The Combination of the Proteasome Inhibitor Bortezomib with Doxorubicin and Dexamethasone (PAD Regimen) as Front-Line Therapy In Newly Diagnosed, High-Risk Multiple Myeloma: Results of a Phase II Prospective Multicenter Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3052-3052 ◽  
Author(s):  
Ioannis Baltathakis ◽  
Evangelos Terpos ◽  
Sosana Delimpasi ◽  
Konstantinos Liapis ◽  
Fotios Panitsas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Front Line ◽  
Grade 3 ◽  
Cell Harvest

Abstract Abstract 3052 The combination of bortezomib, doxorubicin, and dexamethasone (PAD) has shown efficacy in both relapsed/refractory and untreated, symptomatic multiple myeloma (MM). The activity of this regimen is largely attributed to the recognized synergy between bortezomib and doxorubicin. Bortezomib is capable of reversing resistance to chemotherapy in MM with adverse prognostic features (high-risk myeloma), which has an unfavorable outcome with conventional chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT). In addition, disease status prior to ASCT has prognostic significance for survival, underscoring the need for highly efficient remission induction strategies. In a prospectively designed phase II trial, we focused on the efficacy and safety of the PAD combination as front-line treatment for high-risk myeloma. The study recruited patients aged ≤70 years with newly diagnosed, symptomatic MM with high-risk features (defined by at least one of the following criteria: ISS stage II/III according to serum albumin and beta2-microglobulin, and/or detection of 13q deletion by FISH or conventional karyotyping). Between 2005 and 2008, 40 patients were enrolled in the protocol. The median age of patients was 59 years (range: 41–70 years), and 27 (67.5%) were male. Each 21-day cycle of PAD included bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m2 on days 1–4, and dexamethasone 40 mg on days 1–4 and 8–11. According to protocol, patients received 4 induction cycles of PAD before proceeding to stem cell harvest and ASCT. Acyclovir and ciprofloxacin prophylaxis were routinely used. Patients were evaluated for toxicity at each cycle and for response after the end of the fourth cycle. The primary study endpoint was the response rate at the end of induction (assessed by the International Myeloma Working Group uniform response criteria, 2006). Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), ability to mobilize stem cells, and response after ASCT. ISS stage was I in 2 patients (5%), II in 18 (45%), and III in 20 (50%). Nine out of 40 patients (22.5%) presented with renal failure (creatinine >2mg/dl) due to myeloma at diagnosis. Deletion 13q was detected in 19 patients. Bone disease was present in 30 patients (75%) at diagnosis, and 19 (47.5%) had ≥3 lytic lesions on plain skeleton radiograms. Median patient follow-up time was 28.3 months (range, 1.4–49.3). All patients completed the 4 cycles of PAD, with the exception of one who died during the 2nd cycle. The overall response rate assessed after the 4th cycle of PAD was 95%. Complete remission (CR) was achieved in 12/39 (31%), very good partial remission (VGPR) in 15/39 (38.5%), and PR in 10/39 (25.5%). Thirty-one patients were considered eligible for ASCT, and an adequate stem cell harvest was achieved in all. Following ASCT, CR rate reached 52% (16/31) with a CR+VGPR rate of 84% (26/31). PFS was 67% at 2.1 years, and calculated OS was 81.4% at 4 years (Figures 1 and 2). Factors associated with shorter OS were beta2-microglobulin ≥5.5 mg/L (p=0.03), and ISS stage III (p=0.03). By assessment of the glomerular filtration rate (GFR), a significant improvement in renal function was demonstrated after induction with PAD (median GFR pre- and post-induction: 59.7 versus 82.1 ml/min, respectively; p<0.001). Improvement in kidney function was observed irrespective of the type of response. There was only one treatment-related death secondary to infection. Toxicities were manageable in general, and included grade 3–4 neutropenia in 8/40 patients (20%), grade 3–4 thrombocytopenia in 4/40 (10%), and grade 3 peripheral neuropathy in 4/40 (10%). No grade 4 peripheral neuropathy was encountered. We conclude that the PAD regimen is very effective, and produces high-quality responses in a substantial proportion of patients with newly diagnosed, high-risk MM (CR+VGPR: 69.5%). PAD is well tolerated and does not compromise stem cell mobilization and harvest. Upfront treatment with 4 cycles of PAD followed by ASCT resulted in notable PFS and OS rates in this patient group with adverse-prognosis MM. PAD was shown to be particularly beneficial in patients with renal impairment at diagnosis due to myeloma. Disclosures: Baltathakis: Janssen-Cilag: Research Funding. Terpos:Janssen-Cilag: Honoraria. Delimpasi:Janssen-Cilag: Research Funding. Dimopoulos:Janssen-Cilag: Honoraria. Harhalakis:Janssen-Cilag: Research Funding.

A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2546-2546 ◽  
Author(s):  
Angela Dispenzieri ◽  
Emily Blood ◽  
David Vesole ◽  
Rafael Fonseca ◽  
Natalie Callander ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Partial Response ◽  
Progressive Disease ◽  
Response Rate ◽  
Cell Labeling ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

Sequential Approach with Bortezomib as Induction Before Autologous Transplantation, Followed by Lenalidomide as Consolidation-Maintenance in Untreated Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3419-3419 ◽  
Author(s):  
Francesca Gay ◽  
Patrizia Falco ◽  
Claudia Crippa ◽  
Anna Marina Liberati ◽  
Francesca Patriarca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Advisory Committee ◽  
Research Funding ◽  
Response Rate ◽  
Autologous Transplantation ◽  
Pegylated Liposomal Doxorubicin ◽  
Newly Diagnosed ◽  
Sequential Approach ◽  
Grade 3

Abstract Abstract 3419 Poster Board III-307 Background Bortezomib induction before autologous stem cell transplantation (ASCT) has shown its efficacy in newly diagnosed multiple myeloma (MM) patients, both in association with dexamethasone alone (Harousseau JL, et al. Blood 110, 2007, abstr 450) and in combination with doxorubicin and dexamethasone (Popat R, et al. Br J Haematol 141:512-516, 2008). Lenalidomide, a less toxic and more potent thalidomide-derivative, lacks the neurotoxic effects of the parent drug and represents an optimal agent to include in maintenance regimens. Aims These observations provided the rationale for investigating a sequential approach including bortezomib as induction and lenalidomide as consolidation-maintenance in MM patients undergoing ASCT. Methods A hundred and two newly diagnosed patients aged 65–75 years were enrolled in 17 Italian centers. Induction (PAD) included four 21-day cycles of bortezomib (1.3 mg/m2 days 1,4,8,11), pegylated-liposomal-doxorubicin (30 mg/m2 day 4), and dexamethasone (40 mg/day: cycle 1, days 1–4, 8–11, 15–18; cycles 2–4, days 1–4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) followed by stem-cell support. After ASCT, patients received consolidation with four 28-day cycles of lenalidomide (25 mg/day days 1–21 every 28 days) plus prednisone (50 mg every other day) (LP), followed by maintenance (L) with lenalidomide alone (10 mg/day days 1–21 every 28 days) until relapse. Primary endpoints were safety (incidence of grade 3–4 adverse events [AEs]) and efficacy (response rate). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Time-to-event estimates analysis was performed using the Kaplan-Meier method. Results Very good partial response (VGPR) or better was 58% after PAD induction and increased to 82% after MEL100 and to 86% during LP-L. Complete response (CR) rate was 13% after PAD induction, increased to 38% after MEL100 and to 66% during LP-L. After a median follow-up of 2 years, the 2-year PFS was 69%, the 2-year time-to-progression was 75% and the 2-year OS was 86%. During PAD induction, main grade 3–4 AEs were thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%); treatment-related mortality was 3%. During consolidation-maintenance grade 3–4 AEs included neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). Consolidation-maintenance treatment was well tolerated: only 4% of patients required Granulocyte-colony stimulating factor support and no patient required platelet transfusion; dermatological toxicity was easily manageable with dose-reduction and supportive therapy; no treatment-related deaths were reported. Updated results will be presented at the meeting. Conclusion This is the first phase II study in newly diagnosed MM patients to date, where a sequential approach including bortezomib as induction, and lenalidomide as post ASCT consolidation-maintenance was explored. Treatment was correlated with an increase in response rate and in the depth of response (CR rate) and was generally well tolerated. These data suggest that this is a safe and effective regimen for newly diagnosed MM patients. Randomized trials are needed to confirm these results. Disclosures Patriarca: Celgene: Honoraria; Janssen Cilag: Honoraria. Bringhen:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Janssen Cilag : Consultant, advisory committee, Research Funding; Celgene: Consultant, advisory committee, Research Funding; Pharmion: Consultant, advisory committee, Research Funding. Palumbo:Celgene: Honoraria; Janssen Cilag: Honoraria.

scholarly journals A Phase II Multi-Center Study of Lenalidomide, Subcutaneous Bortezomib and Dexamethasone (RsqVD) in Newly Diagnosed Multiple Myeloma - Ctrial-IE (ICORG) 13-17 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2117-2117
Author(s):  
Peter O'Gorman ◽  
Michael E O'Dwyer ◽  
Oonagh Gilligan ◽  
John Quinn ◽  
Mark Coyne ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Partial Response ◽  
Phase Ii ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Cell Mobilization

Abstract Introduction: Lenalidomide, bortezomib and dexamethasone (RVD) is considered a new standard of care regimen for patients with newly diagnosed multiple myeloma. A previous phase I/II study of RVD in front-line myeloma enrolled 66 patients and achieved a partial response rate or better of 100%, overall and a CR/nCR rate of 52% in the phase 2 portion of the study with encouraging tolerability, but high rates of peripheral neuropathy (PN), albeit mainly mild to moderate grade (Richardson et al, Blood 2010). Subcutaneous (SQ) administration of single agent bortezomib has been shown to be non-inferior to IV bortezomib and led to lower rates of PN, a common treatment-related toxicity (Moreau et al, Lancet Oncol 2011). Herein we present preliminary results of the RsqVD Study, a multi-center, open-label single arm phase II trial, incorporating SQ bortezomib with lenalidomide and dexamethasone and including patients who were considered either transplant eligible or ineligible. All patients subsequently received maintenance therapy with lenalidomide until progression, plus the addition of subcutaneous bortezomib twice monthly in high risk patients (ISS stage II or III and/or high risk cytogenetics features, t(4;14, t(14;16) and del17p). The primary endpoint was overall response rate (ORR) after 4 cycles of induction therapy (PR or better). Secondary endpoints include: rate and severity of PN, safety, time to progression, progression-free survival, duration of response and overall survival. Methods: Planned treatment was 4 cycles of lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2as SQ injection on days 1, 4, 8 and 11 of a 21-day cycle. Thromboprophylaxis with aspirin 75 mg/day or higher was mandatory and HSV prophylaxis was as per institutional standard. Following 4 cycles, patients were planned to proceed with stem cell mobilization and autologous stem cell transplant (ASCT) or further induction therapy up to a total of 8 cycles. Following completion of ASCT or induction therapy, all patients were scheduled to receive lenalidomide maintenance in 28 - day cycle until progression, unacceptable toxicity or withdrawal of consent. Patients with high-risk features received SQ bortezomib on days 1 and 15 during maintenance phase. Response was investigator-assessed as per IMWG criteria. Sample size (n=42) was determined to provide 80% power to test an acceptable ORR of >70% versus an unacceptable ORR of <50% (1-sided alpha=0.05) including an estimated drop-out rate of 10%. Results: Between November 2014 and February 2016, 42 patients were enrolled across 8 sites in Ireland. Baseline demographic factors include: 64% males, 36% females; median age of 64 years (45-79 years); 41% ISS stage I, 59% ISS stage II/III. FISH analysis detected t(4;14) in 18% of patients (7/40), t(14;16) in 3% of patients (1/36) and del17p in 10% of patients (4/40). 64% (27/42) patients proceeded to stem cell mobilization and 60% (25/42) to ASCT. The median number of induction cycles completed was 4 (1 to 8 cycles). 40 of a total of 42 patients were considered evaluable for the primary endpoint of ORR. A preliminary analysis of ORR following 4 cycles of induction therapy indicates that 98% (39/40) of patients achieved partial response or better. PN of any grade has been reported by sites in 43% (18/42) of patients to date. Conclusion: RsqVD is a highly effective regimen in newly diagnosed multiple myeloma producing a very high ORR following initial induction therapy, with a lower overall rate of PN described by sites than expected. Full analyses of response and safety data for induction treatment and follow up will be presented, as well as preliminary evaluation of response to subsequent therapy. Disclosures O'Gorman: Janssen Cilag: Research Funding; Celgene: Research Funding. O'Dwyer:Celgene: Consultancy, Honoraria, Research Funding; Glycomimetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Quinn:Celgene: Honoraria; Janssen Cilag: Honoraria. Murphy:Celgene: Honoraria; Janssen Cilag: Honoraria. Crotty:BMS, Takeda, Novartis, Janssen, Roche: Honoraria. Hayden:Celgene: Honoraria; Janssen Cilag: Honoraria; Amgen: Honoraria. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Phase I Study of Bortezomib(Bz), Pegylated Doxorubicin(DOX) and Dexamethasone(dex); ( VDD) with Escalating Doses of Cyclophosphamide(Cy) in Patients with Newly Diagnosed Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 617-617
Author(s):  
Melissa Alsina ◽  
Rachid Baz ◽  
Jose L Ochoa ◽  
Jyotishankar Raychaudhuri ◽  
Kara Kosakowski ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Stem Cell Mobilization ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Long Term Outcome ◽  
Cell Mobilization ◽  
Grade 3

Abstract Abstract 617 Background: The VDD treatment regimen has been shown to be highly effective as initial therapy for multiple myeloma. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We report the results from a Phase I trial combining VDD with escalating doses of cyclophosphamide ( CVDD) in patients (Pts) with newly diagnosed myeloma. Methods: Pts received Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 and Cy 250-750 mg/m2 on day 1, for up to eight 21-day cycles, at four planned dose levels (Cy/Bz: 250/1.0, 500/1.0, 750/1.0, 750/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs) grade 3 non-hematologic toxicity; thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; Grade 4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Pts with Grade 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Pts with at least partial response ( PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after 6 cycles. Responsive pts with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t (4;14), t(14;16) or deletion of 17 p by FISH, completed 8 cycles of therapy. Results: 26 pts have been enrolled to date: 12 in phase l, and 14 additional pts at the maximum planned dose (MPD). Median age 60 yrs, 62% men, 50% IgG MM, 81% with ISS stage II/III. Pts have received a median of 6 cycles; 17 have completed all 6-8 cycles, 1 has discontinued therapy. No DLTs were observed in the phase I portion of study. Dose reductions in cycle 2 and beyond have occurred in 31% of patients. Toxicities to date have been manageable, including all Grade 3/4 hematological toxicities (4-35%), Grade 3 hand foot syndrome( 15%), Grade 3 pneumonia (8%), Grade 3 UTI (8%), and Grade 3/4 metabolic (19%). There were no grade 3/4 PNY. There was 1 treatment-related mortality secondary to infection. The overall response rate in patients that have completed at least 4 cycles of therapy (ORR; ≥PR) is 90%, including 57% ≥VGPR, and 24% CR. ORR and VGPR rates were similar in patients with standard or high risk cytogenetics. Nine patients have proceeded to transplant and all have had successful stem cell mobilization with G-CSF alone. Conclusions: CVDD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at CY 750 mg/m2, Bz 1.3 mg/m2, DOX 30 mg/m2, and Dex 20 mg, with phase II enrollment ongoing. Stem cell mobilization has been successful in all pts, with transplant course in pts otherwise unremarkable. Updated efficacy will be presented at the meeting. Disclosures: Alsina: Millenium: Research Funding, Speakers Bureau; Ortho Biotech: Research Funding, Speakers Bureau.

Frontline Therapy with Bortezomib, Lenalidomide, and Dexamethasone (VRD) Induction Followed by Autologous Stem Cell Transplantation, VRD Consolidation and Lenalidomide Maintenance In Newly Diagnosed Multiple Myeloma Patients: Primary Results of the IFM 2008 Phase II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 624-624 ◽  
Author(s):  
Murielle Roussel ◽  
Hervé Avet-Loiseau ◽  
Philippe Moreau ◽  
Anne Huynh ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Research Funding ◽  
Response Rate ◽  
Phase Ii Study ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Stem Cell Collection

Abstract Abstract 624 Background: Autologous Stem Cell Transplantation (ASCT) is a standard of care for eligible MM patients (pts). Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response and survival in those pts are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Therefore, the IFM (Intergroupe Francophone du Myélome) decided to evaluate the Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) regimen as induction and consolidation therapy followed by Len maintenance in the transplant setting for newly diagnosed pts. Methods: This open-label phase II study was conducted at 10 IFM transplant centers, with enrollment between September and December 2009. Pts under 65 with symptomatic de novo MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (days 1, 4, 8, 11), Len 25 mg (days 1–14), and oral Dex 40 mg (days 1, 8 and 14). Stem cell collection was planned for all pts after high dose cyclophosphamide (3g/m2). All pts then proceeded to intensification prepared with melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts could receive two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 10–15 mg/day. All patients received, unless contraindicated, aspirin prophylaxis or alternative anticoagulation for prevention of deep-vein thrombosis (DVT), anti-viral therapy (valacyclovir) for herpes zoster prevention. Pts with ≥ grade 2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved 1 month after consolidation. The secondary endpoints were the response rate after 3 cycles of VRD, after ASCT and after consolidation; the safety profile of the program, the feasibility and quality of stem cell collection and dthe uration of response (DOR), PFS, OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells was performed before and after ASCT, and after consolidation. Toxicities were graded using the CTCAEv4. Patients: Thirty-one pts with symptomatic MM were enrolled. Baseline characteristics of the pts were: median age = 58 (range 33–65); 55% were women; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 13q deletion in 41% over 27 assessable pts; chromosome 17p del in 18% and t(4;14) translocation in 11%. Results: All pts but one remain on study program at data cut-off (01/08/10). The one pt had discontinued treatment at time of ASCT due to mobilization failure. Therefore, 31 pts are evaluable for response rates after induction therapy, 30 after ASCT and 13 after consolidation. All results are summarized in table 1. In Intent To Treat analysis, the overall response rate (ORR) after ASCT was 94%, including 32% VGPR, 13% CR and 23% sCR. Nine serious AEs were reported. There was no treatment-related mortality. The most common toxicities were: sensory PNY (45%), including 29% grade 1 and 16% grade 2; neuropathic pain (13%); GI tract symptoms (42%) including diarrhea (16%) and constipation (10%); fatigue (10%) and erythrodermia (9%). There was no grade 3/4 PNY. Grade 3/4 hematological toxicities included neutropenia (26%), and thrombocytopenia (6%). No DVT or pulmonary embolism was reported.Six of 31 pts (19%) have had difficulty with mobilization but only 1 pt did not undergo ASCT. Stem cell collection with plerixafor was successful in 4 pts. Median stem cell collection was 7.7 × 106 CD34+ cells/kg. Conclusions: VRD induction followed by ASCT and VRD consolidation produce high quality responses and is well tolerated in newly diagnosed MM pts under 65. Updated efficacy and safety data will be presented at the meeting. Disclosures: Roussel: Janssen: Consultancy, Research Funding, orator; Celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib, lenalidomide as induction and consolidation therapies in frontline MM pts. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding.

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J. Costa ◽  
P. Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Initial Phase ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 633-633 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Hacker ◽  
Sonja Zweegman ◽  
Marie Jose Kersten ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Tumor Lysis ◽  
Grade 3 ◽  
Cell Harvest

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

Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1141-1141 ◽  
Author(s):  
Ruth Wester ◽  
Bronno van der Holt ◽  
Emelie Asselbergs ◽  
Mark van Duin ◽  
Sonja Zweegman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Research Funding ◽  
Fixed Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Standard Risk

Abstract Introduction A phase 2 dose escalation trial of Carfilzomib in combination with Thalidomide and Dexamethasone (KTd) for induction and consolidation in newly diagnosed, transplant-eligible patients with multiple myeloma (MM). We report the results of 4 dose levels. Methods In this multicenter, open-label, phase 2 trial, transplant-eligible patients aged between 18 and 65 years with previously untreated symptomatic MM were included. Patients were treated with 4 cycles of escalating dose of Carfilzomib + fixed-dose thalidomide and dexamethasone (KTd) for induction therapy. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and Dexamethasone 40 mg orally on days 1, 8, 15 and 22. Carfilzomib was escalated to 20/36 mg/m2 in cohort 2, to 20/45 mg/m2 in cohort 3 and to 20/56 mg/m2 in cohort 4. Induction was followed by stem cell harvest after Cyclophosphamide priming (2 to 4 mg/m2) and G-CSF. Hereafter patients received high-dose Melphalan (HDM, 200mg/m2) and autologous stem cell transplantation followed by consolidation treatment with 4 cycles of KTd in the same schedule except a lower dose of Thalidomide (50mg). The primary endpoint was response after induction therapy and overall, specifically complete response (CR) and very good partial response (VGPR). Secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results All 111 patients with a median follow-up of 55, 42, 35 and 28 months, in cohorts 1 to 4, respectively were included in the analysis. Median age was 58 years. ISS stages I/II/III were 41%/34%/23%, respectively, R-ISS stages I/II/III/unknown were 23%/59%/9%/9%, respectively. Of 111 patients, 9 patients stopped treatment during/after induction, 8 patients after cyclophosphamide priming or HDM and 9 patients during consolidation because of toxicity (n=9), non-eligibility for further treatment (n=6), progression (n=5), refusal (n=2) or other reasons (n=4). Overall response rate for all cohorts was 95%. Response after induction was CR/sCR in 18% of patients, ≥ VGPR in 66% of patients, ≥ PR in 94% of patients. After HDM the CR/sCR rate increased to 31% and after consolidation to 64%. Responses between cohorts were in general comparable. See Table 1. Response based on risk status by ISS/FISH in either cohort and accumulated did not show a difference in CR/sCR rate after consolidation between standard-risk (67%) and high risk defined as t(4;14) and/or del17p and/or add1q and/or ISS3 (60%). OS at 30 months was comparable between standard risk and high risk, 91% versus 90%. PFS at 30 months for standard risk and high risk was 79% and 62%, logrank p=0.02 (HR=2.3, 95% CI=1.1-4.5). PFS at 30 months per cohort was 70% (95% CI, 55% to 81%), 70% (95% CI, 45% to 85%), 80% (95% CI, 56% to 92%) and 62% (95% CI, 32% to 82%) in cohorts 1,2, 3 and 4, respectively, and 71% (95% CI, 61% to 79%) in all patients. OS at 30 months per cohort was 90% (95% CI, 77% to 96%), 90% (95% CI, 66% to 97%), 95% (95% CI, 71% to 99%) and 88% (95% CI, 58% to 97%) respectively, and 91% (95% CI, 83% to 95%) in all patients. Gene expression profiling using the Affymetrix U133 Plus 2.0 GeneChips was performed on purified tumor cells for 49 patients. Using the prognostic classifier EMC92 a high-risk group of patients (16%) was identified versus standard risk (in terms of OS: logrank p=0.06 (HR=3.7, 95% CI=0.8-16.8), and in terms of PFS: logrank p=0.14 (HR=2.1, 95% CI=0.8-6.0)). Safety analysis for all 111 patients showed non-hematological grade 3 and 4 toxicity, mainly respiratory disorders (in 15%), GI disorders (13%) and skin lesions (10%). Toxicity between cohorts did not show a significant difference. Cardiac adverse events were limited and included heart failure (n=2 at 27 mg/m2), hypertension (n=2) and chest pain (n=1 at 45mg/m2). Conclusion Carfilzomib, thalidomide, dexamethasone (KTd) is an effective regimen, with increasing CR percentages following KTd consolidation. With escalated doses of Carfilzomib responses and toxicity were comparable to standard dose of 27 mg/m2. Disclosures Zweegman: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kersten:Celgene: Research Funding; Amgen: Honoraria. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

scholarly journals A Phase 2 Study to Assess the Feasibility and Tolerance of the Combination of Elotuzumab, Lenalidomide, and Dexamethasone (ERd) in the Induction, Consolidation, and Maintenance Treatment of Transplant-Eligible Patients Newly Diagnosed with Multiple Myeloma (MM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 603-603 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Tara K. Gregory ◽  
Suman Kambhampati ◽  
Bertrand M. Anz ◽  
Stefano R. Tarantolo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Overall Response Rate ◽  
Response Rate ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Overall Response

Background: The introduction of novel agents such as proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) with and without corticosteroids has revolutionized treatment (tx) and improved survival rates for MM. IMID/PI triplets such as VRD (bortezomib, lenalidomide, dexamethasone), VTD (bortezomib, thalidomide, dexamethasone), or KRD (carfilzomib, lenalidomide, dexamethasone) are preferred inductions for transplant-eligible patients (pts). Unfortunately, the PI often has unique safety events such as peripheral neuropathy (PN) or cardiac issues that can impact the quality of life. Elotuzumab is a mAb with a dual mechanism of action (tagging MM cells and activating NK cells by binding SLAMF7). The combination of elotuzumab, lenalidomide, and dexamethasone (ERd), is active, well-tolerated, and approved by the FDA for pts with relapsed MM. In this study, we will determine the feasibility of incorporating ERd into a transplant-eligible pt population. Methods: Pts with newly diagnosed MM requiring chemotherapy planning to undergo autologous stem cell transplantation (ASCT) were enrolled. Induction of elotuzumab at 10 mg/kg was administered IV on days (D) 1, 8, 15, 22 of the 1st 2 28-day cycles and days 1, 15 of the third and fourth 28-day cycles. Lenalidomide was dosed at 25 mg orally on D 1-21 of each 28 day induction cycle. Dexamethasone was administered IV concurrent with elotuzumab (28mg orally 3-24 hours prior to infusion and 8 mg IV with elotuzumab), with 40 mg orally administered on D 8 and 22 of cycles 3 and 4. After completion of the 4 induction cycles, pts proceeded to mobilization and ASCT though pts who refused transplantation were allowed to proceed directly to consolidation and maintenance if the investigator believed the pt was deriving benefit. 70-120 days after ASCT, 4 cycles of consolidation were administered (dosing similar to cycles 3-4 of induction but with lenalidomide at 15mg). Pts then went on to maintenance with elotuzumab 20 mg/kg IV on D 1, oral lenalidomide 10mg +/- 5 mg D 1-21 and dexamethasone 28mg oral/8 mg IV prior to elotuzumab infusion were dosed in 28-day cycles for up to 24 months. The primary endpoint was the induction feasibility rate (IFR) defined as the percentage of pts successfully completing 4 cycles of induction tx with ERd and able to start ASCT. Secondary end points were complete response rate (≥nCR), overall response rate (≥PR), progression-free survival (PFS) and overall survival (OS). AEs were assessed according to CTCAE V4 and responses were assessed using the revised IMWG criteria. Results: 52 pts were enrolled: 56% male, median age 61 ys, 12% RISS III, 21% high-risk cytogenetics [17p del, t(4;14), and/or t(14;16)]. To date, 26 (50%) pts remain on active tx. 4 pts refused transplantation despite being eligible and were excluded from the IFR calculation. The IFR was 69% and the best overall response rate (ORR) was 92% (69% ≥ VGPR). With a median follow up of 20 mos, median PFS and OS for all pts were not reached. The 18 mo PFS and OS were 83% and 89% respectively. The most common AEs were fatigue (59.6%), diarrhea (42.3%) and nausea (42.3%). PN was seen in 29%, and all events were ≤ G2. There were 28 SAEs in 20 pts, including 12 tx-related SAEs. There was 1 tx-related death due to heart failure in a pt with no history of prior cardiac issues who had subsequent therapy. 29% of pts met the high-risk (HR) criteria (defined as RISS III or high risk cytogenetics) and 29% of pts were considered standard-risk (RISS I and no high-risk cytogenetics). The best ORR was 87% (67% ≥ VGPR) for HR pts and 93% (53% ≥ VGPR) for SR pts and the IFR was 57% for HR pts and 64% for SR pts. The median PFS and OS were 20.5 mos and 22.0 mos respectively for HR pts and have not been reached for SR pts. Conclusions: ERd induction, consolidation and maintenance was feasible and well tolerated in conjunction with ASCT in transplant-eligible pts. Despite high ORR for all pts, HR patients had inferior PFS and OS. This study supports the continued evaluation of this regimen in SR pts. Disclosures Berdeja: Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; Poseida: Research Funding; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding. Gregory:Takeda: Speakers Bureau; Celgene: Speakers Bureau; Poseida: Research Funding; Amgen: Speakers Bureau. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination of elotuzumab, lenalidomide, and dexamethasone in the induction, consolidation, and maintenance treatment of transplant-eligible patients newly diagnosed with multiple myeloma.

Upfront Single Versus Double 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. 991-991 ◽  
Author(s):  
Michele Cavo ◽  
Maria Teresa Petrucci ◽  
Francesco Di Raimondo ◽  
Elena Zamagni ◽  
Barbara Gamberi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Research Funding ◽  
Plasma Cells ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Dose Intensification ◽  
Cytogenetic Profile

Abstract Background The role of single vs double autologous stem cell transplantation (ASCT) in patients with newly diagnosed (ND) multiple myeloma (MM) needs to be prospectively investigated in the novel agent era. Methods The phase III EMN02/HO95 study was designed to compare (first randomization, R1) (stratification according to ISS stage) standard-dose intensification therapy with bortezomib-melphalan-prednisone (VMP) vs high-dose intensification therapy with melphalan at 200 mg/m2 (HDM) followed by ASCT after 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy. A second randomization to consolidation therapy vs no consolidation was performed after intensification therapy, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study endpoint was progression-free survival (PFS) from R1. In centers with a policy of double ASCT, patients were randomized in a 1:1:1 ratio to either VMP or single ASCT (ASCT-1) or two sequential courses (administered 2 to 3 months apart) of HDM and double ASCT (ASCT-2) in order to prospectively compare ASCT-1 with ASCT-2, which was an additional study objective. Results From February 2011 to April 2014, 1510 pts aged ≤65 years with symptomatic NDMM were registered and 1192 of these were eligible for R1. According to the design of the study, 614 eligible patients who received the diagnosis of MM in centers with a double intensification policy were randomly assigned to either VMP (n=199) or ASCT-1 (n=208) or ASCT-2 (n=207). Patients randomized to ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 59 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 18% and 19%, while revised ISS stage III was 9% and 11%, respectively. Cytogenetic abnormalities were detected by FISH analysis of CD138+ plasma cells. A high-risk (HR) cytogenetic profile, defined by t(4;14) and/or del(17p) and/or t(14;16) (HR cyto-3), was observed in 26% of evaluable patients who were randomized to ASCT-1 and in 21% of those randomly assigned to ASCT-2. If amp(1q) and/or del(1p) were added for the definition of high-risk disease, a HR cytogenetic profile that included at least 1 of the 5 above mentioned chromosomal abnormalities (HR cyto-5) was reported in 55% of evaluable patients in the ASCT-1 group and in 54% of those in the ASCT-2 group. Median follow-up from R1 was 27 (IQR: 20-35) months. On an intention-to-treat basis, the median PFS was 45 months in the ASCT-1 arm and was not yet reached for patients in the ASCT-2 arm; 3-year estimates of PFS were 60% and 73%, respectively (HR=0.66; 95% CI=0.45-0.96; P=0.030). PFS benefit with ASCT-2 was retained across predefined subgroups, including patients with β2-microglobulin >3.5 mg/L (HR=0.59; CI=0.34-0.99; P=0.005), bone marrow plasma cells >60% (HR=0.41; CI=0.22-0.77; P=0.006), LDH values above the upper limits (HR=0.52; CI=0.28-095; P=0.034), revised ISS stage II (HR=0.50; CI=0.31-0.80; p=0.004), HR cyto-3 (HR=0.49; CI=0.24-1.02; P=0.057) and HR cyto-5 (HR=0.57; CI=0.35-0.93; P=0.024). In a multivariate Cox regression analysis stratified by ISS stage, randomization to ASCT-2 (HR=0.62; CI=0.40-0.95; P=0.027) and HR cyto-5 (HR=2.63; CI=1.63-4.16; P<0.001) were the leading independent predictors of PFS. Overall survival was not yet mature and no difference between the two treatment groups was evident. Conclusions Upfront double ASCT after bortezomib-based induction therapy for newly diagnosed MM was superior over a single ASCT in terms of prolonged PFS. Clinical benefits of double ASCT were mostly seen in patients with disease-related factors predicting for poor prognosis. Disclosures Cavo: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Offidani:Janssen: Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Janssen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbivie: Honoraria.

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