urine (7.8 - 23.2 g/24h) and achieved only stable disease (SD) during induction. Fifty-eight grade 3-4 SAE reports from 39 (33%) patients have been received and 57% of these were infections. Three patients had grade 3 liver problems and 2 patients grade 3 peripheral neuropathy. Seventeen (14%) patients have reported skin reactions, only 4 of them grade 3 events. Conclusion We present here data on response and safety after observation of all patients until post-induction phase and of 87 % of the patients until start of the consolidation phase. The ORR is 93% when all patients have received induction treatment. Nine patients achieved only SD and seven of them with high tumor burden were withdrawn before mobilization. At least VGPR after ASCT was achieved in 37%. Toxicity caused the withdrawal of 4 (3%) patients and 39 (33%) patients have reported grade 3-4 non-hematological SAEs. In all, 98/120 (82%) patients continue in the study including 80% of the HR patients. Disclosures Silvennoinen: BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cancer patients Finland: Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Schjesvold:Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy. Anttila:Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Research Funding. Säily:Amgen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Janssen Cilag: Honoraria; Boehringer Ingelheim: Honoraria. Sankelo:Celgene, Amgen, Sanofi: Other: Congress travel support. Partanen:Abbvie: Honoraria, Other: Scientific Advisory Board Meeting; Behring: Honoraria; Takeda: Other: Scientific Advisory Board Meeting.

scholarly journals Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (36) ◽  
pp. 4381-4389 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Recommended Dosage ◽  
Disease Response ◽  
Grade 3 ◽  
Minimal Residual

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

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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