GMMG MM5 Trial In Newly Diagnosed Multiple Myeloma To Evaluate PAd Vs VCD Induction Prior To High Dose Treatment Followed By Lenalidomide Consolidation and Maintenance – Final Analysis On Induction Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3369-3369 ◽  
Author(s):  
Hartmut Goldschmidt ◽  
Jan Duerig ◽  
Uta Bertsch ◽  
Christina Kunz ◽  
Thomas Hielscher ◽  
...  
Keyword(s):  
Partial Response ◽  
Induction Therapy ◽  
Research Funding ◽  
Treatment Strategies ◽  
Response Rates ◽  
Complete Response ◽  
Disease Stage ◽  
Induction Treatment ◽  
High Dose ◽  
Good Partial Response

Abstract Background The MM5 phase III trial of the German-Speaking Myeloma Multicenter Group (GMMG) was designed to address two independent primary objectives: 1.) demonstration of non-inferiority of VCD (bortezomib, cyclophosphamide, dexamethasone) induction compared to PAd (bortezomib, adriamycin, dexamethasone) induction therapy with respect to response rate (very good partial response or better). 2.) determination of the best of four treatment strategies with respect to progression-free survival (PFS). The four treatment strategies were defined by PAd vs. VCD induction treatment, high dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) as well as consolidation and maintenance treatment with lenalidomide for 2 years vs. lenalidomide until complete response (CR). Methods 504 patients were included in the trial between July 2010 and October 2012. A non-inferiority analysis of VCD compared to PAd with respect to response rates after induction treatment with a non-inferiority margin of 10% for the difference in response rates (VGPR and better; first primary endpoint) and a safety analysis were performed. During the induction phase the patients were treated with 3 cycles of PAd or VCD. PAd was dosed as bortezomib 1.3 mg/m2, days 1, 4, 8, 11, doxorubicin 9 mg/m2, days 1-4, dexamethasone 20 mg, days 1-4, 9-12, 17-20 (repeated every 28 days). VCD consisted of bortezomib 1.3 mg/m2, days 1, 4, 8, 11, cyclophosphamide 900 mg/m2 day 1, dexamethasone 40 mg, days 1-2, 4-5, 8-9, 11-12 (repeated every 21 days). The route of administration for bortezomib was changed from intravenously to subcutaneously in all study arms by a protocol amendment in February 2012 after inclusion of 314 patients. The non-inferiority analysis was based on intention-to-treat (ITT) population (502 evaluable patients) and per-protocol (PP) population (473 evaluable patients). Responses were assessed according to the response criteria of the International Myeloma Working Group (IMWG). Results In the ITT population, patients treated with PAd or VCD were equally distributed for ISS and Durie-Salmon disease stage, LDH, kidney function and the cytogenetic abnormalities translocation t(4;14), deletion 17p13 and gain 1q21. In the PAd group, the median age of the patients was higher (59.4 vs. 58.7, p=0.04). 229 of 251 patients (91.2%) in the PAd group and 241 of 251 patients (96.0%) in the VCD group completed induction treatment. Observed response rates (PAd vs. VCD) were 4.4% vs 8.4% for complete response, 34.3% vs. 37.0% for ≥ very good partial response and 72.1% vs. 78.1% for ≥ partial response. Non-inferiority of VCD compared to PAd was shown (two-sided p=0.0026). Similar results were obtained in the PP analysis. The proportion of patients with any adverse event (AEs) was comparable in PAd vs. VCD (61.3% vs. 64.0%, p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. 24.0%, p=0.037). VCD led to a significantly higher proportion of leukopenia and neutropenia CTCAE grade 3 and 4 (PAd: 11.3% vs. VCD: 35.2%; p<0.001). There was no significant difference in the number of infections (≥ CTCAE grade 2) during PAd induction compared to VCD induction (24.6% vs. 22.4%; p=0.60). Interestingly, compared to the infection rate (≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4-trial, a reduction in MM5 during induction was observed. In the PAd arm more deaths were observed compared to the VCD arm (6 vs. 1). Conclusion PAd and VCD are well tolerated with more than 90% of the patients receiving all three planned induction cycles. Non-inferiority of VCD compared to PAd was shown in ITT and PP analysis. In conclusion, VCD was found to be a valid alternative to PAd with comparable efficacy and a favourable toxicity profile. Disclosures: Goldschmidt: Celgene: Consultancy, Honoraria, Research Funding; Chugai: Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding. Duerig:Janssen Cilag: Honoraria; Celgene: Honoraria. Schmidt-Wolf:Janssen: Honoraria; Novartis: Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Scheid:Janssen Cilag: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Salwender:Janssen Cilag: Honoraria; Celgene: Honoraria.

Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8508-8508 ◽  
Author(s):  
Katja Weisel ◽  
Anne Marie Asemissen ◽  
Britta Besemer ◽  
Mathias Haenel ◽  
Igor W. Blau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Interim Analysis ◽  
Response Rates ◽  
Complete Response ◽  
Induction Treatment ◽  
High Dose ◽  
Depth Of Response ◽  
Grade 3

8508 Background: High-risk (HR) multiple myeloma (MM) still has a significant impaired prognostic outcome. Addition of CD38 monoclonal antibodies to standard-of-care regimens significantly improved response rates and depth of response in newly diagnosed (ND) and relapsed/refractory MM patients (pts). Here, we report the prespecified end of induction interim analysis (IA) of the investigator-initiated GMMG-CONCEPT trial (NCT03104842), evaluating the quadruplet regimen isatuximab plus carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in HR NDMM pts. Methods: 153 pts with HR NDMM are planned to be included into the trial. HR MM is defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 and ISS 2 or 3 stage disease. Pts receive 6 cycles of Isa-KRd induction, 4 cycles of Isa-KRd consolidation and Isa-KR maintenance. Transplant eligible pts (arm A) undergo high-dose therapy. Transplant ineligible pts (arm B) receive 2 additional cycles of Isa-KRd induction. The primary endpoint is MRD negativity measured by next-generation flow after consolidation. This IA reports on overall response rates (ORR) after induction. Additional MRD analysis will be presented. Results: 50 pts (46 arm A, 4 arm B) were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and > 3 copies 1q21 in 42%. 39/46 pts in arm A and 4/4 pts in arm B completed induction treatment. ORR was 100%, with 5 pts (10.0%) showing partial response (PR), 22 (44.0%; including 4 in arm B) very good partial response (VGPR) and 23 (46.0 %) complete response (CR). Median stem cell yield was 6.6 × 106CD34+ cells/kg. Grade 3/4 treatment-emergent adverse events (≥ 10%) with Isa-KRd included neutropenia (34.0%), leukopenia (26.0%) and thrombocytopenia (14.0%). Main non-hematologic toxicities grade 3/4 were hypertension (12.0%) and infection (8.0%). Conclusions: To the best of our knowledge, we report for the first time on a trial investigating solely HR NDMM and Isa-KRd quadruplet treatment. Isa-KRd induction induces deep responses in HR MM pts. The overall safety profile of Isa-KRd is expected and consistent with previous reports. The study is ongoing, with pts continuing to be included. Clinical trial information: 03104842 .

Prevalence of Oligoclonal Bands in Multiple Myeloma Patients Who Achieved Better Results Than Very Good Partial Response after Treatment with Standard or High Doses Chemotherapy-Final Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4210-4210
Author(s):  
Luiza soares Vieira ◽  
Edvan de queiroz Crusoe ◽  
Manuella de S. Sampaio Almeida ◽  
Lais Sousa ◽  
ana Lucia Perez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
Oligoclonal Bands ◽  
High Dose ◽  
Good Partial Response

Abstract Introduction - Oligoclonal bands (OB) are monoclonal proteins distinct from those originally identified in the multiple myeloma (MM) diagnosis. Some authors consider that appearance of these bands confers a better prognosis and may be linked to immune reconstitution. There is no data of the exact prevalence of OB emergence in patients with very good partial response (VGPR) or better after different treatment schedules. Objectives - To determine the prevalence of OB in MM patients treated with or without high-dose chemotherapy that obtained at least VGPR and its prognostic value. Methods- This is a retrospective and prospective cohort study. Data were collected from records of patients that achieved at least VGPR to identify the OB emergence. Subsequently, new sample collections from the positive patients were made in order to monitor the progress and duration of the maintenance of these bands. Results-Median follow-up was 42m and 101 patients were included. Median age was 58y (29-87) and 55% were male. IgG was the most frequent component (60%). Durie-Salmon IIIA/B was identified in 92% of the population; ISS was 33% in stage I, 30% in stage II, and 31% in stage III. The prevalence of OB identified by SPE and IF was 50.5% (51 cases), with a higher prevalence in those who underwent transplantation and those who achieved complete response (p=0.00139 and p=0.0368, respectively). Progression free survival (PFS) was longer in the OB group (45.4m x 34.7m p = 0.0075). Conclusion - The OB prevalence in this population was 50.5% and oligoclonality resulted in a longer PFS. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3463-3463
Author(s):  
Hideki Nakasone ◽  
Kiriko Terasako-Saito ◽  
Teiichi Hirano ◽  
Atsushi Wake ◽  
Seiichi Shimizu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Induction Treatment ◽  
High Dose ◽  
Induction Phase ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Free Survival

Abstract [Background] Multiple myeloma (MM) is generally considered incurable. Recently, novel drugs, including bortezomib, have demonstrated a survival benefit for newly diagnosed MM patients compared with classical treatments. Complete response (CR) after treatment is known to be associated with superior progression-free survival. Thus, we prospectively evaluated the efficacy and safety of boretezomib + dexamethasone (BD) for patients with newly diagnosed MM, followed by autologous hematopoietic stem cell transplantation (ASCT). We added BD consolidation therapy to aim CR if CR was not achieved after ASCT. [Patients and methods] This clinical study prospectively recruited newly diagnosed MM patients eligible for ASCT between 2010 and 2012. Due to health insurance issues in Japan, two courses of high-dose dexamethasone (HD-DX) had been administrated prior to BD induction treatment until Nov. 2011, while BD was administrated as an initial induction treatment since Dec. 2011. BD induction treatment included 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with 20mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. This BD induction cycle was repeated every 3 weeks for 4 courses. Thereafter, filgrastim-based mobilization and ASCT following high-dose melphalan administration was performed. If patients did not achieve CR after ASCT, BD consolidation therapy (bortezomib: 1.3 mg/m2 on days 1, 8, and 15; dexamethasone 20 mg/day on days 1-2, 8-9, and 15-16) every 4 weeks was added to target CR (Figure 1) (UMIN-CTR: UMIN000002442). [Results] The median observational duration among survivors was 1536 days (range: 464-2023) at this analysis. Of the 47 enrolled MM patients, 46 (male 27; female 19) were eligible for BD induction treatment, while the remaining one achieved CR before BD induction. The median age of the patients was 59 (range: 35-67) years. Of the 44 patients whose karyotype analyses were available, normal karyotype was observed in 35. Abnormal karyotype included complex type in 4, diploid in 1, and other abnormalities in 4. FISH revealed deletion of p53 in 5 of 39 patients whose information was available; deletion of 13-chromosome in 16 of 42, IgH-MAF fusion in 1 of 40; IgH-FGFR3 fusion in 5 of 41; IgH-BCL1 fusion in 9 of 39. Of the 46 MM patients, 19 received HD-DX prior to BD induction, and 34 received ASCT after BD induction treatment (Figure 1). During the BD induction phase, 3 patients experienced disease progression, and BD treatment was discontinued in 9 patients because of their consent withdrawal (n=2) and adverse events (n=7) including interstitial pneumonia in 2, persistent neuropathy in 1, CMV enterocolitis in 1, heart failure in 1, diabetes mellitus in 1, and liver dysfunction in 1. After BD induction phase (n=46), their response was >= CR in 4 (8%), very good partial response (VGPR) in 10 (22%), partial response (PR) in 18 (39%), stable disease (SD) in 2 (4%), and progression or withdrawal in 12 (26%). After ASCT, their response was >=CR in 9 (20%), VGPR in 11 (24%), PR in 12 (26%), SD in 1 (2%), and additional progression or withdrawal in 1 (2%). Of the 24 patients who received ASCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses (range: 1- 8). BD consolidation was discontinued in 4 patients due to persistent neuropathy or cytopenia. Finally, maximum response after ASCT with or without BD consolidation was >= CR in 19 (41%), VGPR in 7 (15%), PR in 6 (13%), < SD in 2 (2%, Figure 2). Through BD consolidation, CR was achieved in 8 of 11 patients with post-ASCT VGPR and 2 of 12 patients with post-ASCT PR. In total, 4-year progression-free survival (PFS) and overall survival (OS) was 43% (95%CI: 28-57%) and 80 % (95%CI: 64-90%), respectively. Focusing on CR patients after ASCT and those who actually received BD consolidation, PFS adjusted for karyotype and age were not different between CR patients after ASCT and after BD consolidation, while patients with VGPR or less after consolidation had significantly lower PFS (Figure 3). [Conclusion] BD induction and ASCT provided CR rate of 27% among ASCT patients, although BD induction may expectedly cause adverse events including persistent neuropathy and viral infections. Patients who achieved CR after ASCT showed good PFS, and targeting CR through BD consolidation might improve CR rate. It is worthwhile to prospectively compare the efficacy of BD consolidation only for patients who failed to achieve CR or universal consolidation strategy. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

Retrospective Comparison of Transplant Outcomes in Patients with Multiple Myeloma According to Induction Therapy with Thalidomide/Dexamethasone (TD) with or without Bortezomib (VTD).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 948-948 ◽  
Author(s):  
Sergio Giralt ◽  
Rupi Thandi ◽  
Muzaffar Qazilbash ◽  
Floralyn Mendoza ◽  
Eric Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Response Rates ◽  
Induction Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Treatment Characteristics ◽  
The Impact

Abstract Background: Thalidomide/Dexamethasone (TD) has become one of the most commonly used induction therapies for patients with symptomatic multiple myeloma (MM) eligible for high dose therapy (HDT) intensification with autologous stem cell transplant (ASCT). Bortezomib (Velcade) has been added to the combination of TD (VTD) in an effort to reduce MM tumor burden further prior to HDT.The impact of this addition on HDT outcomes has not been fully explored. Purpose: To determine the impact of the addition of bortezomib to TD induction therapy in patients with MM undergoing HDT and ASCT consolidation. Patients and Methods: Patients were eligible for this analysis if they had undergone HDT with ASCT for first remission consolidation or primary refractory disease within 12 months of diagnosis between 9/03 and 12/05 and had received either TD or VTD as induction therapy. Patients receiving VTD after TD were excluded. Patients receiving more than 1 chemo regimen other than TD or VTD were excluded. Chemomobilization was NOT considered an exclusion criteria. Results A total of 78 patients qualified for the analysis (27 VTD; 51 TD). Patient and treatment characteristics are summarized in table 1. In brief, the patients receiving VTD had a higher rate of cytogenetic abnormalities and received less cycles of chemotherapy prior to SCT. Although pre-SCT response rates were similar between patients receiving VTD or TD (95% vs 92%) there was a trend for a higher CR rate in the VTD group (15% vs 6%). Post transplants response rates assessed between 3–6 months demonstrated that 28% and 38% of VTD patients achieved near CR and CR respectively while 19% and 23% had these responses post TD induction. There was no difference in 2 year OS and PFS among patients receiving VTD or TD (91% vs 81% and 35% and 56% respectively). Conclusion: Both VTD and TD as induction treatment are associated with high response rates prior to SCT as well as 6 months post SCT. In this retrospective analysis no survival benefit was seen for induction therapy with VTD over TD, despite higher near CR and CR rates. However randomized trials need to be performed addressing type of induction as well as duration of induction therapy prior to high dose therapy consolidation. Patient and Treatment Characteristics Variables VTD TD N 27 51 Median Age 54 (34–71) 56 (34–71) %ISS> 1 76% 65% % CG Abnormal 37% 19% p=.009 B2M @ Dx 2.99 3.19 Cycles Prior to SCT 2 4 p=.00009 % Mel 200 74% 69% Post SCT Maintenance 15/27 23/51

Mature Results From ECOG Study E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for Previously Untreated Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 153-153 ◽  
Author(s):  
Brad S. Kahl ◽  
Hailun Li ◽  
Mitchell R Smith ◽  
Randy D. Gascoyne ◽  
David T. Yang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Induction Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Treatment Plan ◽  
Induction Treatment ◽  
High Dose ◽  
Group Setting ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 153 Introduction Modified R-hyperCVAD is a well-tolerated induction regimen with a high response rate in MCL. We hypothesized that the incorporation of bortezomib (Velcadea) into this regimen would enhance the complete response rates. We further hypothesized that the addition of maintenance rituximab (MR) would improve remission duration. The new regimen, VcR-CVAD with MR, was tested for safety and efficacy in the Eastern Cooperative Oncology Group. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0–2, and adequate end organ function. The treatment plan included: bortezomib 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs × 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1–4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients could elect to receive high dose chemotherapy and autologous stem cell transplantation (SCT) off protocol rather than MR. The primary endpoint of the trial was the CR rate, defined as PET-negative, marrow-negative, to VcR-CVAD induction therapy. Results Seventy-five eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40–76), 58M:17F, 92% stage III/IV, and 40% with elevated LDH. MIPI risk distribution included 37% low, 36% intermediate, 19% high, 8% unknown. Sixty-eight patients (91%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), and patient preference (2). The ORR was 97% (73/75), CR rate 68% (51/75) and PR rate 29% (22/75). Of the 22 PR patients, 11 were so coded due to no bone marrow evaluation and/or PET imaging post therapy. The CR rate in the 64 completely restaged patients was 80%. Forty-four patients proceeded to protocol planned MR while 22 patients received SCT consolidation off protocol. With a median follow up of 3.6 years, the 3-yr PFS for the MR cohort (n = 44) and entire cohort (n = 75) are 73% and 74%, respectively. OS at 3-yrs is 88%, with no difference between MR and SCT patients. The major toxicity of the induction treatment regimen was expected myelosuppression. Grade 3–4 non-hematologic toxicities were rare. No patients developed grade 3–4 neuropathy. There were no serious toxicities during MR. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall OR (97%) and CR rates (68%) in a representative MCL patient population treated in a cooperative group setting. The 3-yr PFS (74%) and OS (88%) are highly encouraging. Remissions in patients receiving MR were as durable as patients receiving SCT consolidation. The value of bortezomib, when added to conventional chemotherapy, is currently being tested in a randomized intergroup trial (E1411). Disclosures: Kahl: Genentech: Consultancy, Research Funding; Roche: Consultancy; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as frontline treatment of mantle cell lymphoma. Smith:Millennium: Research Funding. Advani:Genentech: Research Funding. Horning:Genentech: Employment; Roche: Equity Ownership.

Bone Turnover In Multiple Myeloma: Impact Of Bortezomib-Based Induction Therapy, High-Dose Melphalan, and Lenalidomide Consolidation On Osteoblast and Osteoclast Function Within The GMMG-MM5 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1863-1863 ◽  
Author(s):  
Anja Seckinger ◽  
Tobias Meißner ◽  
Uta Bertsch ◽  
Hans Salwender ◽  
Jan Dürig ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Turnover ◽  
Induction Therapy ◽  
Research Funding ◽  
Induction Treatment ◽  
High Dose ◽  
Myeloma Cells ◽  
Osteoblast Activity ◽  
Osteoclast Function ◽  
High Dose Melphalan

Abstract Introduction In multiple myeloma, initially, there are increased numbers of osteoclasts showing increased activity, but bone formation by osteoblasts is keeping step. In later stages, parts of the bone remodeling compartments are disrupted by the interaction with myeloma cells leading to increased bone resorption which can no longer be compensated (myeloma bone disease, uncoupling of bone formation and bone resorption). Lenalidomide and bortezomib have been shown to target both, myeloma cells and the microenvironment: lenalidomide inhibits osteoclastogenesis, bortezomib is also able to stimulate osteoblast differentiation leading to increased bone formation. Aim of this study is to evaluate the impact of bortezomib-based induction treatment, high-dose therapy, and lenalidomide consolidation on alterations of bone turnover, i.e. surrogates of osteoblast- (osteocalcin, OC) and osteoclast- (collagen type I fragments, CTX-I) function, and their induction by myeloma cells (DKK1-level). Methods Serum was collected during routine sampling within the GMMG-MM5 trial (EudraCT 2010-019173-16), and levels of CTX-I, OC, and DKK1 were assessed by ELISA in triplicates using commercially available assays according to the manufacturer’s instructions (RnD Systems and Immunodiagnostic Systems). The following time points were assessed: at inclusion (n=365), after induction therapy with either PAd (n=88) or VCD (n=84), stem cell mobilization using CAD (n=69), high-dose melphalan (n=92), and 2 months lenalidomide consolidation (n=92). Up to now, serum samples of 69 patients were measured sequentially at five time points in line with the GMMG-MM5 trial. DKK1 levels were correlated with the expression in CD138-purified myeloma cells (Affymetrix microarrays, n=365). Results Prior to treatment, CTX-I levels are increased, those of OC decreased compared to healthy donors (uncoupled bone turnover). DKK1 protein levels are increased and correlate with DKK1-expression in myeloma cells. After induction therapy, osteoclast activity (CTX-I) is decreased below normal values. PAd unlike VCD further decreases osteoblast activity (OC-levels); DKK1-levels are normalized. Subsequent treatment further decreases DKK1-levels below normal values and blocks osteoclast function. After 2 months lenalidomide consolidation, no normalization of osteoblast activity is found. Conclusion The main impact on bone turnover by bortezomib-based induction treatment is a reduction of osteoclast activity alongside a decrease in DKK1-levels. During the reported period, no normalization of decreased osteoblast function was observed. Disclosures: Seckinger: Novartis Pharma: Research Funding. Goldschmidt:Novartis Pharma: Research Funding. Hose:Novartis Pharma: Research Funding.

Velcade, Intravenous Cyclophosphamide and Dexamethasone (VCD) Induction for Previously Untreated Multiple Myeloma (German DSMM XIa Trial).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 131-131 ◽  
Author(s):  
Hermann Einsele ◽  
Peter Liebisch ◽  
Christian Langer ◽  
Martin Kropff ◽  
Hannes Wandt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Induction Treatment ◽  
High Dose ◽  
Prognostic Impact ◽  
Short Period ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Abstract 131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficacious and safer drug combination for induction therapy in MM, we tested the combination of Velcade with Cyclophosphamide and Dexamethasone (VCD). Methods. This trial was designed as an open, prospective, multi-center, uncontrolled, combined phase II/III study. As previously reported (Kropff M et al., Ann Hematol 2009), in the first 30 pts the optimal dose of iv Cyclophosphamide in combination with V and D was defined as 900 mg/m2 on d1. Between 03/2006 and 03/2009 we enrolled an additional 370 pts up to 60 years of age with untreated MM to receive three 3-week cycles of induction treatment with V 1.3 mg/m2 iv d1,4,8,11; D 40 mg/d orally d1,2,4,5,8,9,11,12; and C 900mg/m2 iv d1 before scheduled high dose melphalan and ASCT. The primary endpoint of the study is response rate on day 63 after 3 cycles of VCD according to EBMT and IMWG criteria. Results. Final data from 400 pts from 39 German centers will be presented at the meeting. In the currently evaluable 300 pts (mean age 52.3 years; 1.7% stage I, 21.3% stage II, 77.0% stage III) molecular cytogenetic analysis showed a prevalence of 13q- in 38%, of t[4;14] in 13% and of 17p- in 12% of pts (no changes in 35%). All 300 pts (88.3% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate (ORR = CR+PR) was 84%, with 10% CR and 74% PR, 5.7% MR, 7.3% NC and 2.3% PD. The negative prognostic impact of 13q- or t[4;14] was abrogated (ORR normal 87.3%, 13q- 83.7%, t[4;14] 90.0%), the unfavorable influence of p53 loss in the 17p- subgroup was still detectable (ORR 69.2%) but this did not reach statistical significance. VGPR rates will be reported at the meeting. Serious adverse events were documented in 78/300 (26.0%) patients. Death rate was remarkably low (1.3%, of which one was not related to the trial medication). 155/300 (52%) of pts experienced grade 3/4 non-serious AEs and of these leucopenia (93/300 pts= 31%), thrombocytopenia (7%), neutropenia (6%), anaemia (5%) were the most frequent events. 80 AEs grade 3 or 4 and 45 SAEs were of infectious origin and occurred in 47/300 pts. 80/130 SAEs (61.5%) were at least possibly related to Velcade. 101/300 pts (34%) developed episodes of peripheral neuropathy. PNP was grade 1 in 62/300 pt (20.7%), grade 2 in 31/300 pt (10.3%) and grade 3 in 7/300 pts (2.3%). Conclusion. This analysis demonstrates that proteasome inhibition by Velcade in combination with Dexamethasone and iv Cyclophosphamide (VCD) is an induction regimen for newly diagnosed MM which is highly effective in a short period of time, has a rather low toxicity profile and is feasible for administration in an outpatient setting. Based on these characteristics, VCD qualifies to become a new standard for MM induction therapy. Disclosures: Einsele: OrthioBiotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib is licensed as monotherapy for use in relapsed/refractory MM and in combination with melphalan/Prednisone in the first-line treatment of MM pts ineligible for HD-MEL and ASCT. . Liebisch:OrthoBiotech: Consultancy, Honoraria. Langer:OrthoBiotech: Consultancy. Kropff:OrthoBiotech: Consultancy, Honoraria. Kröger:OrthoBiotech: Honoraria. Ostermann:OrthoBiotech: Honoraria. Mügge:OrthoBiotech: Honoraria. Wolf:OrthoBiotech: Honoraria. Gramatzki:OrthoBiotech: Consultancy, Honoraria. Maschmeyer:OrthoBiotech: Travel Grant. Sezer:OrthoBiotech: Consultancy, Honoraria. Heidemann:OrthoBiotech: Honoraria. Jäger:OrthoBiotech: Honoraria. Dechow:Celgene: Research Funding. Simon:OrthoBiotech: Honoraria. Straka:OrthoBiotech: Consultancy, Honoraria, Research Funding. Fingerle-Rowson:orthoBiotech: Employment. Knop:OrthoBiotech: Honoraria.

scholarly journals Virtual Karyotype Reconstruction By SNPs Array of Newly Diagnosed Multiple Myeloma (MM) Patients Enrolled in the EMN02 Clinical Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2033-2033
Author(s):  
Carolina Terragna ◽  
Angela Flores Dico ◽  
Marina Martello ◽  
Vincenzo Callea ◽  
Gioacchino Catania ◽  
...  
Keyword(s):  
Partial Response ◽  
High Throughput ◽  
Induction Therapy ◽  
Research Funding ◽  
Plasma Cells ◽  
Hippo Pathway ◽  
Complete Response ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Extreme Response

Abstract Background. Array-based technology has been showing a great impact on clinical cancer cytogenetic, especially on genetically heterogeneous disease, such as MM, where relevant lesions might be the hallmarks of different patients’ subgroups, thus becoming of clinical relevance as well. We present herein the results of a molecular sub-study of the EMN02 phase III study (EMN02_HOVON95) which was designed to compare consolidation therapy Bortezomib, Melphalan and Prednisone versus upfront autologous stem cell transplantation, both applied after induction therapy with bortezomib-cyclophosphamide-dexamethasone (VCD). The sub-study was aimed at developing a comprehensive, high throughput genomic profile to be used to stratify uniformly treated MM patients according to their genomic background at baseline and to perform correlations with response to induction therapy. Patients and methods. Data obtained from 170 patients who consecutively entered the study and received three 21-day cycles of VCD induction therapy were analyzed. Baseline patients’ characteristics, including cytogenetic abnormalities, were comparable with those of 717 patients enrolled by participating Italian centres. Highly purified CD138+ bone marrow plasma cells were profiled by SNPs array (Affymetrix 6.0 and CytoScanHD® chip). ChAS (Affymetrix) and Nexus Copy NumberTM 7.5 (Biodiscovery) software were used to perform Copy Number Alterations (CNAs) analyses and clinical correlations, respectively. Results. After induction therapy, 66 out of 170 (38.8%) patients achieved a very good partial response (VGPR) or better, including 15 (8,8%) who attained a complete response (CR). On the contrary, 104/170 (61.1%) patients achieved <=partial response (PR), including 28 with stable disease (SD). Presenting MM cases were studied by SNPs array in order to compute CNAs and acquired loss of heterozygosity (LOH) in the tumor. The frequency distribution of the more relevant CNAs is summarized in table 1. A subgroup of 13/170 (7.6%) patients was characterized by the absence of any macro CNAs (either gains or losses): these cases were mainly characterized by LOH events on chr. 1, 8 and 16, where putative tumor suppressor genes are located (e.g. PLEKOH1 and SIAH1 on chr.1 and 16, respectively). In order to identify novel chromosomal lesions potentially influencing response to induction therapy, we compared the CNAs profile of the extreme response categories, i.e. CR and SD. Neither the absence of CNAs nor the presences of any of those that are prognostically relevant were significantly linked to response to induction therapy. On the contrary, the following two novel lesions resulted highly significant. A 42.9 Kb CN gain on chr.11q22.1-22.2, which only includes the Hippo pathway mediator YAP1, significantly characterized 6% of patients in CR, as compared to 54% of patients with SD (p=0.002). An extended CN loss on chr.14q13.1-13.3, including genes implicated in the progression on cancer (e.g. NKX2-8), significantly characterized 62.5% of patients who achieved CR, as compared to 4% of those with SD (p<0.001). Conclusions. The reconstruction of high-throughput virtual karyotype by SNPs array in a cohort of homogeneously treated, newly diagnosed, MM patients offered the opportunity to obtain a comprehensive overlook of each patient’s sub-chromosomal anatomy. This allowed both to perform a detailed patients’ stratification at diagnosis and to identify, among the whole spectrum of CNAs, those having an impact on response to induction therapy. Figure 1 Figure 1. Disclosures 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. Sonneveld:Celgene: Research Funding, Speakers Bureau; Millennium-Takeda: Research Funding; Onyx: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Cavo:Millenium: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Onyx: Honoraria.

scholarly journals Zdravljenje diseminiranega plazmocitoma na Kliničnem oddelku za hematologijo UKC Ljubljana z avtologno presaditvijo krvotvornih matičnih celic v letih 2014 in 2015.

2016 ◽  
Vol 85 (9) ◽  
Author(s):  
Samo Zver ◽  
Enver Melkić ◽  
Tanja Radevska
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Induction Therapy ◽  
Progressive Disease ◽  
Induction Treatment ◽  
Hematopoietic Stem ◽  
Treatment Mortality ◽  
Good Partial Response ◽  
Autologous Hsct ◽  
Overall Mortality

Introduction. In the period from 01.01.2014 to 31.12.2015 at Clinical Department of Hematology, University Medical Centre Ljubljana, we treated 73 multiple myeloma patients with first autologous  hematopoietic stem cell transplantation (HSCT).Methods and results. Age of patients ranged from 27 to 72 years with the median age of 60 years. Induction treatment at the time of diagnosis consisted of: VD (bortezomib, dexamethasone) 60/73 patients (82%), VCD (bortezomib, cyclophosphamide, dexamethasone)  10/73  patients (14%) and VTD (bortezomib, thalidomide, dexamethasone) 3/73 (5%)  patients. As part of induction therapy, patients received from 1 to 9 cycles of treatment. Response to induction therapy prior to HSC(hematopoietic stem cells) collection was as follows: CR(complete remission )7/73(10%), VGPR (very good partial response) 28/73(38%), PR (partial response) 23/ 73(32%), SD (stable disease) 11/73(15%) andPD (progressive disease) 4/73(5%) patients. Response to induction therapy immediately prior to autologous HSCT: CR9/73 (12%), VGPR32/73 (44%), PR17/73(23%), SD 8/73(11%) and PD6/73(8%) patients. Response to induction therapy and the first autologous HSCT at D+100 after HSCT: CR9/67 (13%), VGPR 34/67 (51%), PR 12/67 (18%), SD 3/67 (4 %) and PD 7/67 (10%) patients (in 6 patients data are missing, because they are not mature yet).  With single HSCT 63 patients were treated, while 10 patients received double or second HSCT. The overall mortality of patients treated during the  period from 01.01.2014 to 31.12. 2015 was 6/73 or 8.2%.Conclusions. The treatment of multiple myeloma with autologous HSCT remains the cornerstone of efficiency,as demonstrated by the increasing share of the most desired responses to treatment, ie. CR and VGPR. The treatment mortality rate was within expectation limits.

First Analysis of HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Adriamycine, Dexamethasone (PAD) Vs VAD as Induction Treatment Prior to High Dose Melphalan (HDM) in Patients with Newly Diagnosed Multiple Myeloma (MM)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 653-653 ◽  
Author(s):  
P. Sonneveld ◽  
B. van der Holt ◽  
I. G.H. Schmidt-Wolf ◽  
U. Bertsch ◽  
L. el Jarari ◽  
...  
Keyword(s):  
Stem Cell ◽  
Partial Response ◽  
Complete Response ◽  
Phase Iii ◽  
Induction Treatment ◽  
P Value ◽  
High Dose ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
High Dose Melphalan

Abstract The randomized, open-label, phase III trial HOVON-65/GMMG-HD4 was designed to evaluate the efficacy of bortezomib prior to HDM for response and progression-free survival (PFS) in patients with newly diagnosed MM. The trial was performed in 75 referral centers in the Netherlands and Belgium (HOVON group) and Germany (GMMG group). Patients with Salmon & Durie (SD) stage II or III, age 18–65 years inclusive, were randomly assigned to 3 cycles of VAD (vincristine 0.4 mg, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20) or PAD (bortezomib 1.3 mg/m2 days 1,4,8,11, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20). No thrombosis prophylaxis was given. Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy, all patients were to receive 1 or 2 cycles of high-dose melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance with thalidomide 50 mg daily (VAD arm) or bortezomib, 1.3 mg/m2 once every 2 weeks (PAD arm) for 2 years. Between May 4, 2005 and May 16, 2008, 833 patients were randomized. After the trial was closed, we here report the planned interim analysis data on response after induction and HDM-1 of the initial 150 (75 per arm) randomized patients. The data of the initial 300 registered patients (150 per arm) will be available by November 1, 2008 and presented. The 2 randomization arms were equal for SD stage of disease, ISS stage, and distribution of chromosomal abnormalities. 134 patients (89%) completed PAD/VAD and 130 patients (87%) completed HDM-1, with no difference between the treatment arms. Full dose bortezomib could be administered in 95 % (PAD1), 79 % (PAD2) and 85 % (PAD3) of patients. Successful stem cell apheresis was achieved in all 132 patients who received CAD. Adverse events CTC grade 2–4 during PAD vs VAD included neurologic or polyneuropathy (PNP) 38% vs 21 %, constitutional symptoms 30 % vs 24 %. PNP of CTC grade 1–4 was more frequent in the PAD arm (p=0.01), while DVT/pulmonary embolism was diagnosed in 10 % during VAD and 6 % during PAD. Responses were assessed according to EBMT criteria including VGPR after PAD/VAD, after HDM-1 and best response on protocol treatment. Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR) in both arms were compared by logistic regression (table 1) Response ITT (%) PAD VAD p-value PAD+ HDM-1 VAD+ HDM-1 p-value CR 5 0 0.06 15 4 0.05 ≥VGPR 41 17 0.001 59 47 0.14 ≥PR 80 64 0.03 92 77 0.01 The (preliminary) overall complete response rate including maintenance was 27 % (PAD arm) and 5% (VAD arm) (p=0.001). Deletion of chromosome 13q did not have a significant impact on response. We conclude that PAD induces significantly more PR+VGPR+CR as compared with VAD, and that this effect is sustained after HDM-1. This trial was supported by the Dutch Cancer Foundation (EudraCT nr 2004-000944-26), the German Federal Ministry of Education and Research and a grant from Johnson and Johnson

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