Dexamethasone and Cyclophosphamide: More Convenient and as Effective as VAD before High-Dose Melphalan and Autologous Transplantation in Newly Diagnosed Multiple Myeloma. Results of a Randomized NMSG Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 793-793
Author(s):  
Ulf-Henrik Mellqvist ◽  
Stig Lenhoff ◽  
Martin Hjorth ◽  
Erik Holmberg ◽  
Gunnar Juliusson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Initial Treatment ◽  
Autologous Transplantation ◽  
Group Versus ◽  
Initial Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
High Dose Melphalan ◽  
Cell Harvest

Abstract Background. High-dose melphalan with autologous stem cell transplantation (ASCT) is established in the first line treatment of myeloma patients. The initial tumour reducing therapy before high-dose treatment is usually VAD, i.e., vincristine and doxorubicin in continuous infusion plus high dose dexamethasone. The anti-myeloma effect of high dose corticosteroids is indisputable but the role of vincristine and doxorubicin is unclear, and never scrutinized in randomized studies. Both of these drugs do have well-known side effects and the administration of VAD is somewhat complicated. Melphalan is very effective in myeloma treatment but not suited for initial treatment because of the stem cell toxicity. However, another alkylating agent like cyclophosphamide is feasible to use before stem cell harvest and has well documented anti-myeloma effect. Trying to simplify initial treatment before ASCT, the Nordic Myeloma Study Group (NMSG) initiated a prospective, randomized multicentre study comparing conventional initial therapy of three 4-week courses of VAD with two 3-week courses of Cy-Dex. Patients and methods. From Nov 2001 to Oct 2003, 315 patients younger than 65 years with symptomatic newly diagnosed myeloma were randomized to receive 3–4 courses of VAD or 2–3 cycles of Cy-Dex (cyclophosphamide 1000mg/sqm and dexamethasone 40mg/d days 1–4 and 9–12). Thereafter, both groups received cyclophosphamide 2g/sqm plus rhG-CSF (filgrastim) sc as mobilization therapy followed by stem cell harvest and subsequent high dose melfalan 200 mg/sqm supported by stem cell infusion. CR was defined as the disappearance of M-protein from serum and urine in agarose gel electrophoresis and < 5 % plasma cells in a bone marrow aspirate. Results. Patients in the Cy-Dex group came quicker to ASCT, 3.2 months versus 4.5 for the VAD group. The study showed no significant difference in the proportion of patients undergoing ASCT, 137/158 pts (87 %) in the Cy-Dex group versus 133/157 pts (85 %) in the VAD group. Neither were there any significant differences in response rate. After the initial therapy there were 54 % major responses (7 % CR and 47 % PR) in the Cy-Dex group versus 55 % (11 % CR and 44 % PR) in the VAD-group. After ASCT the response rates were 76 % (32 % CR and 44 % PR) versus 72 % (34 % CR and 38 % PR) in the Cy-Dex and the VAD group respectively. Also, survival data were identical with a median event free survival time of 29 months and 75 % overall survival at three years, calculated from start of therapy for both groups. Conclusion. This randomized trial indicates that Cy-Dex speeds up and simplifies initial treatment with an efficacy comparable to VAD. Cy-Dex can be recommended as a safe alternative for initial therapy in patients planned to undergo ASCT, and should be further studied in combination with novel agents, such as thalidomide, bortezomib and lenalidomide.

Thalidomide and Dexamethasone Induction Therapy Is Associated with Superior Progression-Free Survival after Autotransplant for Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1171-1171
Author(s):  
Dan T. Vogl ◽  
Selina Luger ◽  
David L. Porter ◽  
Elise A. Chong ◽  
Stephen J. Schuster ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Initial Treatment ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
High Dose ◽  
Free Survival ◽  
Autologous Transplant ◽  
High Dose Melphalan

Abstract BACKGROUND: High-dose melphalan with autologous stem cell support improves survival when incorporated in the initial treatment of multiple myeloma. Published data show that induction thalidomide and dexamethasone (Thal/Dex) has a higher response rate than dexamethasone alone (Dex) or anthracycline induction (VAD or DVD), but the effect of initial induction therapy on outcomes after autologous transplant remains unclear. PATIENTS: We reviewed the records of 164 patients who received high-dose melphalan with autologous stem cell support as part of initial therapy for multiple myeloma at the University of Pennsylvania. Median age was 55 years (range 25 – 72). Durie-Salmon stage at diagnosis was II in 27% and III in 70% of patients. Induction regimens included VAD (62%), DVD (12%), Thal/Dex (11%), Dex (5%), and more than one regimen (10%). Post-transplant therapies for consolidation or maintenance included thalidomide (7%), interferon (23%), tandem autologous transplant (4%), non-myeloablative allogeneic transplant (7%), autologous co-stimulated T-cell infusion (14%), or observation until progression (45%). Patients who received Thal/Dex initial therapy were not significantly different than those receiving anthracycline-containing induction regimens (VAD/DVD), except for lower serum creatinine (median 0.9 vs 1.1 mg/dl; p=0.01), with a trend toward lower beta-2 microglobulin (B2M) and correspondingly lower ISS stage. RESULTS: Median overall follow-up is 29 months (range 7–120). Thal/Dex induction trended towards a higher Very Good Partial Response (VGPR) rate than anthracycline induction (29% vs 14%, p=NS) and a higher overall response rate (76% vs 68%, p=NS). All of the patients who received Thal/Dex as induction therapy are alive, with a median follow-up of 23 months (range 13 – 34), while overall survival in the anthracycline induction group is 85% at 2 years. Progression-free survival at 2 years is 93% for Thal/Dex induction and 58% for VAD/DVD (HR 0.12, p=0.039). The improvement in progression-free survival persists in Cox regression models that include creatinine and either B2M or ISS stage. CONCLUSION: In myeloma patients who undergo autologous stem cell transplant, thalidomide and dexamethasone induction may result in improved progression-free survival compared with VAD or DVD. Further studies of initial therapies for myeloma should assess long-term outcomes after autologous transplant. Progression Free Survival, By Initial Treatment Progression Free Survival, By Initial Treatment

The Effects of Induction Chemotherapy and High-Dose Melphalan with Tandem Autologous Transplantation in Multiple Myeloma: The Prospective Randomized DSMM 2 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 446-446 ◽  
Author(s):  
Christian Straka ◽  
Peter Liebisch ◽  
Burkhard Hennemann ◽  
Bernd Metzner ◽  
Hans Salwender ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Autologous Transplantation ◽  
High Dose ◽  
Significant Difference ◽  
High Dose Melphalan

Abstract The concept of the DSMM 2 study was to give age-adjusted high-dose treatment to elderly myeloma patients in order to balance efficacy and toxicity. The value of conventional induction chemotherapy before high-dose melphalan and autologous stem cell transplantation and the durability of unmaintaned remissions afterwards was addressed. Between September 2001 and September 2006, 434 multiple myeloma patients 60–70 years of age with 0–1 cycle of pretreatment were recruited from 45 centers. The median age was 65 years. The patients were randomized to receive 4 cycles of conventional induction chemotherapy [A1] (n=216; VAD or idarubicin/Dex in 88%) or no induction chemotherapy [A2] (n=218). Instead of induction chemotherapy, patients in [A2] received only one short course of dexamethasone 40 mg orally (days 1–4 and 8–11). Subsequently, stem cells were mobilized after combination chemotherapy with ifosfamide, epirubicin and etoposide (IEV) followed by G-CSF; stem cells could be collected in 97% of the patients. Then the patients proceeded to tandem MEL140 (melphalan 140 mg/m2) and autologous peripheral blood stem cell transplantation with a time interval between high-dose cycles of 2 months. No consolidation or maintenance treatment was scheduled. Analyses were performed in an intent-to-treat approach. 87% of patients completed the first transplant, 74% the second. Overall, the treatment was well tolerated and grade 3/4 infections and stomatitis after high-dose melphalan occurred in 37% and 9% of patients, respectively. The overall mortality (tumor and/or toxicity) during treatment was 7.1%: 4.5% during the induction phase (6.1% in [A1] versus 2.9% in [A2]), 1.5% after mobilization and 1.1% after high-dose therapy. Notably, the best response (EBMT criteria) at the end of treatment in patients randomized to [A1] (16% CR, 64% PR) or [A2] (18% CR, 69% PR) was not different. An early loss of tumor control with disease progression occurred in 6% in [A1] versus 1% in [A2]. With a median follow-up time of 20 months, there was no significant difference in the median event-free survival (EFS) (22 months in [A1] versus 20 months in [A2]) and not in the overall survival (OS) at 4 years (63% in [A1] versus 65% in [A2]). In ≥ 50% of patients, the time between last treatment and progression was > 16 months. The EFS of patients 60–64 years of age and 65–70 years of age was the same. In conclusion, there was no benefit of conventional induction chemotherapy with VAD- or VAD-like regimens in patients receiving tandem MEL140 with autologous transplantation. This induction treatment therefore may be avoided. Tandem-MEL140 is feasible and well tolerated in the majority of elderly patients with symptomatic myeloma. Its profound and durable anti-tumor effect was demonstrated by prolonged unmaintained remissions. The addition of new agents given as consolidation or maintenance probably will further improve treatment results.

scholarly journals Addition of Bortezomib to High Dose Melphalan As Conditioning Regimen for Autologous Stem Cell Transplantation Improves the Response Rate in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4647-4647 ◽  
Author(s):  
Benedetta Dalla Palma ◽  
Lucia Prezioso ◽  
Fabrizio Accardi ◽  
Stefano Bisbano ◽  
Federica De Luca ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
High Dose Melphalan

Abstract High-dose Melphalan (HDM) is the most commonly used conditioning regimen for autologous stem cell transplantation (ASCT) in newly diagnosed transplant-eligible Multiple Myeloma (MM) patients. Recent evidence suggests that the depth of response after induction therapy influences progression free survival (PFS) and, in most studies, overall survival (OS). Actually the effect of the inclusion of new drugs in the conditioning regimen for ASCT is still unknown. Phase I-II clinical study showed that the addition of Bortezomib (Bor) to HDM is safe and a promising conditioning regimen. Thus, in this study we analyzed a single center experience on the use of Bor in combination with HDM (Bor-HDM) as conditioning regimen before ASCT as frontline treatment in MM patients in order to evaluate the safety and the response rates of this combination regimen. We analyzed a total cohort of 48 newly diagnosed MM patients (25 females and 23 males; median age 60 years, range 42-70) admitted consecutively to our Bone Marrow Transplantation Center from 2008 to 2014. Regarding prognostic stratification, 25% of patients were classified as stage III according to International Staging System (ISS), and 12% exhibited high-risk cytogenetic features (defined by presence of del(17p) and/or t(4;14) and/or t(14;16)). All patients with the exception of three underwent to 3-drugs Bor-based induction therapy including Bor (median cumulative dose: 28.9 mg/m2), Thalidomide and Dexamethasone (VTD). After induction therapy and stem cell collection 28 out of 48 patients were treated with Bor-HDM, whereas 20 patients with HDM alone as conditioning regimen before ASCT. HDM was administered on day -2 (median dose: 200 mg/m2), and a single-dose Bortezomib at the dosage of 1.3 mg/m2 was administered on day -1 in the Bor-HDM group. Stem cells were reinfused on day 0 (median number of CD34+ infused: 3.3x106/Kg, range 1.86-6x106/Kg). Responses were evaluated at day 100 after ASCT, and definitions of response were used according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for MM. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher's exact test. pvalue of <0.05 was considered significant. Any significant difference was not observed between Bor-HDM group vs HDM group, regarding age at diagnosis (p=0.77), sex (p=0.24), cumulative induction dose of Bortezomib (p=0.42), dose of Melphalan used for conditioning (p=0.16) and the median number of CD34+ cells infused (p=0.12). Distribution of ISS stage was similar in the two groups (p=0.14), as well as that of high-risk cytogenetic (p=0.14). Moreover the response rates after the induction therapy was not statistically different in the two groups of patients analyzed (sCR + CR: 19% in Bor-HDM group vs 26% in HDM group; VGPR: 33% vs 48%; PR: 48% vs 26%, p=0.22). Any significant difference on hematopoietic recovery rates was not observed in Bor-HDM as compared to HDM alone with a mean time to neutrophil recovery of 12 days (range 9-18) and to platelet recovery of 12 days (range 9-21) in both groups. Bor-HDM conditioning was well tolerated, without increase of neuropathy occurrence. Then we analyzed the response rate after ASCT, showing that the overall response rate (ORR) was significantly higher in Bor-HDM group as compared to HDM (sCR+CR: 56% in Bor-HDM vs 17% in HDM; VGPR 30% vs 28%; PR: 15% vs 56%, p=0.0072) with a higher number of "good quality" response (sCR + CR + VGPR: 86% vs 45%; p=0.0075). The number of sCR was also significantly higher in Bor-HDM as compared to HDM alone (23% vs 0%, p=0.067). Moreover an improvement of the response rate after ABMT was seen more frequently in the Bor-HDM group as compared to the HDM group (p=0.0063). We then observed that the number of patients that underwent tandem ASCT was higher in the HDM group (66% vs 41%), even not reaching a statistical significance. In conclusion, this retrospective analysis suggests that BOR-HDM is safe as conditioning regimen with a higher response rate after ASCT as compared to the standard HDM regimen giving the rational design for randomized studies needed to assess whether this conditioning regimen is superior to HDM alone. Disclosures Giuliani: Celgene: Research Funding; Janssen: Research Funding.

scholarly journals A Phase 2 Multi-Center, Open Label Study of Isatuximab Added to Standard Cybord Induction and Lenalidomide Maintenance Treatments in Newly Diagnosed, Transplant Eligible Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4767-4767
Author(s):  
Rami Kotb ◽  
Engin Gul ◽  
Donna E. Reece
Keyword(s):  
Stem Cell ◽  
Sample Size ◽  
Research Funding ◽  
Response Rate ◽  
Autologous Stem Cell Transplant ◽  
Induction Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
High Dose Melphalan

Abstract Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. For young and fit patients, the current standard first-line therapy is a proteasome inhibitor (PI) containing induction, followed by stem cell collection, high dose Melphalan and autologous stem cell transplantation, followed by maintenance lenalidomide therapy in Canada. The anti-CD38 antibodies showed interesting activity in myeloma, and significant synergism with PI and IMiD based regimens. This CMRG-008 trial is designed to explore the benefit of adding Isatuximab to the current Canadian standard of care (CyBorD induction/Autologous SCT/Maintenance Len) in a single arm phase II trial. Design and Methods: Phase II study. Transplant eligible newly diagnosed myeloma patients (TE-NDMM) will receive Isatuximab added to four cycles of standard induction CyBorD chemotherapy (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycles; Isatuximab 10 mg/kg IV days 1, 8, 15 and 22 of cycle 1; days 1 and 15 of cycles 2-4). After the completion of the induction treatment, subjects achieving at least stable disease will receive stem cell mobilization, collection of hematopoietic stem cells, high dose melphalan chemotherapy, and autologous stem cell transplantation. Maintenance treatment will start at 100 days (+/- 7 days) after the transplantation date (and to be continued until disease progression). The maintenance treatment will consist of Isatuximab administered in combination with Lenalidomide in 28-day cycles (Lenalidomide: 10 mg daily on days 1-21 of every cycle; Isatuximab: 10 mg/kg IV on days days 1, 8, 15 and 22 of cycle 1; days 1 & 15 of cycles 2-3; then day 1 of each subsequent cycle). The objectives: To evaluate the benefit of adding Isatuximab to CyBorD (induction = Isa + CyBorD) and Lenalidomide (maintenance = Isa + Lenalidomide) in transplant-eligible myeloma patients. Primary Endpoint: To determine the response rate (VGPR or better) defined by IMWG criteria at 100 days (+/- 7 days) after the autologous stem cell transplant (ASCT). Secondary Endpoints: A) To determine the response rate (VGPR or better) after induction treatment (before ASCT), and at 12 months, 24 months and 36 months. B) To evaluate additional efficacy outcomes including progression free survival (PFS), and overall survival (OS), time to response and duration of response. C) To confirm the feasibility, safety and tolerability of adding Isatuximab to CyBorD and to maintenance lenalidomide in transplant-eligible newly diagnosed myeloma patients. D) To determine the feasibility of autologous stem cell collection after Isa + CyBorD induction treatment. The key inclusion criteria are having a TE-NDMM with a measurable disease; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-CD38 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and other concurrent severe or uncontrolled medical conditions. Statistics and Sample Size: Considering that the response rate (VGPR or better) after CyBorD induction therapy, high dose chemotherapy and autologous SCT is about 70-78%; and assuming a response rate (VGPR or better) to Isa-CyBorD induction and autologous stem cell transplant at 100 +/- 7 days of 88%; a sample size of 65 evaluable subjects will allow estimating the 95% confidence interval with a precision of +/- 7.9%. For the assumed rate and sample size, the lower bound of the confidence interval will be estimated to be larger than 80%. Assuming a 10% drop out rate, a total study size of 72 patients will be considered. This study is expected to open to recruitment in the third quarter of 2021. Clinicaltrials.gov #: NCT04786028. Disclosures Kotb: Janssen: Honoraria; Merck: Honoraria, Research Funding; Amgen: Honoraria; Akcea: Honoraria; Celgene: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Millennium: Research Funding; Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

High-Dose Melphalan, Etoposide, Total-Body Irradiation, and Autologous Stem-Cell Reconstitution as Consolidation Therapy for High-Risk Ewing’s Sarcoma Does Not Improve Prognosis

2001 ◽  
Vol 19 (11) ◽  
pp. 2812-2820 ◽  
Author(s):  
Paul A. Meyers ◽  
Mark D. Krailo ◽  
Marc Ladanyi ◽  
Ka-Wah Chan ◽  
Scott L. Sailer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progressive Disease ◽  
Peripheral Blood Stem Cell ◽  
High Dose ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Stem Cell Support ◽  
Total Body ◽  
High Dose Melphalan ◽  
Cell Support

PURPOSE: To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing’s sarcoma (ES). PATIENTS AND METHODS: Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS: Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post–stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION: Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

How I Treat Frontline Transplant-eligible Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Aurore Perrot
Keyword(s):  
Multiple Myeloma ◽  
Randomized Clinical Trials ◽  
Human Monoclonal Antibody ◽  
Autologous Transplantation ◽  
Proteasome Inhibitors ◽  
Standard Of Care ◽  
Adaptive Strategy ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Melphalan

High dose Melphalan supported by autologous transplantation is the standard of care for eligible patients with newly diagnosed multiple myeloma for more than 25 years. Several randomized clinical trials have recently reaffirmed the strong position of transplant in the era of proteasome inhibitors and immunomodulatory drugs combinations, demonstrating a significant reduction of progression or death in comparison with strategies without transplant. Immunotherapy is currently changing the paradigm of multiple myeloma management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved in the setting of newly diagnosed multiple myeloma. Quadruplets become the new standard in the transplantation programs, but outcomes remain heterogeneous with various response depth and duration. Otherwise, the development of sensitive and specific tools for disease prognostication allows to consider adaptive strategy to a dynamic risk. I discuss in this review the different available options for the treatment of transplant-eligible multiple myeloma patients in frontline setting.

Single Autologous Stem Cell Transplant Using Busulfan and Cyclophosphamide as Conditioning Regimen in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4436-4436
Author(s):  
Giampaolo Talamo ◽  
David F. Claxton ◽  
Joseph Drabick ◽  
David W. Dougherty ◽  
Jeff Sivik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Single Agent ◽  
Conditioning Regimen ◽  
High Dose ◽  
Cell Transplant ◽  
Transfusion Threshold ◽  
Significant Difference ◽  
High Dose Melphalan

Abstract Autologous peripheral blood stem cell transplantation (ASCT) has been shown to improve survival in patients with multiple myeloma (MM). High-dose melphalan is considered the current standard of care among the preparative regimens used in ASCT for MM patients. We report the results of ASCT in 79 consecutive MM patients using a conditioning regimen with busulfan and cyclophosphamide (Bu/Cy), given as single ASCT and without maintenance therapy. Peripheral blood stem cells were mobilized with cyclophosphamide 5,000 mg/m2 IV + etoposide 1,000 mg/m2 IV, followed by granulocyte colony stimulating factor (G-CSF) 5 mg/Kg/day until the end of stem cell collection. A median of 41.1 × 106 CD34+ cells/Kg (range, 2.1–139.7 × 106) of ideal body weight were mobilized. The conditioning regimen consisted of busulfan 1 mg/Kg PO or 0.8 mg/Kg IV every 6 hours x 16 doses (days -7 to -3), and cyclophosphamide 60 mg/Kg/day IV for 2 days (days -3 to -2). Patients achieved neutrophil engraftment (absolute neutrophil count &gt;500/μL) at a median of +13 days (range, +6 to +21 days), and platelet engraftment (platelets &gt;20,000/μL unsupported by transfusion) at a median of 14 days (range, +11 to +24). Using a transfusion threshold of hemoglobin &lt;8.0 g/dL and platelets &lt;10,000/μL, patients required a median of 2 units of RBC transfusions (range, 0–8), and 1 platelet transfusion (range, 0–15) until hematologic engraftment. Forty-eight and 20 patients reached PR and CR, respectively, for an overall RR of 86%. At a median followup of 41 months (range 2–132 months), the estimated median overall survival (OS) and progression-free survival (PFS) were 45 months [95% confidence interval (CI) = 38–92] and 20 months (95% CI = 15–25), respectively. Veno-occlusive disease developed in 4 pts, and it was lethal in 1 of them. The Bu/Cy regimen was overall well tolerated, and transplant-related mortality was 4%. No statistically significant difference in terms of OS and EFS were observed between the group of patients receiving oral (n=13) vs IV busulfan (n=66). OS was not statistically different between the group receiving ASCT in first remission (n=62) and the group receiving ASCT as salvage therapy, i.e., upon MM progression (n=17), either calculating OS from the day of ASCT or from the day of MM diagnosis. We conclude that our reported clinical outcomes of the Bu/Cy regimen are equivalent to those obtained in historical controls with high-dose melphalan followed by a single ASCT. Thus, given the equivalent effectiveness but greater complexity of administration of the Bu/Cy regimen compared with that of single agent melphalan, we believe the latter should remain the agent of choice for ASCT in MM.

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 ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 633-633 ◽  
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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