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  • 1
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    Thalidomide / Dexamethasone (TD) Vs. Bortezomib (Velcade)â/Thalidomide / Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcadeâ as Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM): Results of a Phase III PETHEMA/GEM Trial.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 130-130
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 130-130
    Abstract: Abstract 130 In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Velcadeâ in patients 65 years-old or younger with newly diagnosed symptomatic MM, followed by ASCT with MEL-200. The primary end points were response rate after induction and after ASCT and time to progression. TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus Velcade 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus Velcadeâ consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of Velcadeâ (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. As of December 31, 2008, 305 patients (median age: 57 yrs, M: 156, F:149; IgG. 181, IgA: 71, light chain: 43, others: 10) entered the study and are the basis of the current analysis. Fifty-six (18%) patients had soft-tissue extramedullary plasmacytomas (EMP) and the stage according to the ISS was I in 39%, II in 41 %, III in 19 % and unknown in 1%. The prognostic factors, including cytogenetics, was similar in the 3 arms. Fifty-five (18%) patients had high-risk cytogenetics (t(4;14), t(14;16) and/or 17p deletion). Two-hundred and ninety-nine patients (TD:103, VTD: 99 and VBMCP/VBAD/Velcade®: 97) were evaluable for response and toxicity to induction therapy. The ≥ PR rate was 64%, 82% and 75% with TD, VTD and VBMCP/VBAD/Velcade®, respectively (p=NS). The IF negative CR rate was significantly higher with VTD (29%) and with VBMCP/VBAD/Velcade® (25%) than with TD (14%) (p=0.009 and p=0.04, respectively). Progressive disease (PD) was significantly higher with TD than with VTD (21% vs. 8%, p=0.009). In the overall series, PD was significanty higher in patients with EMP (34% vs. 12%, p=0.0002) with a significanty higher PD rate for TD as compared with VTD (40% vs. 14%, p=0.05). In patients with poor cytogenetics the CR rate was significantly higher with VTD than with TD (42% vs. 5%, p=0.009). In this high-risk group the PD rate was higher with TD (37%) and with VBMCP/VBAD/Velcade® (23%) than with VTD (0%) (p=0.009 and p=0.04, respectively). The incidence of thrombotic events ≥ grade 3 was higher in the TD arm (9% vs. 1% vs. 3%, p=0.07 and p=0.01) while ≥3 peripheral neuropathy was higher with VTD (14% vs. 0% and 1%, p 〈 0.0001 and p=0.0003). Treatment was discontinued due to toxicity in 11 patients (TD: 3, VTD: 6, VBMCP/VBAD/Velcade®:2). Eight patients died during induction period (TD:5, VTD: 2, VBMCP/VBAD/Velcade®: 1) One-hundred seventy-seven patients were evaluable for response after ASCT. The post-ASCT CR rate with TD, VTD and VBMCP/VBAD/Velcade® was 40%, 59% and 48%, respectively, being significantly higher with VTD than with TD (p=0.05). The estimated overall survival at 2 years is 82% with no significant differences among the 3 arms. TTP and PFS were significantly shorter with TD (p=0.05 and p=0.012, respectively). In summary, VTD results in a higher pre- and post-ASCT CR rate as well as in a lower PD rate than TD, particularly in patients with high-risk cytogenetics or with EMP. The TTP and PFS are shorter with TD. Intermediate results are observed with VBMCP/VBAD/Velcade®. Longer follow-up is needed to establish whether or not these results will translate into a significantly different long-term outcome. Updated data will be presented at the meeting. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Thalidomide and bortezomib are not yet approved in Spain. Cibeira:Jansse-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. de la Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Honoraria; Celgene: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.130.130
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
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    Smoldering Multiple Myeloma (SMM) at High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) as Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1935-1935
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1935-1935
    Abstract: Abstract 1935 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease ( 〉 50% at 2 years): 〉 10% of PCs in BM, serum MC 〉 30g/L, 〉 95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn't focus on high-risk patients. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progresión (TTP) to symptomatic disease. The high risk population was defined by the presence of both 〉 PC 10% and MC 〉 30g/L or if only one criterion was present, patients must have a proportion of aberrants PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (ammended in May 2010 into monthly). The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn't meet inclusion criteria). This second interim analysis was planned when all patients were recruited. According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%. After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p 〈 0.0001). It should be noted that 10 out of these 21 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developped G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. In conclusion, this second interim analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·7), with excelent tolerability; moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures: Mateos: Celgene: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma. De La Rubia:Celgene: Honoraria. Rosiñol:Celgene: Honoraria. Lahuerta:Celgene: Honoraria. Palomera:Celgene: Honoraria. Oriol:Celgene: Honoraria. Garcia-Laraña:Celgene: Honoraria. Hernández:Celgene: Honoraria. Leal-da-Costa:Celgene: Honoraria. Alegre:Celgene: Honoraria. Quintana:Celgene: Employment. Baquero:Celgene: Employment. García:Celgene: Honoraria. San Miguel:Celgene: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1935.1935
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 991-991
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 991-991
    Abstract: Abstract 991 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: 〉 10% of PCs in BM, serum MC 〉 30g/L, 〉 95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both 〉 PC 10% and MC 〉 30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly). The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria). According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%. After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p 〈 0.0001). It should be noted that 13 out of these 28 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). Estimated 3-years overall survival (OS) from the inclusion in the trial was 98% for Len-dex arm and 82% for no treatment arm (p=0·05) and this difference was more evident if we evaluate the OS from the moment of diagnosis (HR: 6.7; 95% IC (0.7–57); p=0.03). As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developed G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. Two patients in the Len-dex arm developed second primary malignancies (SPM): one developed polycythemia vera JAK2+, but the analysis of a frozen DNA sample obtained at the moment of inclusion in the trial demonstrated that JAK2 was already positive. The second-one was a prostate cancer in a patient with previous history of prostate enlargement plus elevated prostate specific antigen (PSA) who was closely followed by the urologist. In conclusion, this analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·2), with a trend to improve the overall survival; in addition, tolerability is acceptable and concerning SPM, no safety warnings are at the present time. Moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures: Mateos: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Baquero:Celgene: Employment. Quintana:Celgene: Employment. García:Celgene: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.991.991
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
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    Persistent Benefit of VTD (Bortezomib/Thalidomide/Dexamethasone) As Pretransplant Induction Therapy for Multiple Myeloma: Long-Term Follow-up of a Randomized Phase 3 Pethema/GEM Study
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3457-3457
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3457-3457
    Abstract: Background: The randomized PETHEMA/GEM phase III trial GEM05menos65 (www.clinicaltrials.gov NCT00461747) demonstrated that pretransplant induction therapy with VTD resulted in a significantly higher CR rate both, pretransplant and postransplant and in a significantly longer progression-free survival (PFS) when compared with thalidomide/dexamethasone (TD) and combination chemotherapy plus bortezomib (VBMCP/VBAD/B) (Rosiñol et al, Blood 2012). We report here the long-term results of the trial, five years after the last patient was included. Methods: From April 6, 2006 to August 5, 2009, 386 patients younger than 65 years with newly diagnosed symptomatic multiple myeloma (MM) were randomized to receive three different induction regimens: six 4-week cycles of TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) vs. six 4-week cycles of VTD (TD at identical doses plus i.v. bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) vs. combination chemotherapy plus bortezomib (4 cycles of alternating VBMCP and VBAD chemotherapy followed by two cycles of i.v. bortezomib at the usual dose of 1.3 mg/m2 on days 1,4,8,11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. All patients were planned to undergo ASCT with high-dose melphalan at 200 mg/m2 followed by maintenance therapy with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN) for 3 years. One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics [t(4;14), t(14;16) and/or 17p deletion]. Patient characteristics at diagnosis and prognostic factors such as ISS, cytogenetics and maintenance arm were similarly distributed in the 3 arms. Results: After a median follow-up of 70.6 months, VTD resulted in a significantly longer PFS when compared with TD and VBMCP/VBAD/B (56.1 vs 29.2 vs 39.9 months, p=0.005) (Figure 1). The estimated overall survival (OS) at 8 years was 60% with no significant differences among the 3 arms. In the overall series, the PFS was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk (15.7 vs. 44.3 months, p=0.003). In the TD and in the VBMCP/VBAD/B arm patients with high-risk cytogenetics had a significantly shorter PFS than patients with standard-risk (8.9 vs 32.8 months, p=0.04 in TD group; 14.1 vs. 43.3 months, p=0.05 in VBMCP/VBAD/B group). However, there was no significant difference in the VTD arm (23.6 vs 56.1 months, p=0.2). Patients with high-risk cytogenetics had a significantly shorter OS in the overall series (median 42.1 months vs not reached, p=0.00001) and this was observed in the three treatment arms: VTD median 37.1 months vs not reached (p=0.001), TD median 54.2 months vs not reached (p=0.06), VBMCP/VBAD/B median 30.2 months vs not reached (p=0.007). The achievement of a deeper response at the end of induction was associated with a longer PFS and OS. Thus, patients achieving CR at the end of induction had a significantly longer PFS than patients achieving a lower degree of response (median 62 vs. 28 months, p=0.00001), irrespective of the treatment arm. Furthermore, on an intention to treat basis, patients who were in postrasplant CR had a significantly longer PFS (p 〈 0.00001) and OS (p 〈 0.00001) than those who did not reach CR after ASCT (p 〈 0.001). In the overall series the OS after progression was 30.5 months and was not significantly different among the 3 arms (VTD 25.4 months, TD 50 months, VBMCP/VBAD/B 30.2 months, p=0.4). Patients with high-risk cytogenetics had a significantly shorter OS after relapse in the overall series (13.3 months vs. 37.5 months, p=0.001), in the VTD arm (13.3 vs 33.9, p=0.01) and in the VBMCP/VBAD/B arm (8.5 vs 38 months, p=0.01). Conclusions: Our long-term results confirm that induction with VTD results in a significantly longer PFS when compared with TD and VBMCP/VBAD/B. Patients with high-risk cytogenetics had a worse outcome even with the use of novel drugs. Finally, the PFS of 56 months achieved with VTD is the longest ever reported in the first line treatment of younger patients with MM elegible for ASCT and support the use of VTD as the standard of care for pretransplant induction therapy. Figure 1: PFS according to the induction arm Figure 1:. PFS according to the induction arm Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Celgene Corporation: Consultancy. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Gutierrez:Janssen: Honoraria; Celgene: Honoraria. Martinez-Lopez:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3457.3457
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 5
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    Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 7 ( 2006-10-01), p. 2165-2172
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 7 ( 2006-10-01), p. 2165-2172
    Abstract: Standard first-line treatment for elderly multiple myeloma (MM) patients ineligible for stem cell transplantation is melphalan plus prednisone (MP). However, complete responses (CRs) are rare. Bortezomib is active in patients with relapsed MM, including elderly patients. This phase 1/2 trial in 60 untreated MM patients aged at least 65 years (half older than 75 years) was designed to determine dosing, safety, and efficacy of bortezomib plus MP (VMP). VMP response rate was 89%, including 32% immunofixation-negative CRs, of whom half of the IF– CR patients analyzed achieved immunophenotypic remission (no detectable plasma cells at 10–4 to 10–5 sensitivity). VMP appeared to overcome the poor prognosis conferred by retinoblastoma gene deletion and IgH translocations. Results compare favorably with our historical control data for MP—notably, response rate (89% versus 42%), event-free survival at 16 months (83% versus 51%), and survival at 16 months (90% versus 62%). Side effects were predictable and manageable; principal toxicities were hematologic, gastrointestinal, and peripheral neuropathy and were more evident during early cycles and in patients aged 75 years or more. In conclusion, in elderly patients ineligible for transplantation, the combination of bortezomib plus MP appears significantly superior to MP, producing very high CR rates, including immunophenotypic CRs, even in patients with poor prognostic features.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2006-04-019778
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    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 6
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    Multicenter, Randomized, Open-Label, Phase III Trial of Lenalidomide-Dexamethasone (Len/dex) Vs Therapeutic Abstention in Smoldering Multiple Myeloma at High Risk of Progression to Symptomatic MM: Results of the First Interim Analysis.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 614-614
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 614-614
    Abstract: Abstract 614 Smoldering MM (sMM) is a plasma cell (PC) disorder defined by the presence of ≥10% of PC and/or a serum M-component (MC) ≥3g/dl without end-organ damage. Recent studies have identified a subgroup of sMM at high risk of progression to active MM ( 〉 50% at 2 y): patients with both PC ≥10% & MC ≥3g/dl (Kyle R. NEJM 2007) or ≥95% aberrant PC (aPC) by immunophenotyping (Pérez E. Blood 2007) or abnormal FLCs (Dispenzieri A. Blood 2008). Standard of care for sMM is monitoring without treatment until disease progression. Several small studies have explored the value of early treatment with either conventional agents (melphalan/prednisone) or novel drugs (thalidomide, interleukin-1b), with no clear benefit. It should be noted that these trials didn't focus on high-risk sMM. In this phase III trial we investigated whether early treatment prolongs the time to progression (TTP) in sMM patients at high risk of progression to active MM. Patients were randomized to receive Len-dex versus no treatment. The high risk population was defined by the presence of both PC ≥10% and MC ≥3g/dl or if only one criterion was present, patients must have a proportion of aPC within the total PCBM compartment by immunophenotyping of ≥95% plus immunoparesis. 120 patients are planned to be recruited. The 60 patients randomized to the Len-dex arm receive nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1-21 plus dexamethasone at dose of 20 mg daily on days 1-4 and 12-15 (total dose: 160mg) (induction phase); subsequently maintenance with Lenalidomide at dose of 10 mg on days 1-21 every two months administered until disease progression. Between October 2006 and June 2008, 80 patients were randomized. In this interim analysis, we present the first 40 patients recruited. According to baseline characteristics, both groups were well balanced. In an ITT analysis (n=40), based on IMWG criteria, the overall response rate was 90%, including 53% PR, 21% VGPR, 11% CR and 5% sCR. If we select the group of 16 patients who completed the nine cycles, the ORR was 100%, including 27% VGPR, 13% CR and 7% sCR. After a median follow-up of 16 months (range:12-20), no disease progression was observed in the Len-dex arm, while 8 patients progressed to active MM in the therapeutic abstention arm with a median TTP from inclusion in the trial of 17.5 months (p 〈 0.002). It should be noted that 6 of these 8 patients developed bone lesions as a symptom of active MM. As far as toxicity is concerned, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 2 patients G3 asthenia, 1 pt G3 diarrhea and 3 patients G3 DVT. Serious AEs occurred in 5 patients, 3 of these were dexamethasone-related (GI bleeding, delirium and glaucoma) and 2 were lenalidomide-related (two infections). Two SAEs lead to early discontinuation of the treatment (infection and delirium), and another 2 additional patients discontinued at pt's request. Four patients needed to reduce lenalidomide from 25 to 15 mg due to non-hematological AEs (asthenia (2), diarrhea (1) and GI bleeding (1). In conclusion, these preliminary results show that in sMM patients at high-risk for progression to active MM, delayed treatment is associated with early progression (median time 17.5 months) with bone disease, while so far Len-dex has been able not only to prolong the TTP (without any progression so far) but also to induce CRs with a manageable and acceptable toxicity profile. Disclosures: Mateos: Celgene: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma patients. de la Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Quintana:Celgene Corporation: Employment. Garcia:Celgene Corporation: Employment. San-Miguel:Celgene Corporation: Honoraria, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.614.614
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 7
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    Maintenance Therapy After Stem-Cell Transplantation for Multiple Myeloma with Bortezomib/Thalidomide Vs. Thalidomide Vs. alfa2b-Interferon: Final Results of a Phase III Pethema/GEM Randomized Trial
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 334-334
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 334-334
    Abstract: Abstract 334 Introduction: The Spanish Myeloma Group (PETHEMA/GEM) conducted a randomized phase III trial comparing induction with thalidomide/dexamethasone (TD) vs. bortezomib/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). The induction part of the study has been recently published and the maintenance results are reported here. End-points: The primary end-point was progression-free survival (PFS) and the secondary end-points were increase of response rate, overall survival (OS) and safety. Patients and Methods: The maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV: 89; T: 87, alfa2-IFN: 90). Response and survival were evaluated on an intention-to-treat basis. Responses, relapses and progressions (EBMT criteria) were monitored by an external contract research organization and centrally reassessed. Results: Patient's characteristics at diagnosis such as age, M-protein type, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization for maintenance after ASCT was CR: 51%, nCR: 12%, PR: 34%, MR 2% and SD: 1% and was well balanced in the three groups. The CR rate with maintenance was improved by 19% with TV, 15% with T and 17% with alfa2-IFN (p=NS). After a median follow-up of 34.9 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (figure 1, p=0.0009). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to progressions was not significantly diferent among the three arms (35% vs 24% vs 20%, p=NS). The discontinuation rate due to toxicity was higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p=0.17). Patients with high-risk cytogenetics [t(4;14), t(14;16) and/or del 17p] had a trend towards a shorter PFS (p=0.1) and a significantly shorter OS (p=0.03). The incorporation of bortezomib was not able to overcome the poor impact of high-risk cytogenetics. Conclusion: The addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with single agent alfa2-IFN with no increased toxicity. However, the addition of bortezomib did not overcome the poor impact of high-risk cytogenetics. Disclosures: Rosiñol: Janssen, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Granell:Janssen: Honoraria; Celgene: Honoraria. de Arriba:Jansen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria; Onix: Honoraria; Novartis: Honoraria. Bladé:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.334.334
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
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  • 8
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    A Phase III PETHEMA/GEM Randomized Trial of Postransplant (ASCT) Maintenance in Multiple Myeloma: Superiority of Bortezomib/Thalidomide Compared with Thalidomide and Alfa-2b Interferon,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3962-3962
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3962-3962
    Abstract: Abstract 3962 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing induction with TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). Primary end points : response rate after induction and after ASCT and time to progression. Patients and Methods: The maintenance program consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib-1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV:90; T: 89, alfa2-IFN: 87). Response and survival were evaluated on an intention-to-treat basis. Responses and progressions reported by the investigators were centrally reassessed. Results: the patient's characteristics at diagnosis such as age, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization after ASCT was CR: 51%, VGPR: 23%, PR: 24% and SD: 2% and was well balanced in the three groups. The CR rate with maintenance was improved by 23% with TV, 11% with T and 19% with alfa2-IFN (p=NS). After a median follow-up of 24 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (PFS at 2 yrs: 78% vs. 63% vs. 49%, p=0.01). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to toxicity was significantly higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p= 0.17). Conclusion: the addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with IFN with no increased toxicity. Disclosures: Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Martinez:Janssen: Honoraria; Celgene: Honoraria. de la Rubia:Janssen: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Blade:Janssen: Honoraria; Celgene: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3962.3962
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 9
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    Kinetics of Response to Bortezomib/Thalidomide/Dexamethasone (VTD) in Multiple Myeloma: Implications for the Choice and Design of Pretransplantation Induction Regimens
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2108-2108
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2108-2108
    Abstract: Background: Autologous stem-cell transplantation (ASCT) is the standard of care for younger patients with multiple myeloma (MM). The degree of tumor reduction after ASCT is the crucial factor associated with a prolonged PFS and OS, being the M-protein decrease at the time of transplant the most important predictor of residual disease after ASCT. While there is an agreement that bortezomib and dexamethasone associated to a third drug is the induction of choice, which should be the third drug (thalidomide, lenalidomide, doxorubicin or cyclophosphamide) and the optimal number of cycles remain unknown. The results of phase 3 PETHEMA study GEM05menos65 showing a CR rate of 35% increasing overtime during the 6 induction cycles of VTD (Rosiñol et al, Blood 2012) prompted us to study the kinetics of response to VTD and TD in this study and in similar historic data with the VD regimen in phase 2 PETHEMA VELCA/DEXA trial (Rosiñol et al, JCO 2007). Objective: To study the kinetics of response by cycle during the 6 cycles of induction with VTD, TD and VD using a random effects model methodology. Patients and Methods: In GEM05menos65 study patients were randomized to receive 6 induction cycles of either VTD or TD followed by ASCT. One hundred and thirteen patients were treated with TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) and 122 with VTD (TD at identical doses plus bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) (Rosiñol et al, Blood 2012) and had complete data set for this analysis. In VELCA/DEXA study 40 patients received 6 induction cycles of bortezomib and dexamethasone on an alternating basis (Rosiñol et al, JCO 2007). Linear random effects models were employed to analyze the tumor response kinetics using the absolute decrease value of the serum M-protein after each cycle. Because the nonlinearity in the change of the M-protein overtime, a piecewise linear model was used to estimate mean changes in M-protein in each of the 6 cycles. Results: Three different comparisons were made: 1) the decrease of the M-protein by cycle within each treatment group, 2) the total M-protein decrease at the end of induction with VTD compared to TD and VD and 3) the decrease by cycle comparing VTD vs TD and VTD vs VD. Concerning the M-protein decrease by cycle within each arm, statistically significant decreases versus the previous cycle were observed in the first 5 cycles of VTD, the first 3 of TD and the first 4 of VD. The serum M-protein reduction at the end of the 6 induction cycles was significantly higher with VTD when compared with TD (p 〈 0.0001) and VD (p 〈 0.0001). Finally, when comparing the serum M-protein decrease between VTD and TD by cycle, the M-protein reduction was significantly higher with VTD in the first 5 cycles and the same analysis between VTD and VD showed that the serum M-protein decrease was significantly higher with VTD in the first 3 cycles (Tables 1 and 2). Conclusions: In the cycle by cycle analysis VTD continued to improve M-protein reduction significantly in the first 5 cycles. When compared with TD and VD, the M-protein decrease at the end of induction was significantly higher with VTD. Furthermore, in the cycle by cycle comparison there was a significantly higher efficacy of VTD over TD in the first 5 cycles and over VD in the first 3 cycles. Our results suggest a synergistic rather than only an additive effect between thalidomide and bortezomib supporting the use of an IMiD as the drug of choice to be combined with bortezomib and dexamethasone. Finally, our study supports an induction period beyond 3 or 4 cycles when using a bortezomib/IMiD regimen in order to maximize the induction efficacy. Table 1. Comparison between VTD versus TD by cycles overtime. Serum M-protein (g/dl) Change (VTH-TH) Estimate SE 95% CI P-value C1 – Baseline -3.0747 0.3461 (-3.7539, -2.3954) 〈 .0001 C2 – C1 -1.1343 0.1294 (-1.3883, -0.8802) 〈 .0001 C3 – C2 -0.4474 0.09586 (-0.6356, -0.2593) 〈 .0001 C4 – C3 -0.2140 0.08224 (-0.3753, -0.05257) 0.0094 C5 – C4 -0.1339 0.07550 (-0.2821, -0.01428) 0.0765 C6 – C5 0.01862 0.05395 (-0.08725, 0.1245) 0.7300 Table 2. Comparison between VTD versus VD by cycles overtime. Serum M-protein (g/dl) Change (VTH-VD) Estimate SE 95% CI P-value C1 – Baseline -3.1553 0.2243 (-3.5957, -2.7150) 〈 .0001 C2 – C1 -1.3748 0.2279 (-1.8223, -0.9272) 〈 .0001 C3 – C2 -0.4266 0.2354 (-0.8887, 0.03552) 0.0703 C4 – C3 -0.05473 0.2439 (-0.5337, 0.4242) 0.8225 C5 – C4 -0.02217 0.2530 (-0.5189, 0.4745) 0.9302 C6 – C5 0.06493 0.2908 (-0.5060, 0.6358) 0.8234 Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Gutierrez:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Martinez-Lopez:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Feng:Janssen: Employment. van de Velde:Janssen: Employment. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2108.2108
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
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    A Phase III PETHEMA/GEM Study of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma: Superiority of VTD (Bortezomib/Thalidomide/Dexamethasone) Over TD and VBMCP/VBAD Plus Bortezomib
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 307-307
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 307-307
    Abstract: Abstract 307 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200. Primary end points: response rate after induction and after ASCT and time to progression. Patients and Method: TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. Four patients failed the eligibility criteria. 386 patients (median age: 56 yrs; M: 207, F: 179; IgG: 233, IgA: 85, light chain: 57, IgD: 9, Ig M: 2) were analyzed. The stage according to the ISS was I in 147 patients, II in 160, III in 75 and unknown in 4 and 66 patients (17%) had extramedullary soft-tissue plasmacytomas (EMP). Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics (t(4;14), t(14;16), and/or 17p deletion). One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Prognostic factors, including cytogenetics, were similar in the 3 arms. Response, survival and toxicity were evaluated on an intention-to-treat basis. Responses reported by investigators were centrally reassessed. Result: The IFE negative CR rate was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (22%) (p=0.0001 and p=0.01, respectively). The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p=0.001). In patiens with high-risk cytogenetics, the CR rate was significantly greater with VTD when compared with TD (35% vs. 0%, p=0.002) and with VBMCP/VBAD/B (35% vs. 22%, p=0.02). The CR rate to VTD in patients with 17p deletion was 58% while none of the patients with this cytogenetic abnormality responded to TD or to VBMVP/VBAD/B (p=0.03 and p=0.02, respectively). Of interest, the CR rate in patients with t(11;14) was significantly lower than in patients lacking this abnormality (11% vs. 27%, p=0.01). This low CR rate in patients with t(11;14) was similar in the 3 arms. In the overall series, PD was significantly higher in patients with EMP (24% vs. 11%, p=0.01) with a significantly higher PD rate for TD as compared to VTD (40% vs. 12%, p=0.02). The incidence of thrombotic events was 2%, 6% and 5% for VTD, TD and VBMCP/VBAD/B, respectively (p=NS). The frequency of grade ≥ 3 peripheral neuropathy was 12% with VTD compared to 1% in both the TD and the VBMCP/VBAD/B arms (p= 0.0002). Treatment was discontinued due to toxicity en 16 patients (VTD:9, TD:4, VBMCP/VBAD/B:3). Nine patients died during the induction period (3 in each arm). On an intention to treat basis, the post-ASCT CR rate was higher in the VTD arm compared with TD (46% vs. 24%, p=0.004) and VBMCP/VBAD/B (46% vs. 38%, p=0.1). The estimated overall survival (OS) at 4 years was 76% with no significant differences among the 3 arms. After a median follow-up of 27 months, the progression-free survival (PFS) was not reached with VTD while it was 27 and 38 months with TD and VBMCP/VBAD/B, respectively (p=0.006). In the overall series, patients with high-risk cytogenetics had a significantly shorter OS (p=0.00007) and PFS (p=0.004). In addition, when compared with the good-risk group, patients with high-risk cytogenetics showed a trend towards a shorter PFS either after induction with VTD (median not reached vs. 17 months, p=0.05) and with TD (median 28 vs. 15 months, p=0.09). Conclusion: Induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics. The post-ASCT CR rate was also significantly higher with VTD than with TD and there was a trend when compared with VBMCP/VBAD/B. Finally, VTD resulted in a significantly longer PFS. However, longer follow-up is required to establish whether or not VTD will overcome the poor prognosis of patients with high-risk cytogenetics. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Bortezomib and Thalidomide are not approve for first line in Spain. Cibeira:Janssen-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Blade:Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.307.307
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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