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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 307-307 ◽  
Author(s):  
Laura Rosiñol ◽  
María Teresa Cibeira ◽  
Maria Victoria Mateos ◽  
Joaquin Martinez ◽  
Albert Oriol ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Research Funding ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Grade 3

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.

Characteristics and Outcome Of 66 Patients With Extramedullary Plasmacytomas (EMPs) Included In a Phase III Pethema/GEM Study Of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3188-3188
Author(s):  
Laura Rosiñol ◽  
Raquel Jiménez-Segura ◽  
Ana Isabel Teruel ◽  
Javier De La Rubia ◽  
Maria Victoria Mateos ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Statistical Significance ◽  
Phase Iii ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Extramedullary Disease ◽  
The Difference ◽  
Extramedullary Plasmacytomas

Abstract Introduction In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) initiated a randomized phase III trial (GEM05menos65) comparing induction with thalidomide/dexamethasone (TD) vs. bortezomiv/thalidomide/dexamethasone (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 and maintenance therapy with interferon vs, thalidomide alone or bortezomib/thalidomide. The results of the overall series has been previously published. However, the efficacy of novel agents in patients with extramedullary disease is not well stablished. Primary end points to describe the characteristics and outcome of patients with EMPs homogeneously treated in the GEM05menos65 trial. Patients and Methods 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 i.v. 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 i.v. 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. 66 patients (17%) had extramedullary plasmacytomas (median age: 54 years, M: 33, F: 33). The isotype was IgG: 41, IgA 11, Bence-Jones: 10, IgD:4; kappa:41, lambda: 25.The stage according to the ISS was I in 27 patients, II in 26 and III in 13 patients. The location of the EMPs was soft-tissue masses arising from lytic lesions in 60 patients, testicular mass with no contact with bone in 1 case and was not specified in 6 cases. Nine patients had multiple extraosseous plasmacytomas. 17 patients received induction therapy with VBMCP/VBAD/B, 23 with TD and 26 with VTD. Results Cytogenetic information was available in 51 out of the 66 cases with EMPs and 12 of them (23%) showed high-risk cytogenetics. There were no differences in the incidence of high-risk cytogenetics (t(4;14), t(14;16) and del 17p) in patients with and without EMPs (23% vs 21%). The incidence of t(4;14) in patients with and without EMP was 16% vs 23%, respectively. The incidence of del 17p was 10% and 6% in patients with and without EMPs.The IFE negative CR rate was significantly higher with VTD as compared to TD (42% vs 13%, p=0.02) while there was no significantly differences among VTD and VBMCP/VBAD/B (42% vs 29%, p=NS). Patients with EMP had a significantly higher rate of PD during induction therapy as compared to patients without EMPs (24% vs 11%, p=0.01). This higher rate of PD in patients with EMP was observed in the 3 induction arms (VBMCP/VBAD/B 24% vs 9%, TD 40% vs 19%, VTD 12% vs 6%). 43 patients received ASCT as part of the treatment design. On an intention to treat basis, the pos-ASCT CR rate was higher with VTD arm compared to TD (50% vs 22%, p=0.07) but not significantly different from VBMCP/VBAD/B (50% vs 41%, p=0.7). After a median follow-up of 46 months, there was no significant differences in PFS between patients with or without EMP (26.9 vs 39.9 months, p=0.47). Although the difference did not reach statistical significance, there was a trend towards a shorter PFS for patients with EMPs with high-risk cytogenetics (median 12.1 vs. 28.3 months, p=0.13). In patients with EMPS, the PFS was not reached in the VTD arm versus 26.9 months with VBMCP/VAB/B and 22.8 moths with TD. The OS was significantly shorter in patients with EMPs as compared to patients without EMPs (median 69.9 months vs not reached, p=0.02) Conclusion 1) In the present study the frequency of EMPs was 17%, 2) the incidence of high-risk cytogenetics in patients with EMPs was similar to that observed in patients with no extramedullary disease, 3) patients with EMPs had a higher rate of progressive disease irrespective of the induction arm as compared to patients without EMPs, being VTD the best treatment option, 4) finally, the OS was significantly shorter in patients with EMPs. Disclosures: Rosiñol: Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Mateos:Jansen: Honoraria; Celgene: Honoraria. Tomas:MedImmune: Research Funding. Gutiérrez:Jansen: Honoraria; Celgene: Honoraria. San Miguel:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 763-763 ◽  
Author(s):  
Antonio Palumbo ◽  
Francesca Gay ◽  
Andrew Spencer ◽  
Francesco Di Raimondo ◽  
Adam Zdenek ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Study Endpoint ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

SWOG S1216: A phase III randomized trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients (pts) with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) (NCT01809691).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5001-5001
Author(s):  
Neeraj Agarwal ◽  
Catherine Tangen ◽  
Maha H. A. Hussain ◽  
Shilpa Gupta ◽  
Melissa Plets ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Performance Status ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Meaningful Improvement ◽  
Intention To Treat ◽  
Grade 3

5001 Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 < PSA; ≤-4 vs. > 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]

High Dose Imatinib Induction Therapy (800 mg/day, 6 Months) In Pre-Treated Chronic Phase CML Patients Improves Cytogenetic and Molecular Responses but Does Not Improve Overall and Progression Free Survival – Final Results of the CELSG Phase III CML11 “ISTAHIT” Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2271-2271
Author(s):  
Andreas L Petzer ◽  
Dominic Fong ◽  
Thomas Lion ◽  
Irina Dyagil ◽  
Zvenyslava Masliak ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
De Novo ◽  
Chronic Phase ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 2271 Introduction: Imatinib 400 mg/day represents the current standard treatment for de novo as well as pre-treated CML patients in chronic phase (CP). Recent randomized phase III trials revealed conflicting results concerning the potential higher efficacy of dose-increased imatinib in de novo treated CP-CML. Methods: We here present the final analyses including response data, OS, EFS and PFS of the multicenter, randomised, 2-arm phase III CELSG “ISTAHIT” trial evaluating imatinib high dose (HD) induction (800 mg/day, 6 months) followed by 400 mg/day as maintenance (experimental arm B) compared to continuous imatinib standard dose (400mg/day; arm A) in pre-treated CP CML patients. ClinicalTrials.gov Identifier: NCT0032726. Results: From a total of 243 patients screened for inclusion, 16 patients were not eligible (mainly due to non sufficient numbers of metaphases obtainable from the bone marrow before the start of the study). Of the remaining 227 patients, 113 patients were randomized into arm A and 114 patients into the experimental arm B. Subsequent data are presented as per protocol. No significant differences between treatment groups were observed regarding sex (55.5% female, 44.5% male), age (median: 46.3 years, range 18 –76), Sokal scores at diagnosis (30% low, 41% intermediate, 16% Sokal high risk, 13% unknown) and different pre-treatments, which included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly Ara-C). The median observation time was 673 days. Cytogenetic responses were generally higher in the experimental arm B and revealed statistically significant differences in major cytogenetic responses (MCyR) at 3 and 6 months (month 3: 25.8% arm A, 48.3% arm B, p=0.002; month 6: 41.9% arm A, 58.8% arm B, p=0.029) as well as in complete cytogenetic responses (CCyR) not only during imatinib HD therapy (month 3: 7.5% arm A, 29.9% arm B, p<0.001; month 6: 20.4% arm A, 47.4% arm B, p<0.001) but also thereafter (month 12: 31.8% arm A, 52.9% arm B, p=0.006). The primary endpoint of the study, the achievement of an improved MCyR at 12 month was, however, not significantly different (56.8% arm A, 64.4% arm B). In line with improved cytogenetic responses, major molecular response (MMRIS) rates were also significantly better at 3, 6 and even at 24 months in the HD arm B (month 3: 3.7% arm A, 15.9% arm B, p=0.003; month 6: 9.4% arm A, 34.6% arm B, p<0.001; month 24: 26.5% arm A, 42.5% arm B, p=0.034). Surprisingly, however, this impressing improvement in cytogenetic and molecular remissions in patients achieving high dose imatinib as induction therapy did not translate into a better OS and PFS, both of which were comparable in the two treatment arms (OS: p=0.25; EFS: p=0.37). Moreover, the EFS was even significantly worsened in the experimental arm B (p=0.014). Grade 3/4 non-haematological toxicities during the first 6 months of therapy were comparable, whereas grade 3/4 haematological toxicities were significantly more common in the imatinib HD arm B. Conclusions: Although high dose imatinib induction induces more rapid and higher cytogenetic and molecular remission rates in pre-treated CP CML patients, OS as well as PFS were not improved and EFS was even worsened in the high dose induction arm B. Therefore we conclude that imatinib 400mg/day remains the standard of care for pre-treated CP-CML patients. Disclosures: Petzer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Imatinib 800mg is not licensed as the initial therapy of chronic phase CML. Lion: Novartis: Honoraria, Research Funding. Bogdanovic: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griskevicius: Novartis: Research Funding. Kwakkelstein: Celgene: Employment. Rancati: Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gastl: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1911-1911 ◽  
Author(s):  
Meena Bansal ◽  
David S. Siegel ◽  
Jaeil Ahn ◽  
Rena Feinman ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Best Response ◽  
Grade 3

Introduction: Patients with high-risk multiple myeloma (HRMM) who have undergone autologous stem cell transplant (ASCT) will inevitably relapse and have a progression free survival (PFS) ranging from 8-14 months (Gaballa et al, American Journal of Hematology, 2016) and 24-39 months while on lenalidomide (Len) maintenance therapy (Jackson et al, The Lancet Oncology, 2019). Unlike in solid tumors, PD-1 blockade has no single agent activity in relapsed and refractory multiple myeloma (MM) patients suggesting that immune stimulating agents, immunomodulatory agents (IMiDs), such as lenalidomide (Len) or pomalidomide (Pom) are necessary in combination with anti-PD-1 blockade to increase depth and duration of response post-ASCT. The Keynote-023 study revealed an overall response rate (ORR) of 76% with the combination of pembrolizumab (Pem), Len and dexamethasone (Dex). Similarly, the Keynote 135 study using the combination of Pem, Pom, and Dex revealed an ORR of 60%. Unfortunately, the phase III studies comparing an IMiD vs Pem with the IMiD upfront at the early relapsed setting were halted because of increased deaths on the Pem arm and a decreased median PFS. With our Phase II study currently on clinical hold by the FDA, we are presenting here the 2-year follow-up of the original patient cohort including some preliminary safety and efficacy data of Pem-Len-Dex in HRMM patients as post-ASCT consolidation (NCT02906332). Methods: Patients with HRMM who have undergone induction therapy followed by single or tandem melphalan-based ASCT were considered eligible 2-6 months post ASCT. HRMM criteria are defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Patients received Pem 200 mg IV at day 1;Len 25 mg po daily at days 1-14; and Dex 40 mg daily at days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of Pem + Len without Dex at the same dose and frequency. Survival outcomes post-ASCT were measured using the log-rank test. Results: Of 15 patients screened, 12 received at least one dose of therapy and were deemed evaluable. One patient withdrew consent and did not follow up after cycle 2. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 66.7% had a p53 deletion by FISH, 41.6% received induction Bortezomib-Len-Dex; 33% received induction Carfilzomib-Len-Dex, and the remaining 24.9% received other bortezomib-based induction. Best ORR during the 2 year follow up showed 8 patients (73%) achieving stringent complete remission, 2 patients (18%) showing complete remission and 1 (9%) achieving very good partial remission. Table 2 shows best response to treatment by cycle of therapy. Table 3 shows best response during follow-up visits, which were 3 months apart. Of the 11 patients who completed therapy, 8 had minimal residual disease (MRD) status assessed and among them, 7 were MRD negative by flow cytometry, tested 30 days after the fourth cycle. With a median follow-up of 32.2 months, median PFS was 27.6 months. The PFS rates at 1 year and 2 year are 91.3% and 65.2%, respectively. All patients had adverse events (AEs), AEs were attributed to Pem, Len, or Dex rather than from ASCT. Of the 90 AEs that were reported, 5.6% were grade 3 and 94% were grade 1 or 2 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were graded as 1 or 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, which was not considered to be related to Pem. Conclusions: The combination of Pem, Len, and Dex given to HRMM patients in the post-ASCT consolidation setting is well tolerated. In comparison to historical controls of HRMM patients post-ASCT with a median PFS of 8-14 months, the PFS rates of 91.3% and 65.2% at 1 and 2 year post-ASCT respectively suggest an efficacy signal for the use of Pem, Len, and Dex as post-ASCT consolidation. Larger prospective studies are needed to validate these results. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

scholarly journals Intensification Therapy with Bortezomib-Melphalan-Prednisone Versus Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 673-673 ◽  
Author(s):  
Michele Cavo ◽  
Meral Beksac ◽  
Meletios A Dimopoulos ◽  
Lucia Pantani ◽  
Francesca Gay ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Phase Iii ◽  
Stage Iii ◽  
The Novel ◽  
Advisory Committees ◽  
Phase Iii Study

Abstract Background The role of upfront autologous stem cell transplantation (ASCT) for younger patients with newly diagnosed (ND) multiple myeloma (MM) has been questioned in the novel agent era. Methods A prospective, multicenter, phase III study was designed to compare (first randomization, R1) (1:1 ratio; stratification according to ISS stage) four 42-day cycles of bortezomib-melphalan-prednisone (VMP) given at the same dosing schedule reported in the VISTA study (NEJM 2008; 359:906-17) vs either a single course or two sequential courses of melphalan at 200 mg/m2 (HDM) followed by single or double ASCT, respectively, as intensification therapy after three to four 21-day cycles of induction therapy with bortezomib-cyclophosphamide-dexamethasone and subsequent collection of peripheral blood stem cells. A second randomization (R2) to consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was performed after intensification, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study end point was progression-free survival (PFS) from R1. Results From February 2011 to April 2014, 1510 patients aged ≤65 years with symptomatic NDMM were registered. Of these, 1192 were eligible for R1 and were randomly assigned to receive either VMP (n=497 patients) or HDM (1±2 courses) (n=695 patients). Median age was 58 years in both groups, ISS stage III was 21% in VMP and 20% in HDM, while revised ISS stage III was 9% in both groups. Data on cytogenetic abnormalities, as detected by FISH analysis of CD138+ plasma cells, were available in 71% of patients (n=354) randomized to VMP and in 76% of those (n=529) assigned to HDM. The frequency of conventionally defined high-risk cytogenetic changes, including t(4;14) and/or del(17p) and/or t(14;16), was 25% in both arms. Median follow-up from R1 was 26 (IQR: 19-37) months. On an intention-to-treat basis, median PFS was 44 months in the VMP arm and was not yet reached in the HDM arm; 3-year estimates of PFS were 57.5% and 66%, respectively (HR=0.73; 95% CI=0.59-0.90; P=0.003). PFS benefit with HDM was retained across predefined subgroups, including patients with ISS stage I (HR=0.69; CI=0.48-0.98; P=0.037), revised ISS stage II (HR=0.70; CI=0.54-0.91; P=0.008), revised ISS stage III (HR=0.54; CI=0.30-0.97; P=0.040), standard-risk cytogenetics (HR=0.75, CI=0.56-1.01; P=0.055) and a high-risk cytogenetic profile (HR=0.54; CI=0.37-0.80; P=0.002). The probability of achieving a very good partial response or higher quality response was 85.5% in the HDM group vs 74% in the VMP group (odds ratio=1.90; CI=1.42-2.54; P<0.001). In a multivariate Cox regression analysis stratified by ISS, randomization to HDM (HR=0.67; CI=0.53-0.85; P=0.001) and absence of high-risk cytogenetic abnormalities (0.71; CI=0.53-0.95; P=0.021) were the leading independent predictors of prolonged PFS. Overall survival was not yet mature and no difference between the two treatment groups was evident. Detection of minimal residual disease (MRD) after intensification therapy was performed by multiparameter flow cytometry and PET/CT in a subgroup of patients, and details are provided in a separate abstract (E. Zamagni et al). Overall, MRD negativity favorably affected PFS and OS. Conclusions In comparison with VMP as standard-dose intensification therapy, upfront HDM and ASCT significantly improved PFS and increased the rate of high quality responses. An updated analysis with a longer follow-up will be reported at the meeting. Results of this phase III study, the largest so far reported, support the conclusion that upfront ASCT still continues to be the reference treatment for fit patients with NDMM, even in the novel agent era. Disclosures Cavo: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Beksac:Celgene, Janssen Cilag Amgen, Novartis, Takeda: Honoraria, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Janssen-Cilag: Other: Advisory Board; Mundipharma: Other: Advisory Board. Hájek:Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; BMS: Honoraria; Celgene: Consultancy, Research Funding. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Galli:Celgene: Honoraria; Janssen: Honoraria; Sigma-tau: Honoraria. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria.

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.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 130-130 ◽  
Author(s):  
Laura Rosiñol ◽  
Ma Teresa Cibeira ◽  
Joaquin Martinez ◽  
Maria Victoria Mateos ◽  
Albert Oriol ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
High Risk Group ◽  
Phase Iii ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Phase Iii Trial ◽  
Grade 3

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.

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,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3962-3962 ◽  
Author(s):  
Laura Rosiñol ◽  
María Teresa Cibeira ◽  
Maria Victoria Mateos ◽  
Joaquin Martinez ◽  
Albert Oriol ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Single Agent ◽  
Phase Iii ◽  
Hematological Toxicity ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Maintenance Program ◽  
Response Status ◽  
Grade 3

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.

Phase I/II Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 187-187 ◽  
Author(s):  
Jatin J. Shah ◽  
Lei Feng ◽  
Elisabet E. Manasanch ◽  
Donna Weber ◽  
Sheeba K Thomas ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Depth Of Response ◽  
High Risk Disease ◽  
Grade 3

Abstract Background: Induction therapy prior to autologous stem cell transplantation (ASCT) continues to improve with the use of multi-drug combination regimens. Panobinostat (pano), a deacetylase inhibitor, was recently approved in combination with bortezomib/dexamethasone for relapsed myeloma based on the phase III PANORMA I trial for RRMM. The addition of pano in PANORAMA demonstrated a near doubling in CR rate from 15 to 27%. We previously reported phase I trial data of RVD + pano in newly diagnosed myeloma (NDMM) and demonstrated the pano can be safely combined with RVD. Based on the encouraging preliminary data we pursued a phase II dose expansion to further explore the potential improvement in depth of response with RVD + pano in NDMM. Methods: The primary objective was to determine the safety/tolerability of pano and RVD in NDMM. Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival. Patients had to have NDMM with indication for therapy and be eligible for ASCT with adequate organ function. Panobinostat 10 mg was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m2 was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle. Adverse events (AEs) were graded by NCI-CTCAE v4 and responses were assessed by the modified International Uniform Response Criteria. Results: 42 patients (pts) were enrolled; 12 in the dose escalation and 30 in the dose expansion. The median age was 60 (range 44-79); male (n=30); ISS stage I (n=28); ISS stage II (n=10); ISS stage III (n=4); 14/42 pts had high risk myeloma (1 pt with t(4:14) and del17p; 1 pt with del 17p and 1q21; and 12 pts with only 1q21 amplification). Among 42 pts, 2 completed only 1-2 cycles and 1 pt was inevaluable for response. Among the 39 pts who completed 4 cycles and were evaluable for efficacy the ORR (≥PR) after 4 cycles was 93% (36/39) including nCR/CR in 17/39 (44%), VGPR in 10/39 (26%), PR in 9/39 (23%), and SD in 3/39 (8%) pts. In 12 of 14 pts with high risk disease, who were evaluable for response, the ORR was 100% (12/12); the nCR/CR in 6/12 pts; VGPR in 4/12 pts; and 2/12 pts achieved a PR. 25/42 (59%) pts completed induction therapy and underwent consolidation with ASCT; 5 pts completed induction therapy, came off study and did not proceed to ASCT. 8 pts choose a delayed transplant approach, completed induction therapy and stem cell collection. 6 of those 8 pts remain on trial with maintenance therapy (len/dex/pano) per protocol. 2 pts, neither with high risk disease, progressed after cycles 10 and 11 with extramedullary disease and plasma cell leukemia/central nervous system involvement, respectively. 4 additional patients have completed 2, 3, and 5 cycles of therapy and are pending ASCT. Grade 3-4 hematologic adverse events included anemia (5); neutropenia (10); thrombocytopenia (16). Grade 3-4 nonhematologic toxicities included ALT elevation (1); AST elevation (1); constipation (2); diarrhea (4); dyspnea (2); fatigue/muscle weakness (5); syncope (2); MI (1); nausea (3); peripheral neuropathy (2); rash (1); DVT/VTE (3). Infectious complications included grade 2 (G2) urinary tract infection (2); G2 upper respiratory tract infection (5); pneumonia (5); osteomyelitis/musculoskeletal (3); infection (3). Treatment emergent serious adverse events related to therapy observed were: G3 pneumonia (9); G2 fever (5), G3-4 venous thromboembolic events (2); G3 diarrhea (2); atrial fibrillation (2). Other events included 1 pt each with G3 cellulitis, G3 myocardial infarction (MI), G3 febrile neutropenia, G2 diarrhea, G2 seizure, G3 hypotension and G3 sinusitis. 1 pt had a second primary malignancy - a newly diagnosed breast cancer during cycle 9 of therapy. Conclusions: Panobinostat 10 mg can be safely combined with full dose RVD in NDMM. The side effect profile with use of subcutaneous bortezomib demonstrated minimal gastrointestinal toxicity/diarrhea and was a well-tolerated combination. The combination of RVD+ pano lead to rapid disease control with high response rate after 4 cycles of therapy and ORR of 93% and significant depth of response with a 4 cycle nCR/CR rate of 44%. Enrollment in dose expansion is near completion and full data will be presented at ASH and supports the study of panobinostat in a randomized trial for NDMM. Disclosures Shah: Celgene: Consultancy, Research Funding. Thomas:Celgene: Research Funding; Novartis: Research Funding; Idera Pharmaceuticals: Research Funding. Orlowski:Genentech: Consultancy; Acetylon: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy.

scholarly journals Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study

2018 ◽  
Vol 36 (22) ◽  
pp. 2259-2266 ◽  
Author(s):  
Bruce D. Cheson ◽  
Neil Chua ◽  
Jiri Mayer ◽  
Greg Dueck ◽  
Marek Trněný ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Analysis ◽  
Intention To Treat ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
Overall Survival Benefit

Purpose To perform an updated analysis of the randomized phase III GADOLIN trial in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated with obinutuzumab (GA101; G) and bendamustine (B). Patients and Methods Patients with histologically documented, rituximab-refractory CD20+ indolent non-Hodgkin lymphoma received G 1,000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2 to 6) plus B 90 mg/m2/d (days 1 and 2, all cycles) or B 120 mg/m2/d monotherapy. Patients who did not experience disease progression with G-B received G maintenance (1,000 mg every 2 months) for up to 2 years. The primary end point was progression-free survival (PFS). Results Of 413 randomly assigned patients (intention-to-treat [ITT]: G-B, n = 204; B monotherapy, n = 209), 335 had follicular lymphoma (FL; G-B, n = 164; B monotherapy, n = 171). After a median follow-up of 31.8 months, median PFS in ITT patients was 25.8 months (G-B) and 14.1 months (B monotherapy; hazard ratio [HR], 0.57; 95% CI, 0.44 to 0.73; P < .001). Overall survival (OS) also was prolonged (HR, 0.67; 95% CI, 0.47 to 0.96; P = .027). PFS and OS benefits were similar in patients with FL. Grade 3 to 5 adverse events (AEs) were reported by 148 (72.5%) and 133 (65.5%) patients in the G-B and B monotherapy arms, respectively, most commonly neutropenia (G-B, 34.8%; B monotherapy, 27.1%), thrombocytopenia (10.8% and 15.8%), anemia (7.4% and 10.8%), and infusion-related reactions (9.3% and 3.4%). Serious AEs occurred in 89 G-B patients (43.6%) and 75 B monotherapy patients (36.9%); fatal AEs occurred in 16 (7.8%) and 13 (6.4%), respectively. Conclusion This updated analysis confirms the PFS benefit for G-B shown in the primary analysis. A substantial OS benefit also was demonstrated in the ITT population and in patients with FL. Toxicity was similar for both treatments.

Sign in / Sign up

Export Citation Format

Share Document