scholarly journals Bortezomib Maintenance (BM) or Consolidation (BC) Following Aggressive Immunochemotherapy and Autologous Stem Cell Transplant (ASCT) for Untreated Mantle Cell Lymphoma (MCL): 8 Year Follow up of CALGB 50403 (Alliance)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 146-146 ◽  
Author(s):  
Lawrence D Kaplan ◽  
Matthew J. Maurer ◽  
Wendy Stock ◽  
Nancy L. Bartlett ◽  
Noreen Fulton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Dropout Rate ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction

Abstract Introduction: Aggressive chemo-immunotherapy followed by peripheral blood stem cell autografting (ASCT) in CALGB (Alliance) 59909 achieved a median progression-free survival (PFS) in MCL of 5 years (Damon et al JCO, 2009), but late recurrences occurred. Using the CALGB 59909 treatment backbone, we evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM)in a randomized phase II trial. Interim results of CALGB (Alliance) 50403 were previously presented (ASH 2015) demonstrating 5 yr PFS 70% and 69% for the BM and BC arms respectively. We now report final 8 year follow up results from this trial and compare outcomes to CALGB 59909, which differed from CALGB 50403 only by the absence of post-transplant bortezomib. Methods: The primary endpoint was PFS measured from randomization for each treatment arm. Induction therapy was with 2-3 cycles of augmented R-CHOP (2000 mg/m2 cyclophosphamide) and methotrexate (300 mg/m2) followed by high-dose cytarabine/etoposide/rituximab(R)/filgrastim (EAR) stem cell mobilization and cyclophosphamide/carmustine/etoposide (CBV) ASCT. After 2 doses of post-transplant R, patients were randomized to BC (1.3 mg/ m2 IV days 1, 4, 8, 11 of a 3-week cycle for 4 cycles) or BM (1.6 mg/m2 IV weekly x4 every 8 weeks for 18 months) beginning at approximately day 90. Minimal residual disease (MRD) was analyzed using patient-specific PCR probes for the bcl-1 / IgH junction or the IgH CDR3 region. Results: 151 patients were enrolled from 10/2006 - 6/2010 at 14 sites; 147 who received treatment are included in this analysis. Median age was 59 years (29-69); stage II (2.7%), III (11.6%), IV (85.0%); MIPI low (52.4%), intermediate (30.6%), high (17.0%); blastoid histology (12.9%); bone marrow involvement (81.0%); Ki67 was evaluated in 86 and was >30% in 17.4% of patients. 118 (80%) underwent ASCT and 102 (68%) were randomized. Most withdrawals (45) were for progression (10) or adverse events (AEs) (19) including 4 treatment-related deaths. Fifty-two patients were randomized to BM and 50 to BC. Following randomization, 34 (65%) completed BM and 33 (66%) completed BC. Withdrawal for AEs occurred in 14 (28%) of BC and 7 (13%) of BM patients (p = 0.09), most for cytopenias or peripheral neuropathy. With a median follow-up 7.8 years from randomization (8.3 from registration), the median PFS from randomization for the BM arm was not reached and was 8.9 years (95% CI 7.2 to not reached) for the BC arm. Both arms had median PFS significantly greater than the null hypothesis setting median PFS to 4 years (p < 0.001; 1-sided test of exponential parameter)The 8-year PFS estimates in the BM and BC arms were 77% (95% CI 66-90%) and 58% (95% CI 44-76%), respectively. Among all 147 patients treated on CALGB 50403, 8-year PFS from time of registration was 43.6% (35.6-53.3%). PFS from registration was not significantly extended in CALGB 50403 compared with CALGB 59909 (log rank p=0.24), but using a landmark analysis from time of transplant, PFS was significantly extended in CALGB 50403 (log rank p=0.005)(fig 1). Baseline patient characteristics in the two studies were not significantly different. In CALGB 50403, 8-year PFS from registration by MIPI was 52.0% (95% CI 41.1-66.0%) in MIPI low risk, 37.5% (95% CI 25.3-55.4%) in intermediate risk, and 28.2% (95% CI 13.7-57.9%) in high-risk. Bone marrow MRD results were collected for 42 patients post-induction therapy; 8-year PFS estimates were 80.2% (95% CI 62.2-100%) (n=17) and 43.2% (95% CI 27.3-68.2%) (n=25) for MRD-negative and MRD-positive patients, respectively (p=0.009). Conclusions: Induction chemotherapy followed by ASCT and either BC or BM was efficacious and tolerable, although BC was associated with more withdrawals for toxicity. PFS was not significantly different between BC and BM. The comparison between studies 50403 and 59909 with long-term follow up continues to suggest a PFS benefit from the addition of BC or BM among patients undergoing transplant. This did not translate into a PFS benefit from time of study enrollment possibly due to the higher pre-transplant dropout rate in 50403. MRD-negativity following induction chemo-immunotherapy is highly associated with improved PFS and the role of ASCT in post-induction MRD-negative patients is currently under investigation in a randomized clinical trial. Support: U10CA180821, U10CA180882, U24CA196171; ClinicalTrials.gov Identifier: NCT00310037 Disclosures Kaplan: Bayer Pharmaceuticals: Consultancy. Maurer:Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Bartlett:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blum:Acerta: Consultancy; Astra-Zeneca: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board. Leonard:AstraZeneca: Consultancy; Juno: Consultancy; BMS: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Biotest: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; United Therapeutics: Consultancy; Sutro: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy.

scholarly journals Donor Lymphocyte Infusion for Primary Cutaneous T Cell Lymphomas: A Study from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and the French Study Group on Cutaneous Lymphomas (GFLEC)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3341-3341 ◽  
Author(s):  
Sarah Faiz ◽  
Henry Abi Rached ◽  
Edouard Forcade ◽  
Noel Milpied ◽  
Marie Beylot-Barry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Post Transplant ◽  
T Cell Lymphomas ◽  
Cutaneous Lymphomas

Abstract Introduction: Primary cutaneous T cell lymphomas (PCTCL) including Mycosis fungoides (MF) and Sézary syndrome (SS) account for 75% of primary cutaneous lymphomas. The 5-year survival is 18-40% in patients with advanced-stage PCTCL. Management strategies and prognosis of PCTCL depend on the disease stage (affected body surface area, blood, visceral and nodal involvement). Allogeneic hematopoietic cell transplantation (allo-HCT) can be used to treat advanced stages in young adults who are otherwise in good health. However, post-transplant relapse is still an issue with no clear guidelines regarding its management. Here we describe the largest study investigating donor lymphocyte infusions (DLI) in patients who relapsed after allo-HCT for PCTCL. Patients and methods: We conducted an observational, retrospective, French multicenter study. Between January the 1st 2000 and December the 31st 2017, all patients who underwent an allo-HCT for PCTCL regardless of the subtype and who received DLI for a post-transplant relapse were included. Data were collected using the ProMISE database. As needed, centers were asked to provide additional data. Statistical analyses were carried out by the Lille University Hospital (CHRU Lille) Biostatistics Methodology Unit and were performed using SAS software (SAS Institute version 9.4). Results: All 13 patients who received DLI after allo-HCT for a PCTCL in France were enrolled in the study (Figure 1). Mean duration of follow-up was 718 days. See table 1 for study population characteristics. Four patients (30%) presented acute graft versus host disease (GVHD) following allo-HCT, of which no incidences were superior to grade 2. Those four patients relapsed at day 342, 463, 499 and 659 after allo-HCT. Five patients (38%) presented chronic GVHD of which three had an extensive presentation. Those three patients relapsed at day 1082, 1568 and 1861. Table 2 details relapses and relapse management in our cohort. Table 3 shows parameters relative to allo-HCT, post-therapeutic management, and follow-up. Objective response rates to DLI was 62% (n=8). Five patients (38%) showed complete response and three patients exhibited partial response (32%). Five patients (38%) did not respond to DLI. The median best response duration to DLI was 181 days. Six out of the eight patients who responded to DLI relapsed (75%); the median time before the relapse after DLI was of 405 days. The two patients who have received DLI and did not relapse on January the 1st 2018 had 321 and 1350 days follow-up. Progression-free survival (PFS) was 46% at 1 year and 19% at 5 years (Figure 2). Overall survival rates were 100% at 1 year and 59% at 5 years (Figure 3). Six patients (46%) presented GVHD after DLI of which three cases were chronic GVHD. Two of them was an extensive presentation. One patient had received an allo-HCT from a female donor. One patient received bone marrow transplant carrying a 9/10 mismatch. All other patients received peripheral blood stem cell (PBSC) transplantation; two of them received a geno-identical stem cell transplantation from sibling donors and three patients received non-sibling donor HSCT with a 10/10 mismatch. Only three patients received DLI following SFGM-TC guidelines. Four patients died before January the 1st 2018 in our cohort. One patient died because of direct complications of the HSCT and related treatments. Two patients died because of a disease relapse. One patient died from unrelated cause (severe pulmonary). Conclusion: With a 5-year survival rate of 59% from the date of post-transplant relapse, DLI appears to be an effective treatment in cases of patient relapse after allo-HCT for PCTCL. DLI should be considered in the management of post-transplant relapse whenever possible. To our best knowledge, this is the largest study cohort investigating DLI in the post-transplant setting Disclosures Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Peffault De Latour:Amgen Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding.

scholarly journals Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4496-4496 ◽  
Author(s):  
Luke Eastburg ◽  
David A. Russler-Germain ◽  
Ramzi Abboud ◽  
Peter Westervelt ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Mortality ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Post Transplant ◽  
Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Outcomes of Myeloma Patients with t(11;14) Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3282-3282 ◽  
Author(s):  
Jonathan L Kaufman ◽  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Charise Gleason ◽  
Craig C Hofmeister ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Data Monitoring Committee ◽  
The Other ◽  
Control Group ◽  
Advisory Committees ◽  
Post Induction ◽  
Standard Risk

Abstract Background: In the cytogenetic risk-stratification of myeloma, identification of t(11;14) on plasma cells has long been regarded as a standard risk prognostic factor. More recently, there have been reports of inferior PFS and OS relative to the standard risk myeloma patients. These results carry significance in the current day, as an ongoing phase I trial of Bcl-2 inhibitor (venetoclax) reported an ORR of 40% among myeloma patients with t(11;14) leading way for individualized therapeutic approach for myeloma. In this context, we evaluated the clinical outcomes of t(11;14) myeloma patients receiving uniform modern day induction therapies to evaluate the prognostic implication of this translocation. Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with RVD induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, we have FISH probes for t(11;14) tested in 867 patients. Among these patients, we identified 122 patients with t(11;14). Excluding 247 patients that had del 17p, t(4;14), t (14;16) and complex karyotype on metaphase cytogenetics, we have identified 527 patients that formed the control group of standard risk myeloma. Demographic and outcomes data for the patients were collected from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the patients is 61 years (range 16-83). 32% of the patients are above the age of 66. Other patient characteristics include: M/F 56%/44%; W/AA 62%/36%; ISS I/II/III 48%/30%/22%; Isotype IgG/IgA/FLC 60%/18%/19%. Response rates are summarized in table 1. Post induction responses ≥VGPR are lower for t(11;14) compared with non-t(11;14): 49.5% vs 76.3% p<0.001 and similarly best VGPR for t(11;14) vs non-t(11;14): 76.3% vs 91.4% p=0.001. The median progression-free survival for the t(11;14) and non-t(11;14) groups were 51 months (95% confidence interval (CI), 30.628-71.372) and 75 months (95% CI, 57.882-92.118) months, respectively (P<0.001), at a median follow up of 39 months. This difference is more pronounced among patients not receiving maintenance therapy (29 vs 62 months, p=0.001). The median overall survival (OS) for t(11;14), and non-(11;14) groups were not reached at a median follow up of 38 months. Conclusions: Even with the use of modern day induction regimens, patients with t(11;14) have inferior outcomes compared to the other patients standard risk myeloma. The lower rates of ≥VGPR post-induction and the shorter median PFS suggests more novel regimens such as venetoclax should be studied earlier in the course to improve the outcomes of t(11;14) patients on par with the other standard risk myeloma patients. Disclosures Kaufman: Janssen: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Lonial:Amgen: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Splenic Irradiation and a Reduced-Intensity Conditioning Regimen Prior to Allogeneic Stem-Cell Transplantation for Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3170-3170 ◽  
Author(s):  
Ojas H. Vyas ◽  
Esha Kaul ◽  
Aaron S. Rosenberg ◽  
Gunjan L Shah ◽  
Urvi Ajay Shah ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Disease Response ◽  
Hematologic Response ◽  
Complete Hematologic Response

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelofibrosis (MF). Reduced-intensity conditioning (RIC) regimens have been used to extend this therapy to older and sicker patients. Splenectomy prior to HSCT for MF has been shown to enhance neutrophil engraftment and decrease transfusion requirements, but has a reported operative mortality of 9% or higher. Splenic irradiation (sXRT) has been historically used as a palliative treatment in MF. We present our experience with a RIC regimen incorporating extracorporeal photopheresis (ECP) in combination with either pre-HSCT splenectomy or sXRT. Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients underwent conditioning consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2by continuous infusion over 48 hours on days -4 and -3, and a total dose of 600 cGy total body irradiation (TBI) administered in 3 fractions on days -2 and -1 (PPT). sXRT, when employed, was given in the week prior to start of PPT (days -6 to -11) with total doses ranging from 300 to 500cGy. Cyclosporine and methotrexate were used for GVHD prophylaxis. Patients surviving a minimum of six months were considered evaluable for response assessment. Complete hematologic response was defined as resolution of clinical signs of MF as well as normalization of peripheral blood counts (Hgb>10gm/dL, ANC>1000/µL, Platelets >100K and all counts below upper limit of normal) and the absence circulating blasts. Histological response could not be assessed due to lack of follow-up bone marrow data. Clinical improvement, stable disease, progressive disease, spleen response were defined using revised IWG-MRT guidelines. Overall survival (OS) was estimated using the Kaplan Meier method from time of stem cell transplant to death. Non-relapse mortality (NRM) was estimated from time of transplant to death, treating death due to MF and relapse as competing risks. Results: Ten patients (7 females, 3 males) with MF underwent allogeneic HSCT with PPT conditioning between February 2001 and December 2012. Median age was 54 years (40-60 years). Median time from diagnosis to transplant was 48 months (6-137 months). MF was primary in 8 and secondary to essential thrombocytosis in 2 patients. According to DIPSS scoring, 1, 2, 5 and 2 patients were low, intermediate-1, intermediate-2 and high risk respectively. Donors were equally distributed between matched related and matched unrelated. Bone marrow was used as the source in all but one patient. Nine patients (90%) had palpable splenomegaly. Six underwent splenectomy of which 1 died of a related complication (sepsis from abscess in the splenic bed). Three received sXRT prior to HSCT with no associated complications. All but one patient (who had a prior splenectomy) engrafted successfully. Median time to engraftment was 18 days (sXRT 18 days, splenectomy 19 days) for neutrophils and 26 days for platelets regardless of splenic therapy. Only 2 patients developed acute grade III-IV GVHD and 1 patient developed extensive chronic GVHD. 4/7 patients with a prior splenectomy were evaluable for disease response. Of these 2 had complete hematologic response, 1 had clinical improvement with eventual relapse, and 1 had progressive disease. Among the 3 patients receiving sXRT, 2 patients had complete hematologic response as well as a spleen response and 1 had stable disease.Three patients were alive at last follow-up. Causes of death included disease relapse (n=2), GVHD (=3) and sepsis (n=2). Cumulative incidence of NRM was 40% at 1 year. Five year OS was estimated at 30%. Discussion: Our data demonstrates that splenic XRT is well tolerated and equivalent to splenectomy in terms of engraftment outcomes and disease response. Survival and GVHD outcomes with PPT conditioning were similar to those reported with other RIC regimens. PPT is a reasonable conditioning regimen for these patients. Further study to optimize timing of HSCT and patient selection to reduce NRM is needed. Disclosures Comenzo: Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Supermobilizers with High CD34 + Cell Collection for Autologous Transplant and Impact on Survival Outcomes in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1837-1837
Author(s):  
Eyal Lebel ◽  
Katherine Lajkosz ◽  
Esther Masih-Khan ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Survival Outcomes ◽  
Advisory Committees ◽  
Cd34 Cells

Abstract Introduction: Autologous stem cell transplantation (ASCT) is standard therapy for selected patients with newly diagnosed multiple myeloma (MM). Studies in MM and lymphoma have suggested that ability to mobilize and collect a higher yield of CD34 + cells predicts for improved survival outcomes, perhaps reflecting better bone marrow reserve (Bolwell 2007, Raschle 2011). We aimed to validate this hypothesis by correlating high CD34 + cell collection ("supermobilizers") and survival outcomes in a large myeloma cohort with long follow-up. Methods: We retrospectively reviewed MM patients (pts) who underwent ASCT at our centre 2000-2010, correlating number of CD34 + cells collected with post-transplant progression-free survival (PFS) and overall survival (OS). Stem cells were mobilized using cyclophosphamide 2.5 g/m 2 IV (day 1), G-CSF 10 ug/kg/day SC (starting on day 4), and leukapheresis (day 11), targeting 4x10 6/kg but accepting a minimum of 2x10 6/kg to support a single transplant. Using a cut-off used in previous studies, pts were categorized as "supermobilizers" if ≥8x10 6/kg CD34+ cells were collected. Results: 621 pts were analyzed. Most pts (422/605; 70%) received high dose dexamethasone (HDD) alone or in combination with vincristine and adriamycin (VAD) for pre-transplant induction therapy (pre-dating the novel agent era) with only 18% (110/605) receiving more contemporary bortezomib-based induction (mostly cyclophosphamide, bortezomib and dexamethasone; CyBORD). The median number of CD34 + cells collected for all pts was 13.9x10 6/kg (range 2.1-61.8). The median CD34 + cells re-infused was 6.2x10 6/kg (range 2.1-25), as some cells were reserved for 2 nd ASCT, but median CD34+ cells collected correlated with CD34 + cells infused (Pearson coefficient 0.81, p&lt;0.001). At a median follow-up of 74 months (m), we were surprised to report an inferior PFS of 24.1m for the supermobilizers collecting ≥8x10 6/kg vs 33.7m for the &lt;8 group (p=0.038, Figure 1a), without differences in OS (p=0.612, Figure 1b). No further discrimination in PFS was observed when using a more extreme supermobilizer cut-off of 15x10 6/kg. To further understand the counterintuitive result of shorter PFS with higher mobilization capacity, we explored the continuous relationship between CD34 + cells and PFS, identifying another optimal cut-off of 4.5x10 6/kg. Pts collecting in the mid-range (4.5-8; n=129) achieved the best PFS of 34.5m, significantly improved over 24.1m in the ≥8 group (n=478) and 11.4m in the small group at the extreme lower collection range (n=14; ≤4.5x10 6/kg)(Figure 1c). A similar pattern was seen with OS (Figure 1d). Clinical and laboratory parameters that may impact both collection capacity and survival, such as age, ISS, and kidney dysfunction, were investigated as confounders but were similar between collection groups and did not predict for PFS in multivariable analyses. Treatment variables, however, differed between groups: the lower collection groups more often received bortezomib-based induction (29%, 31% and 14% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p&lt;0.001) resulting in deeper responses pre-transplant (VGPR 50% in the ≥8 group vs 43% in the 4.5-8 group, p=0.024) (Table 1). Use of maintenance therapy post-ASCT also differed (50%, 40% and 28% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p=0.006). Discussion: In this large cohort of 621 MM patients, we report that "supermobilizers" who collected ≥8 x 10 6 CD34 + cells/kg exhibit inferior PFS from transplant than those with less robust mobilization. We suspected that this unexpected observation was due to confounding variables, and identified differences in treatment, primarily greater use of bortezomib-based induction and post-transplant maintenance therapy in the lower collection group. This group was able to achieve deeper responses (≥VGPR) even before transplant than the supermobilizer group, leading to improved PFS. Although bortezomib is routinely used as induction therapy pre-transplant currently and is not felt to be stem cell toxic, it may impair mobilization to a lesser degree, leading not to abject failure of collection but lowered capacity to achieve "supermobilizer" status. Although more research is needed to validate this hypothesis, we can at minimum conclude that high stem cell collection does not appear to predict for a long-term survival advantage. Figure 1 Figure 1. Disclosures Reece: Millennium: Research Funding; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; BMS: Honoraria, Research Funding. Trudel: Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Chen: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) Induction, Autologous Transplantation and Post-Transplant, Response-Adapted, Measurable Residual Disease (MRD)-Based Dara-Krd Consolidation in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 860-860 ◽  
Author(s):  
Luciano J. Costa ◽  
Saurabh Chhabra ◽  
Kelly N. Godby ◽  
Eva Medvedova ◽  
Robert F. Cornell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Best Response

Background: The CD38-targeting antibody daratumumab, when combined with a proteasome inhibitor or with an immunomodulatory agent (IMiD) increases depth and duration of response in multiple myeloma (MM). Depth of remission post initial therapy as assessed by MRD predicts long term outcome in NDMM. We hypothesized that the combination of daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) would be safe and highly active in patients with NDMM. In addition, we assessed the feasibility of using MRD by next generation sequencing (clonoSEQ® method, sensitivity 10-6) to inform the use and duration of post-transplant Dara-KRd consolidation. Methods: Eligible patients (pts) had NDMM requiring treatment, creatinine clearance &gt;40 ml/min, adequate liver and cardiac function, ECOG performance status 0-2 with no age limit. Treatment cycles consisted of daratumumab 16 mg/kg IV days 1,8,15,22 (with typical reduction in frequency with subsequent cycles), carfilzomib 56 mg/m2 IV days 1,8,15, lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. Patients received 4 cycles of Dara-KRd as induction, autologous transplantation, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status at each phase of therapy. MRD was evaluated by clonoSEQ® (NGS-MRD; Adaptive Biotechnologies, Seattle, WA) at end of induction, post-transplant, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negative remission (&lt;10-5) as defined by IMWG consensus. Secondary endpoints included MRD &lt;10-6, complete response (CR) by IMWG criteria at end of induction and upon completion of consolidation, and rate of imaging (assessed by PET/CT scan) plus MRD-negative CR. Patients received therapy until achievement of two consecutive MRD reads &lt;10-5 (confirmed MRD-negative remission; e.g., post-induction and post-transplant or post-transplant and during consolidation). Confirmed MRD-negative pts received no further therapy and were observed with surveillance for MRD resurgence 6 and 18 months after treatment discontinuation. Patients completing consolidation without confirmed MRD-negative remission received standard lenalidomide maintenance (NCT03224507). Results: Currently 69 pts have been enrolled, 38 have completed induction and 22 have completed post-transplant assessment. Median age was 61 (range 38-79) years, 13 (19%) had ISS 3, and 20 (29%) had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. Sixty-six (96%) pts had MRD trackable by clonoSEQ® and 100% of the expected MRD datapoints were successfully obtained. All patients responded by end of induction cycle 2, 92% of pts obtained VGPR or better after induction and 91% of patients who have reached transplant obtained CR/sCR as best response on therapy (Figure). MRD-negative remission (&lt;10-5) rate was 34%, 70% and 80% after induction, transplant and at best response, respectively (Figure). Rates of MRD &lt;10-6 were 28%, 45% and 65% respectively. No patient discontinued therapy due to toxicity. One patient died from metapneumovirus pneumonia post-transplant, considered not related to investigational agents. Most common grade 3 and 4 AEs were neutropenia (n=7), infection (n=6), insomnia (n=4), hyperglycemia (n=2) and rash (n=2). There were 15 serious AEs including pneumonia (n=5), fever and neutropenia (n=2), pulmonary embolism (n=1), and atypical hemolytic uremic syndrome (n=1). All 11 patients who have achieved confirmed MRD-negative remission and discontinued therapy also achieved imaging plus MRD-negative CR and none had relapse or resurgence of MRD with short follow up (0.8-7.3 months). Longer follow-up, post-induction and post-transplant MRD assessment for at least 69 and 41 pts, respectively, will be presented at the meeting. Conclusion: This is the first report of monoclonal antibody-based quadruplet regimen with MRD-based response-adapted therapy in NDMM. Dara-KRd induction, autologous transplant and Dara-KRd consolidation guided by MRD is feasible, safe and leads to high proportion of patients achieving CR/sCR, IMWG MRD-negative CR, imaging plus MRD-negative CR and MRD &lt;10-6. This approach can form the basis for clinical efforts to reduce the burden of continuous therapy in those with confirmed MRD-negative remissions. Figure Disclosures Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Cornell:Takeda: Consultancy; KaryoPharm: Consultancy. Silbermann:Janssen, Sanofi: Other: Consultant/Advisor. Dhakal:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Hari:Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Carfilzomib for newly diagnosed multiple myeloma

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

scholarly journals Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2149-2149
Author(s):  
Romil Patel ◽  
Neeraj Y Saini ◽  
Ankur Varma ◽  
Omar Hasan ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Advisory Committees ◽  
First Remission ◽  
Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

scholarly journals Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 863-863 ◽  
Author(s):  
Robert M. Rifkin ◽  
Jason M. Melear ◽  
Edward Faber ◽  
William I. Bensinger ◽  
John M Burke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Safety Profile ◽  
Employment Equity ◽  
Advisory Committees ◽  
Depth Of Response ◽  
Equity Ownership ◽  
Grade 3

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (&gt;2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (&gt;5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the &gt;CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

Multiple Myeloma In Complete Remission After Autologous Stem Cell Transplantation: Impact of Bone Marrow Plasma Cell Assessment by Conventional Morphology on Disease Progression

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2946-2946
Author(s):  
Carlos Fernández de Larrea ◽  
Natalia Tovar ◽  
María Rozman ◽  
Laura Rosiñol ◽  
Juan I. Aróstegui ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Bone Marrow Aspirate ◽  
Advisory Committees ◽  
Bone Marrow Plasma ◽  
Serum And Urine

Abstract Abstract 2946 Background: The achievement of complete remission (CR) is the crucial step for a long-lasting response and prolonged survival after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). The European Group for Blood and Marrow Transplantation (EBMT) criteria for CR include the negativity of serum and urine immunofixation (IFE) and less than 5% of bone marrow plasma cells (BMPCs). Additionally, the International Myeloma Working Group (IMWG) has even proposed a stringent CR category, which requires to rule out the clonal nature of the BMPCs. However, few studies have addressed this issue in patients with MM and negative IFE. The aim of the present study was to determine the impact of plasma cell count in the bone marrow aspirate on the long-term outcome of patients with MM with negative IFE after ASCT. Methods: Thirty-five patients (16M/19F; median age at ASCT 55 years, range 26–68) with MM who underwent ASCT from March 1994 to December 2008, were studied. All patients had achieved a negative serum and urine IFE after high dose therapy with melphalan-based regimens. Bone marrow aspirate was performed when negative serum and urine IFE was achieved and at least three months from ASCT (median 3.24 months). The analysis was based on microscopic revision for May-Grünwald-Giemsa stained bone marrow smears performed according to standard procedures. BMPC percentage was calculated independently by two observers counting 500 bone marrow total nucleated cells in random areas from two different slides (1000 cells on each patient). Results: Median BMPCs percentage was 0.8 (range 0.1–5.8). Only two patients had more than 3% BPMCs. These results are in contrast with a recent report from the Mayo Clinic group, where 14% of the patients with MM and negative IFE had 5% or more BMPCs. In univariate Cox-model regression analysis, the number of BMPCs significantly correlated with progression-free survival (PFS)(p=0.021) with no impact on overall survival (OS)(p=0.92). This statistical significance on PFS was retained in the multivariate analysis, when baseline prognostic factors such as age, hemoglobin level, serum creatinine, β2-microglobulin and Durie-Salmon stage were added to the model (p=0.003). To establish the best predictive cut-off for progression and survival, a receptor-operator curve (ROC) analysis was developed. It showed the value of 1.5% BMPCs, with a sensitivity of 53%, specificity of 90% and area under the curve of 0.66 for predicting progression. Ten patients had more than 1.5% BMPC, and 25 equal or less than 1.5% BMPC. Median PFS was 8.5 years (CI 95% 2.6 to 14.3) and was not reached in patients with ≤1.5% BMPCs versus 3.1 years in patients with >1.5% BMPCs, with a hazard ratio probability to progression of 3.02 (CI 95% 1.18 to 9.71)(p=0.016) in the group with more than 1.5% of BMPCs (Figure 1). Median OS was not reached in patients with ≤1.5% compared with a median of 9.7 years in those with more than 1.5% BMPCs (p=0.195) (Figure 2). It is likely that serological CR with very low percentage of BMPCs (i.e. ≤1.5%) is equivalent to negative MRD assessed by MFC or molecular studies. In fact, all 8 patients in continued CR between 9 and 16 years beyond ASCT (“operational cures”) are in the group with ≤1.5% BMPCs, while all patients in the group with >1.5% BPMC have relapsed within the first 9 years from ASCT (Figure 1). Conclusion: The percentage of BMPCs in patients with MM in CR after ASCT is a strong predictor of progression. Bone marrow morphology examination is an easy, inexpensive, and non-time consuming test and it should be the first step in the estimation of the residual tumor mass in patients with MM in CR after ASCT. Disclosures: Rosiñol: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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