Daily Weight-Based Busulfan with Cyclophosphamide and Etoposide (Bu/Cy/VP) Produces Comparable Outcomes to 4-Times-Daily Busulfan Dosing for Lymphoma Patients Undergoing Autologous Stem Cell Transplantation (ASCT)

Abstract INTRODUCTION: High dose busulfan (Bu) is an integral component of many commonly-used preparative regimens for both allogeneic and autologous transplantation. Data on the efficacy and toxicity of q6 vs. q24 hour dosing are of significant clinical interest. In order to facilitate a therapeutic dose-monitoring protocol, we transitioned from q6 to q24 Bu dosing as part of our standard Bu/Cy/VP ASCT preparative regimen for patients with Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL) in July 2012. We present comparative outcomes of q24 Bu dosing vs historical controls receiving q6 Bu. METHODS We retrospectively reviewed 400 consecutive eligible lymphoma patients who underwent ASCT from 2007-2013 with Bu/Cy/VP. All patients received Cy 60 mg/kg IV over 4 hours on days -3 and -2 and VP 60 mg/kg as continuous infusion on days -5 and -4. Bu was given at a dose of either 0.8 mg/kg q6 (N = 307) x 14 doses for patients transplanted between 2007-July, 2012 or 2.8 mg/kg q 24 hours (N = 93) on days -9 through -6 for subsequent patients. Outcomes assessed from date of transplant were: relapse, non-relapse mortality (NRM), relapse-free survival (RFS) and overall survival (OS). Toxicity was assessed using pulmonary and liver function tests (PFTs and LFTs) at specified time-points before and after ASCT. In addition, for a subset of 22 patients receiving q24 Bu, we measured serial Bu serum levels after the first dose of Bu with an in-house liquid chromatography-tandem mass spectrometry assay using turbulent flow online extraction technology (Bunch, et al. J Chromatogr B Analyt Technol Biomed Life Sci, 2010. 878(31): p. 3255-8) and subsequently determined the cumulative Bu area-under the curve (AUC). RESULTS Baseline patient and disease characteristics of patients dosed with q6 and q24 Bu were similar. The median age was 55 (range 20-78) years; 63% were males. 18% had HL and 82% had NHL with a comparable distribution of subtypes in both groups. Patients in both groups had comparable rates of prior chemotherapy regimens and of complete/partial remission at the time of ASCT. Due to a change in institutional guidelines, plerixafor was more commonly incorporated in peripheral blood stem cell mobilization regimen in the q24 group compared to q6 cohort (70% vs. 39%, P <0.001). However, CD34+ doses were same in the two dosing cohorts. In terms of toxicity of the two dosing approaches, there was no significant difference in FEV1 or DLCO before and after transplant in the q6 vs q24 cohorts. LFTs measured at four time points were generally lower with q24 Bu, particularly AST and alkaline phosphatase (P=0.007 each), but these difference were not clinically significant. The median follow-up was longer in the q6 than q24 group (48.2 months vs. 21.3 months, P < 0.001). 18 month outcomes of the two dosing cohorts were comparable (see Table and Figure). We observed significant variation in AUC with weight-based dosing of Bu (AUC range 12,104 - 23,084 µM-min) with a median of 17,568 µM -min, which has served as a baseline for subsequent therapeutic-dose monitoring. CONCLUSIONS Q24 Bu dosing in combination with Cy/VP is more convenient than q6 hours, has equivalent outcomes, and results in no increase in either hepatic or pulmonary toxicity. Consistent with previous reports, there is a significant range of Bu AUC levels, with a standard deviation of 12%. These data provide rationale for our prospective clinical trial of real-time therapeutic dose monitoring with q24 Bu dosing. Table 1. Q6 dosing Q24 dosing P-value OS 78% 80% 0.79 RFS 63% 61% 0.99 NRM 5% 3% 0.95 Relapse 30% 36% 0.46 18 month outcomes of q6 vs q24 Bu dosing Figure 1. RFS and OS for lymphoma patients undergoing ASCT with Bu/Cy/VP treated with q6 vs. q24 hour weight-based Bu dosing. Figure 1. RFS and OS for lymphoma patients undergoing ASCT with Bu/Cy/VP treated with q6 vs. q24 hour weight-based Bu dosing. Figure 2. Figure 2. Disclosures Hill: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Majhail:Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

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A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2020-143095 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Daniel Guy ◽

Marcus Watkins ◽

Fei Wan ◽

Nancy L. Bartlett ◽

Amanda F Cashen ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Complete Response ◽

High Dose ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3 ◽

Stem Cell Collection

Introduction The management of younger fit patients with mantle cell lymphoma (MCL) varies widely with no consensus on an optimal induction therapy. To date, the treatments with the longest progression-free survival incorporate a chemotherapy backbone that includes high dose cytarabine, followed by consolidation with an autologous stem-cell transplantation (ASCT) (Hermine et al. Lancet 2016, Eskelund et al. Br J Haematol 2016). Recent data showed that a regimen of bendamustine/rituximab followed by cytarabine/rituximab achieved high complete response rates with high minimal residual disease (MRD) negativity (Merryman RW et al. Blood Adv 2020). We hypothesized that adding the Bruton tyrosine kinase inhibitor acalabrutinib to the same chemotherapeutic backbone would be safe and increase complete response rates as well as minimal residual disease (MRD) negativity pre-transplant, and potentially improve clinical outcomes. Methods We conducted a single arm, single institution pilot study registered at clinicaltrials.gov (NCT03623373). Patients with untreated MCL, who were between ages 18-70 and were candidates for ASCT, were eligible. Patients received six 28-day cycles of treatment. Cycles 1-3 consisted of bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2 on day 1 and acalabrutinib 100mg BID on days 1 through 28. Cycles 4-6 consisted of rituximab 375 mg/m2 on day 1, cytarabine 2 g/m2 (1.5 g/m2 if age>60) q12 hours on days 1 and 2, and acalabrutinib 100mg BID on days 1 through 7 and 22 through 28. Restaging PET/CT and response assessment based on the Lugano classification were obtained following cycles 3 and 6. After cycle 6 patients underwent leukapheresis and stem-cell collection as preparation for ASCT. Blood for MRD status was collected after cycles 2, 4 and 6 and will be evaluated using the ClonoSeq assay (Adaptive Biotechnologies). The primary objective was to determine the stem cell mobilization success rate. Secondary objectives included safety and tolerability, overall response rate (ORR), pre-transplant complete response rate (CR), and the MRD negativity rate during and after completion of therapy. Results The trial enrolled 14 patients from December 2018 to February 2020. One patient withdrew consent prior to start of treatment and another was found to have an undiagnosed adenocarcinoma shortly after starting MCL treatment. Both are excluded from the analysis. The median age was 57 years (range 52-66). 11 patients were males (92%), all patients had an ECOG performance status of 0-1. 11 patients (92%) presented with stage IV disease. The mean MCL International Prognostic Index (MIPI) score was 6.3 (25% high-risk, 42% intermediate-risk and 33% low-risk). Of the 12 patients who began treatment, 9 completed all 6 cycles. Three patients did not complete therapy due to: insurance issues (n = 1), and thrombocytopenia (n = 2) following cycle 5 and 4. The side effect profile showed expected hematologic toxicities with grade 3-4 cytopenias in all patients, mostly during cytarabine cycles. In total, 100% of patients developed grade 3-4 thrombocytopenia and 83% of patients developed grade 3-4 neutropenia. Three episodes of febrile neutropenia were observed. One patient had a grade 3 transaminase increase, and one patient had grade 3 diarrhea. No bleeding events or treatment related deaths occurred. The remainder of the side effects were low grade and the treatment was generally well tolerated. Of the 12 evaluable patients, 10 responded (ORR 83%) with 9 achieving CR (75%). One patient achieved PR prior to being removed from the study due to thrombocytopenia and then achieved CR off study. Two patients experienced PD during induction. With a median follow up of 9 months, no responding patients have relapsed. The median CD34+ stem cell collection was 3.84x106 cells/kg (range 2.77 - 5.9). MRD results will be presented at the meeting. Conclusions This is the first study attempting to combine BTK inhibition with a high dose cytarabine containing regimen. The addition of acalabrutinib to a regimen of bendamustine/rituximab followed by cytarabine/rituximab appears to be safe. The R-ABC combination will be further tested in the recently activated intergroup trial EA4181. Disclosures Bartlett: Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy. Fehniger:ImmunityBio: Research Funding; HCW Biologics: Research Funding; Kiadis: Consultancy; Nkarta: Consultancy; Indapta: Consultancy; Wugen: Consultancy; Orca Biosystems: Consultancy; Compass Therapeutics: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; EUSA: Consultancy; WuGen: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy.

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A Comparison of Chemotherapy + G-CSF Versus Plerixafor (Mozobil®) + G-CSF for Stem Cell Mobilization In Patients with Multiple Myeloma Treated with Lenalidomide

Blood ◽

10.1182/blood.v116.21.2258.2258 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2258-2258

Author(s):

Tomer M Mark ◽

Adriana C Rossi ◽

Roger N Pearse ◽

Morton Coleman ◽

David Bernstein ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Yield ◽

High Dose ◽

Advisory Committees ◽

Cd34 Cells ◽

Stem Cell Collection

Abstract Abstract 2258 Background: Prior use of lenalidomide beyond 6 cycles of therapy in the treatment of multiple myeloma (MM) has been shown to negatively impact stem cell yield, but this phenomenon can be overcome with the addition of high-dose cyclophosphamide to standard G-CSF mobilization. We hypothesized that the use of plerixafor (Mozobil®) would compare similarly to chemotherapy in rescuing the ability to collect stem cells in lenalidomide-treated myeloma. Methods: We performed a retrospective study comparing the efficacy of plerixafor + G-CSF mobilization (PG) to chemotherapy + G-CSF (CG) (either high-dose cyclophosphamide at 3g/m2 or DCEP [4-day infusional dexamethasone/ cyclophosphamide/ etoposide/cisplatin]) in 49 consecutive stem cell collection attempts in patients with MM exposed to prior lenalidomide. The primary endpoint was the ability to collect sufficient stem cells for at least two transplants (minimum 5×106 CD34+ cells/kg), comparing results in terms of total exposure to lenalidomide and time elapsed from lenalidomide exposure until the mobilization attempt. The secondary endpoint was number of apheresis days required to meet collection goal. Resilts: Twenty-four patients underwent PG mobilization and twenty-five with CG (21 with G-CSF + cyclophosphamide, 4 with G-CSF+DCEP). The two groups did not differ in terms of total amount of lenalidomide exposure: median number of lenalidomide cycles for patients mobilized with PG was 6.5 (range 1.2–86.6), vs. 6 (range 2–21.6), for patients mobilized with CG (P = 0.663). The median time between mobilization and last lenalidomide dose was also similar between the two groups: 57.5 (range 12–462) days for PG vs. 154 (range 27–805) days for CG (P = 0.101). There was an equivalent rate of successful collection of 100% for PG and 96% for CG, P = 0.322. One patient failed collection in the CG group due to emergent hospitalization for septic shock during a period of neutropenia; no patient collected with PG had a serious adverse event that interrupted the collection process. Stem cell yield did not differ between the two arms (13.9 vs. 18.8 × 106 million CD34+ cells/kg for PG vs. CG respectively, P = 0.083). Average time to collection goal was also equal, with a median of time of 1 day required in both groups, (range 1–2 days for PG, 1–5 days for CG, P = 0.073). There was no relationship between amount of lenalidomide exposure and stem cell yield with either PG (P = 0.243) or CG (P = 0.867). Conclusion: A plerixafor + G-CSF mobilization schedule is equivalent in efficacy to chemotherapy + G-CSF in obtaining adequate numbers of stem cells for two autologous stem cell transplants in patients with MM exposed to lenalidomide; however, PG may be a less toxic approach than chemomobilization. Number of lenalidomide cycles has no impact on chances of stem cell collection success using either method. Disclosures: Mark: Celgene Corp: Speakers Bureau; Millenium Corp: Speakers Bureau. Zafar: Celgene Corp: Speakers Bureau. Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding.

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Modified-CVAD Or Modified-Cbad Compared To High Dose Cyclophosphamide For Peripheral Blood Stem Cell Mobilization In Patients With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.2036.2036 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2036-2036

Author(s):

Suzanne C Gettys ◽

Alison M Gulbis ◽

Kaci Wilhelm ◽

Yvonne T Dinh ◽

Gabriela Rondon ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Febrile Neutropenia ◽

Peripheral Blood Stem Cell ◽

High Dose ◽

Time To Progression ◽

Advisory Committees ◽

Cd34 Cells ◽

Significant Difference ◽

Cell Mobilization

Abstract Background Peripheral blood stem cell (PBSC) mobilization in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (auto-HCT) is commonly carried out using growth factors alone. Approximately 10-15% of patients receive chemomobilization, which assists with cytoreduction and improving the cell yield; however, an optimal regimen has not been established. Here we report our experience with three chemomobilization regimens that have been used at our center: i) cyclophosphamide alone (Cy) ii) modified cyclophosphamide, vincristine, doxorubicin, dexamethasone (mCVAD) and iii) modified cyclophosphamide, bortezomib, doxorubicin, dexamethasone (mCBAD). Methods This is a single-center, retrospective chart review of patients with multiple myeloma undergoing mobilization for an auto-HCT with Cy, mCVAD, or mCBAD between January 1, 2006 and September 30, 2012. A total of 120 patients were identified as initiating stem cell mobilization with Cy (n=39), mCVAD (n=66) or mCBAD (n=15) for multiple myeloma within the defined time period. For the purpose of this study, we combined mCVAD and mCBAD into one group (n=81). The primary objective of this study is to compare successful mobilization and collection (≥ 2 x 106 CD34+ cells/kg collected) between high dose Cy (2-4 g/m2 x1) and mCVAD (cyclophosphamide 350 mg/m2 q12h x 4 days, vincristine 0.4mg continuous infusion daily x 4 days, doxorubicin 10 mg/ m2 continuous infusion daily x 4 days, dexamethasone 40 mg IV daily x 4 days) + mCBAD (same as previous, except using bortezomib 1.3 mg/m2 bolus x 4 days instead of vincristine). Secondary objectives include optimal mobilization (≥ 4 x 106 CD34+ cells/kg), median number of leukapheresis sessions required, use of plerixafor, post-transplant time to neutrophil engraftment, disease status at day 100, time to progression, and incidence of febrile neutropenia, hospitalization, and ICU admissions with each mobilization regimen. Results The groups were well-matched with regard to demographic characteristics. [Table] All 120 achieved a successful mobilization (≥ 2 x 106 CD34+ cells/kg collected) and 118 achieved an optimal mobilization (≥ 4 x 106 CD34+ cells/kg collected). There was no significant difference in the number of leukapheresis sessions (median 2, range 1-7) or plerixafor use (20.5% Cy vs. 8.6% mCVAD or mCBAD, p=0.08). There was no significant difference in the incidence of febrile neutropenia (10.3% Cy vs. 12.4% mCVAD or mCBAD, p=1.00), hospital admissions (18% Cy vs. 21% mCVAD or mCBAD, p=0.81), or ICU admissions (0% Cy vs. 1.2% mCVAD or mCBAD, p=1.00) between the groups. All 14 patients who had an episode of febrile neutropenia were hospitalized. One patient in the mCVAD or mCBAD group was admitted to the ICU with sepsis and renal failure, but was eventually discharged. There were no mobilization-related deaths in either study group. There was no significant difference in the time to neutrophil engraftment for the two groups (median 11 days, range 9-13). The median time to progression was 11.8 months in the Cy group and 9.1 months in the mCVAD or mCBAD group. Conclusion Cy, mCVAD or mCBAD can be used for successful PBSC mobilization in patients with multiple myeloma undergoing an auto-HCT without any unexpected toxicity. These approaches may be further evaluated in a randomized, prospective trial. Disclosures: Off Label Use: Cyclophosphamide, mCVAD, and mCBAD will be discussed as mobilization regimens used for patients with multiple myeloma. Vincristine and doxorubicin do not have specific indications for use in multiple myeloma. Qazilbash:Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees.

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A Retrospective Study on Safety, Efficacy and Cost of the Chemo-Mobilization for Patients Planned to Undergo Autologous Hematopoietic Stem Cell Transplant: The Secom Study

Blood ◽

10.1182/blood.v124.21.5903.5903 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5903-5903

Author(s):

Surapol Issaragrilsil ◽

Yeow-Tee YT Goh ◽

Anskar Y.H. Leung ◽

S Fadilah S Abdul Wahid ◽

Hwai Tzeng Cheng

Keyword(s):

Stem Cell ◽

Febrile Neutropenia ◽

Board Of Directors ◽

High Dose Chemotherapy ◽

High Dose ◽

Asian Countries ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Grade 3 ◽

The Cost

Abstract Introduction: Failure of hematopoietic stem cell (HSC) mobilization occurs in 5 to 30% patients planning for high dose chemotherapy and autologous HSC transplantation worldwide. It has adverse impact on patient outcomes and significantly increases health care burden. Data regarding HSC mobilization based on chemotherapy + granulocyte colony stimulating factor (G-CSF) in Asia are currently limited. Objective: The primary objective was to determine the safety and efficacy of HSC chemo-mobilization protocols in Asia for patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) planning for autologous HSCT. The secondary objective was to provide an estimate of the cost of chemo-mobilization in Asian countries Study Design: This was a multicenter, multinational retrospective observational study. Patients with NHL or MM undergoing chemo-mobilization for planned autologous HSCT between 1 Jan 2009 to 31 Dec 2012 in five Asian countries including Thailand, Singapore, Malaysia, Hong Kong and Taiwan, were retrospectively included in the study. Patient demographics, disease diagnoses, previous treatment history as well as complete blood counts prior to chemo-mobilization and apheresis, were collected. Results: A total of 526 patients (male/female = 207/219) were analyzed (diagnoses: NHL=257; MM=269). 160 patients were recruited from Thailand, 98 from Malaysia, 161 from Taiwan, 59 from Singapore and 48 from HK. Median age for the overall group was 53 years (range: 15-82). The most common mobilization regimen was cyclophosphamide + G-CSF; 235 (87.4%) in MM and 72 (28%) in NHL patients. 448 (85.2%) patients had reached at least HSC yield of 2 x 106CD 34+ cells/kg in 1 or 2 apheresis days. During chemo-mobilization, 108 (20.5%) patients were without negative clinical events (grade 3/4 neutropenia, febrile neutropenia, prolonged hospitalization, bone pain, fever, gastrointestinal, line infections or others). Grade 3/4 neutropenia and febrile neutropenia occurred in 401 (76.2%) and 72 (13.7%) patients, respectively. Median number of apheresis sessions was 2 (range: 1-5). Median cost of mobilization was 6,200USD (9,000-48,000). The respective median costs in USD (range) was; 3,500 (1,500-28,500) in Thailand, 6,900 (2,300-29,600) in Malaysia, 7,700 (3,400-48,000) in Taiwan and 9,200 (900-45,400) in Singapore. 436 (82.9%) patients proceeded to receive high dose chemotherapy and HSCT but 94 (17.87%) patients did not, due to insufficient HSC yield (n=26, 4.94 %), progression of disease (n=18, 3.42 %), patient not fit/ withdrawal from study (n=19, 3.61 %), patient expiry (n=11, 2.09 %) and other reasons (n=20, 3.80 %). Conclusion: Cyclophosphamide and G-CSF is the most common mobilization regimen used in Asian countries. Current chemo mobilization regimens are associated with a satisfactory rate of successful stem cell collection but with a high rate of significant toxicity. More than three-quarter of patients suffered from grade 3/4 toxicity during chemo-mobilization, however, only 20% of them had febrile neutropenia. Variations exist in the cost of chemo-mobilization in Asia, both among and within countries. Disclosures Goh: Novartis Pte Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceuticals Inc: Research Funding; Bristol-Myres Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hospira Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Factors Influencing Long-Term Hematopoietic Function Following Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.2186.2186 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2186-2186

Author(s):

Alissa Visram ◽

Natasha Kekre ◽

Christopher N. Bredeson ◽

Jason Tay ◽

Lothar B. Huebsch ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Infection Rates ◽

Advisory Committees ◽

Cd34 Cells ◽

Significant Difference

Abstract Background/Objective: Mobilized peripheral blood hematopoietic progenitor cells are the most common stem cell source for autologous hematopoietic stem cell transplantation (auto-HSCT). Successful short-term stem cell engraftment requires collection of at least 2x106 CD34+ cells/kg. The American Society of Bone Marrow Transplantation (ASBMT) recommends a stem cell infusion target of 3-5 x106 cells/kg (Giralt et al. 2014). However, the number of CD34+ cells to reinfuse to ensure long-term engraftment has not been established. Plerixafor, a reversible CXCR4 antagonist, increases CD34+ cell yield at collection even in patients who are predicted poor mobilizers (PPM). Although plerixafor could be used universally for all collections, this may not be the most cost-effective strategy (Veltri et al. 2012). This study sought to determine the minimum number of CD34+ cells/kg required for adequate long-term hematopoiesis, identify factors associated with poor long-term hematopoiesis, and determine if plerixafor mobilization improved long-term peripheral blood counts. Methods: A retrospective chart review was conducted on patients who underwent auto-HSCT between January 2004 and September 2013 at The Ottawa Hospital, for management of hematological malignancies. Peripheral blood cell counts were collected from 1 to 5 years after auto-HSCT, or until disease relapse. Poor long-term hematopoiesis was defined as an ANC <1 x109/L, hemoglobin <100 g/L, or platelets <100 x109/L. Patients were stratified into groups based on the infused CD34+ concentration (in cells/kg), and the proportion of patients with poor long-term hematopoiesis at 1, 2, 3, 4, and 5 years post auto-HSCT was compared with chi square tests. Long-term clinical outcomes (platelet and packed red blood cell transfusions, and post auto-HSCT infection rates) were compared between plerixafor-mobilized patients and PPM (defined as patients with pre-collection CD34+ <2 x 106 cells/kg) with standard mobilization regimens. Results: This study included 560 patients who underwent auto-HSCT, 210 with multiple myeloma and 350 with lymphoma. At 1 and 5 years post auto-HSCT 377 and 104 patients were included, respectively. A dose dependent improvement 1 year after auto-HSCT was seen in patients who received 0-2.99 x 106 CD34+ cells/kg (24.4%, n= 41) compared to patients who received 5-9.99 x 106 CD34+ cells/kg (11%, n=154, p=0.051) and ³10 x 106 CD34+ cells/kg (4.5%, n=66, p=0.006). Though there was a trend towards lower CD34+ infusions and poorer hematopoietic function (see table 1), there was no statistically significant difference in hematopoietic function based on CD34+ infusion concentrations after 1 year post auto-HSCT. 10 patients received <2 x106 CD34+ cells/kg, of whom the rate of inadequate hematopoiesis was 33% at 1 year (n=6) and 0% (n=1) at 5 years post auto-HSCT. Factors that increased the risk of poor hematopoiesis over the course of study follow up, based on a univariate analysis, included advanced age (OR 1.189, p=0.05), multiple prior collections (OR 2.978, p=0.035), and prior treatment with more than two chemotherapy lines (OR 2.571, p=0.02). Plerixafor-mobilized patients (n=25), compared to PPM (n=197), had a significantly higher median CD34+ cell collection (4.048 x109/L and 2.996 x109/L cells/kg, respectively, p=0.005). There was no significant difference in overall cytopenias, transfusion requirements, or infection rates between plerixafor-mobilized and PPM patients over the course of the study follow up. Conclusion: Low pre-collection CD34+ counts, advanced age, multiple prior collections, and more than two prior chemotherapy treatments adversely affected long-term hematopoiesis post auto-HSCT. We support the transfusion target of 3-5 x 106 cells/kg, as proposed by the ASBMT, given that at 5 years post auto-HSCT there was no statistical or clinically significant difference in hematopoietic function with higher CD34+ infusion targets. While mobilization with plerixafor significantly increased overall CD34+ cell collection when compared with PPM, long-term hematopoietic function and clinical outcomes were not different. This finding supports the practise of limiting plerixafor use only to patients who are PPM, thereby facilitating adequate stem cell collection and early engraftment, as opposed to universal plerixafor mobilization. Disclosures Sabloff: Lundbeck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Alexion: Honoraria.

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Carfilzomib Combined with Thalidomide and Dexamethasone (CARTHADEX) As Induction Treatment Prior to High-Dose Melphalan (HDM) in Newly Diagnosed Patients with Multiple Myeloma (MM). A Trial of the European Myeloma Network EMN

Blood ◽

10.1182/blood.v118.21.633.633 ◽

2011 ◽

Vol 118 (21) ◽

pp. 633-633 ◽

Cited By ~ 5

Author(s):

Pieter Sonneveld ◽

Emilie Hacker ◽

Sonja Zweegman ◽

Marie Jose Kersten ◽

Edo Vellenga ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Tumor Lysis Syndrome ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Tumor Lysis ◽

Grade 3 ◽

Cell Harvest

Abstract Abstract 633 Introduction: This independent phase 2 trial was designed to evaluate carfilzomib (C) combined with thalidomide and dexamethasone during induction and consolidation for feasibility, response and progression-free survival (PFS) in patients with newly diagnosed symptomatic MM, who were candidates for high-dose therapy. Patients with symptomatic MM and measurable disease, age 15 to 65 and no significant co-morbidity were eligible. At diagnosis Fluorescent in situ Hybridization (FISH) was performed of recurrent translocations, trisomy 9, del(17p), del (13q) and add(1q) Patients received 4 cycles of carfilzomib at 20 mg/m2 on days 1 & 2 followed by 27mg/m2 on days 8,9,15,16 of cycle 1 and on days 1,2, 8, 9, 15 & 16 of all subsequent 28-day cycles, thalidomide 200 mg days 1 – 28 of a 28 day cycle and dexamethasone 40 mg days 1, 8, 15 & 22 of a 28 day cycle. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Following HDM (200 mg/m2) and autologous stem cell transplantation (ASCT), consolidation therapy consisted of 4 cycles of carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, thalidomide 50 mg days 1–28 of a 28 day cycle and dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was response, other endpoints were complete response (CR) according to IMWG criteria, immunofixation-negative CR (sCR), VGPR all pre-and post HDM, PFS and overall survival (OS). An interim analysis was planned after 20 evaluable patients, primarily to guard against excessive toxicity and/or lack of response. Results: While recruitment is still ongoing, 34 patients have been included, of which the first 20 patients were are evaluated for response and toxicity, with a median follow-up of 5 months. One patient was excluded because unavailability of data. Median age was 60 yr and ISS stages I/II/III were 8/6/5, respectively. Four patients went off treatment because of intolerance to thalidomide (n=1), tumor lysis syndrome with renal failure (n=1) or respiratory infections (n=2). Adverse events CTC grade 3+4 included tumor lysis syndrome (n=2), metabolic disorders (n=4), cardiovascular including DVT (n=5), gastrointestinal (n=2), skin rash (n=2) and reversible renal failure (n=3). Peripheral polyneuropathy grades 1+ 2 was observed in 7 (35%) of patients, but no grade 3 or higher. Responses after cycle 1 were CR + sCR 5%, VGPR 32%, PR 47%, SD 10%, NE 5% and after induction overall CR + sCR 21%, VGPR 47%, PR 16%, SD 10%, NE 5%. Median time to maximum response was 1 cycle. Secondary analysis revealed that responses occurred across cytogenetic subgroups as determined by FISH, i.e. add (1q) (n=2), t(4;14) (n=2), del(17p) (n=1) and del(13q) (n=5). Stem cell harvest was accomplished with standard CD34+ yield in all patients and HDM/ASCT was performed with complete hematologic recovery in 4/4 patients. Conclusion: Carfilzomib combined with thalidomide and dexamethasone during induction and consolidation is feasible and effective. The complete data including response after consolidation will be reported at the ASH meeting. This EMN trial was registered as NTR2422. Carfilzomib and an unrestricted grant was provided by ONYX Pharmaceuticals. Disclosures: Sonneveld: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Zweegman:Celgene: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria.

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Clinical, Metabolic and Molecular Responses After 4 Courses of R-DHAP and After Autologous Stem Cell Transplantation for Untreated Mantle Cell Lymphoma Patients Included in the LyMa Trial, a Lysa Study

Blood ◽

10.1182/blood.v120.21.152.152 ◽

2012 ◽

Vol 120 (21) ◽

pp. 152-152 ◽

Cited By ~ 8

Author(s):

Steven Le Gouill ◽

Mary Callanan ◽

Elizabeth Macintyre ◽

marie-Hélène delfau-Larue ◽

Caroline bodet-Milin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Response Rates ◽

High Dose ◽

Molecular Response ◽

Advisory Committees ◽

Mantle Cell

Abstract Abstract 152 Mantle cell lymphoma (MCL) is a rare B-cell malignancy characterized by the t(11;14) translocation. The European MCL network has demonstrated that a sequential R-CHOP/R-DHAP chemotherapy regimen prior to autologous stem cell transplantation (ASCT) provides better disease control than R-CHOP (Hermine et al, ASH 2010, abstract 110) and that molecular minimal residual disease (MRD) measured by IGH real-time quantitative polymerase chain reaction (PCR) before and after ASCT is an important prognostic factor to predict progression-free survival (PFS) (Pott et al. Blood. 2010;115(16):3215–23). Indeed, the use of high-dose aracytine upfront before ASCT is now recommended and molecular remission appears to be a major objective for future clinical trials in MCL. It therefore appeared interesting to appreciate response rates combining standard evaluation (Cheson 1999), FDG-PET imaging (Cheson 2007) and PCR techniques after rituximab plus upfront high-dose aracytine (R-DHAP) followed by ASCT. Response rates after 4 courses of R-DHAP were one of the objectives of the LyMa trial (NCT00921414). This trial is a randomized, open-label, phase III study that evaluates the efficacy of rituximab maintenance therapy in MCL patients aged between 18 and 66 years old, undergoing first-line treatment with 4xR-DHAP and exhibiting a response after ASCT (R-BEAM). Patients who do not reach a sufficient partial remission after R-DHAP are planned to receive 4 additional courses of R-CHOP before ASCT. The LyMa trial started in September 2008 and was designed to enroll 299 patients over a 4 years period. To date (August 2012), 295 patients have been included. Herein, we report response rates according to the combination of Cheson 1999 and 2007 criteria plus molecular response rates after 4xR-DHAP and after ASCT for the first 200 enrolled patients (last inclusion in August 2011). Results: One patient withdrew consent and the analysis is therefore on 199 patients. The cohort's median age is 57.2 years (range 29.7–65.7) and 41 patients are female (20%). At diagnosis, simplified MIPI was low in 104 cases (52%), intermediate in 55 (28%) and high in 40 (20%).Twenty-five patients (12.5%) presented with a blastoid variant. The panel of pathologist experts confirmed the diagnosis in all reviewed cases. Among the 199 evaluable patients, 182 (91%) received 4 courses of R-DHAP and 12 patients (all in PR according to Cheson 99 criteria) received 4 additional courses of R-CHOP because of insufficient clinical response after R-DHAP. Among these 12 patients, 5 reached CR/CRu after R-CHOP. Ultimately, 164 patients (82%) proceeded to ASCT (158 after R-DHAP and 6 after RDHAP/R-CHOP) and 154 (77.4%) have been randomized between rituximab maintenance or no maintenance. In an intention-to-treat (ITT) analysis and according to Cheson 1999 criteria, 152 patients (76.3%) reached CR (n=74) or CRu (n=78) after 4 courses of R-DHAP while 25 patients reached PR and 8 presented with SD/Prog. According to Cheson 2007 criteria (n= 170; PET not done in 17 cases and data missing in 12 cases), 129 patients reached CR while 41 patients remained FDG-TEP positive. Response rates according to Cheson 1999 and 2007 criteria for transplanted patients (n=164) were CR (n=109)/CRu (n=45) in 94% and CR in 84.5% (129 patients underwent FDG-PET after ASCT), respectively. Regarding MRD, diagnosis samples were available for 186/199 patients. Forty-one diagnosis samples have not yet been analyzed and 14 proved to be not informative. To date, the molecular response on peripheral blood (PB) after 4 courses of R-DHAP has been assessed in 103 cases and found negative in 80 cases and positive in 22 cases (not evaluable in one case). MRD on bone marrow (BM) after 4 courses of R-DHAP has been measured in 97 cases and found negative in 59 and positive in 36 (not evaluable in one case). After ASCT, PB and BM MRD were found negative in 91 patients (95 samples have been analyzed to date) and 67 (87 samples analyzed), respectively. Thus, in the LyMa trial,CR/CRu rates after only 4 courses of RDHAP, according to Cheson 1999 and 2007 criteria, are very high confirming the major anti-tumoral impact of high-dose aracytine upfront in MCL. In addition, these encouraging results seem to be confirmed at the molecular level strengthening the interest of an MRD-guided management of MCL patients. Results will be updated at the time of the meeting and patients' outcome according to disease status will be presented. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

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High-Dose Therapy and Autologous Stem Cell Transplantation for Multiple Myeloma: Analysis from Registry of Monoclonal Gammopathy of Czech Myeloma Group

Blood ◽

10.1182/blood.v120.21.4528.4528 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4528-4528

Author(s):

Roman Hajek ◽

Ivan Spicka ◽

Vladimir Maisnar ◽

Tomas Pika ◽

Evzen Gregora ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Autologous Stem Cell Transplantation ◽

Monoclonal Gammopathy ◽

High Dose ◽

Newly Diagnosed ◽

Time To Progression ◽

Advisory Committees

Abstract Abstract 4528 Background: The role of high-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) in the treatment of Multiple Myeloma (MM) continues to evolve in the era of novel agent. Although data from clinical trials with novel agens are very promising, it is evident that ASCT remains the golden standard for all available patients; moreover combination with proteasome inhibitors and immunomodulatory agens will ensure further benefits and prolongation of overall survival to patients. Aim: To investigate the indication, frequency and results of HDM and ASCT in MM patients in the era of novel agens. Methods: Before inclusion to the Registry of Monoclonal Gammopathy (RMG) of the Czech Myeloma Group (CMG), all persons signed the informed consent forms. Out of 1448 newly diagnosed patients (654 aged≤ 65 years) reported in the RMG in the period 2007–2011, 26.7% (386/1448) underwent ASCT as part of primo therapy. A cohort of 229 patients underwent ASCT as part of the first, second and third relapse (R1–3) treatment in the same time period. Time to progression in different disease settings, objective response rate, and safety were included as exploratory outcomes. Efficacy was assed using the IMWG criteria. A distinctive aspect of this analysis involves comparison of frequency of ASCT during this period of time. Results: A total of 59% (386/654) of newly diagnosed patients under 65 years underwent ASCT as part of primo therapy. Frequency of indication between patients with age ≤ 65 years was similar (56–63%) during the last five years. Melphalan 200mg/m2 was the most frequently used HDM (94%) in primo therapy. The same was true for R1 (73%), R2 (46%) but not R3 where most frequent (49%) HDM was melphalan 100mg/m2. Transplant related mortality day+100 ranged between 0.8 to 1.1% during five consecutive years for all treatment settings together and was zero for primo therapy in the year 2007 and 2009–10. Overall responses to ASCT (primo therapy vs. R1 vs. R2 vs. R3) were: ORR 93% (30.5%≥CR) vs. 93% (20%≥CR) vs. 72% (8%≥CR) vs. 54% (4.1%≥CR). Medians of Time to Progression (TTP from the time of ASCT; primo therapy vs. R1 vs. R2 vs. R3) were: 26.2 vs. 15.6 vs. 5.8 vs. 4.8 months and the difference were statistically significant (p<000.1). Conclusion: ASCT is a safe treatment strategy in MM independently of disease advance, although for patients with more advanced disease, reduced dose of melphalan (100mg/m2) should be considered. ASCT is very effective treatment not only for newly diagnosed MM patients but also for patients in the first relapse. The indication in relapse setting should be considered more frequently than is currently common in the shadow of enthusiasm for novel drugs. Acknowledgment: This work was supported by national grants IGA NT12215-4, IGA NT12130-4, GACR P304/10/1395, IGA NT11154-4, MSM 0021622434 Disclosures: Hajek: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen Cilag: 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. Maisnar:Janssen Cilag: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer (Schering): Honoraria.

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Bortezomib With High-Dose Melphalan, Arsenic Trioxide, and Ascorbic Acid In a Preparative Regimen For Multiple Myeloma: 5-Year Follow Up

Blood ◽

10.1182/blood.v122.21.5547.5547 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5547-5547

Author(s):

A. Megan Cornelison ◽

Yvonne Dinh ◽

Manish Sharma ◽

Nina Shah ◽

Qaiser Bashir ◽

...

Keyword(s):

Board Of Directors ◽

High Dose ◽

Refractory Disease ◽

Advisory Committees ◽

Significant Difference ◽

Preparative Regimen ◽

First Remission ◽

High Dose Melphalan

Abstract Background Bortezomib and high-dose melphalan was associated with a higher complete remission (CR) rate in a phase II trial by the IFM group. Four doses of bortezomib 1 mg/m2 IV were given on days -6, -3, +1 and +4. (Roussel M et al. Blood 2010. 115:32-37).In a randomized phase II trial we reported that the addition of bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA), and melphalan followed by autologous hematopoietic stem cell transplantation (auto-HSCT) failed to demonstrate a statistically significant improvement in CR rate or survival in patients (pts) with newly diagnosed or relapsed multiple myeloma (Sharma M et al. Cancer. 118:2507-15).This study was limited by a short follow up (median 36 months) and inclusion of pts with relapsed and refractory disease. In this retrospective analysis, we evaluated the long-term (5-years) impact of the addition of bortezomib to this preparative regimen in pts who underwent auto-HCT in first remission or with primary refractory disease. Methods Forty-three pts underwent auto-HCT in first remission or with primary refractory disease. All patients received ATO 0.25 mg/kg intravenously on days -9 to -3, AA 1000 mg intravenously on days -9 to -3, and melphalan 100 mg/m2 intravenously on days -4 and -3. Pts received either no bortezomib (n=13), or bortezomib at a dose of either 1 mg/m2 of 1.5 mg/m2 on days -9, -6, and -3. The primary endpoint was CR rate and secondary endpoints were progression free survival (PFS) and overall survival (OS). Results Pt characteristics are shown in the attached Table. The median follow-up for all surviving pts was 61.4 months (range, 15-80 months). Pts in the bortezomib and non-bortezomib arms were matched for age, gender, high-risk cytogenetic abnormalities, time to auto-HSCT, use of bortezomib in induction, and disease burden at auto-HSCT (Table). Only 5 (17%) pts in the bortezomib and 4 (30%) in the non-bortezomib group received maintenance therapy. There was no significant difference in the time to neutrophil engraftment or treatment-related mortality TRM between the bortezomib and non-bortezomib groups. The CR rate in the bortezomib group and the non-bortezomib group was 20% and 53%, respectively (p=0.03). There was no significant difference in rates of CR + very good partial remission (VGPR), or CR + VGPR + partial remission (PR) between the bortezomib and non-bortezomib groups (p=0.72 and 1.00, respectively). The median PFS in the bortezomib group and the non-bortezomib group was 25.4, and 40.0 months, respectively (p=0.13, Figure 1). The median OS was 61.6 months in the bortezomib group and not reached in the non-bortezomib group (p=0.22, Figure 2). There was no significant impact of high-risk cytogenetics, lactic dehydrogenase (LDH) or b2 microglobulin levels, or maintenance therapy on PFS or OS. Conclusions After long-term follow up of 5 years, the addition of bortezomib to a preparative regimen of ATO, AA, and high-dose melphalan did not result in a significant improvement in CR rate, PFS, or OS. The lack of benefit with bortezomib may be due to the inclusion of ATO and AA in the regimen, or the schedule of bortezomib, which was only given before melphalan. Disclosures: Shah: Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Qazilbash:Celgene: Membership on an entity’s Board of Directors or advisory committees Other; Millenium: Membership on an entity’s Board of Directors or advisory committees, Membership on an entity’s Board of Directors or advisory committees Other.

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Dose Escalation Phase 2 Trial of Carfilzomib Combined with Thalidomide and Low-Dose Dexamethason in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma. a Trial of the European Myeloma Network

Blood ◽

10.1182/blood.v124.21.2118.2118 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2118-2118 ◽

Cited By ~ 1

Author(s):

Pieter Sonneveld ◽

Emilie Asselbergs ◽

Bronno Van der Holt ◽

Sonja Zweegman ◽

Marie jose Kerstens ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees ◽

Phase 2 Trial ◽

High Dose Melphalan ◽

Dose Levels

Abstract Background: Carfilzomib has significant activity in newly diagnosed Multiple Myeloma (MM). We present an update of a Phase 2 trial of dose-escalated Carfilzomib combined with Thalidomide and Dexamethasone (CTd). Introduction: This investigator sponsored, dose escalation phase 2 trial was designed to evaluate the clinical efficacy of standard dose Carfilzomib (C) (20/27 mg/m2) combined with Thalidomide (T) and Dexamethasone (D) (CTd) as induction therapy followed by high-dose Melphalan and autologous stem cell transplantation (ASCT), followed by consolidation therapy with CTd in transplant eligible patients with newly diagnosed symptomatic MM,. The second objective was to establish the maximum tolerated dose of Carfilzomib in this combination. Fifty patients were included in the first part who received 4 cycles of C at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, T 200 mg p.o. days 1 through 28 of a 28 day cycle and D 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In the second part 3 cohorts of 20 patients each were treated with escalated dose of C at 20/36 mg/m2,20/45 mg/m2 and 20/56mg/m2, respectively with T and D at the same dose. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and ASCT, followed by consolidation therapy consisting of 4 cycles CTd with C 27 mg/m2 (part1, n=50) or 36 mg/m2 or 45 mg/m2 or 56 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, respectively, combined with T 50 mg days 1-28 of a 28 day cycle and D 20 mg days 1, 8, 15, 22 of a 28 day cycle. Thrombosis prophylaxis was prescribed. The primary endpoint was very good partial response (VGPR) after 4 CTd cycles: secondary endpoints were complete response (CR), stringent CR (sCR) and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS). Results: 111 patients were included as of 1st July 2014. We here report the response of all cohorts with a median follow-up of 34, 19, 12 and 6 months, respectively. Median age was 58 yr and ISS stages II and III were 40% and 27%, respectively. The CTd regimen was well tolerated. Fifteen patients discontinued treatment because of non-eligibility (n=3), refusal (n=2), toxicity (n=7) or progression (n=3). Safety analysis was available for all treatments in cohorts 27mg/m2 through 45mg/m2 and for induction cycles in cohort 56mg/m2. Non-hematological SAEs for the two lower dose levels were infections (n=8), polyneuropathy gr 2 (n=5), cardiac (n=3) and tumor lysis syndrome (n=2) (ASH 2013). Non-hematological SAEs for dose level 45mg/m2 (n=22) included thrombosis (n=1), reversible gastrointestinal event (n=2) and infections (n=5). At dose level 56mg/m2 SAEs were thrombosis (n=2), infections (n=3), reversible cardiac event (n=1). In 111 patients 4 cardiac events were observed (2 grade 2, 2 grade 3) 3 of which resolved completely. Two patients discontinued therapy because of thrombosis (n=1) and pneumonia (n=1). Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 85/85 patients and HDM/ASCT was performed with complete hematologic recovery in 77/78 patients. The primary endpoint ≥VGPR and CR was achieved in 94% and 56% (27mg/m2), 75% and 65% (36mg/m2), 91% and 55% (45mg/m2), 75% and 20% (56mg/m2, induction only). Of 25 CRs in dose levels 36mg/m2 and 45mg/m2, 9 (36%) were stringent CR with no clonal plasma cells in bone marrow and negative serum-free lite. VGPR + CR increased from 63% after induction to 73% after HDM/ASCT and 86% after consolidation, respectively. For CR these figures were 18%, 34% and 58%, respectively. Overall response and CR were not significantly different between dose cohorts. Responses did not differ between poor risk (gain 1q or t(4;14) or del17p) and standard risk FISH. At a median follow-up of 21 months for dose levels 27mg/m2, 36mg/m2 and 45mg/m2 ,78% of patients are alive without progression or relapse. PFS at 18 months is 88 %. Three patients died of myeloma. There were 2 second primary malignancies. Analyses for revised ISS and molecular subgroups will be presented. Conclusion: C combined with T and D is a safe and effective regimen for newly diagnosed MM. Dosing of Carfilzomib up to 56mg/m2 was well tolerated. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals, an Amgen subsidiary. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria.

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