Bortezomib-Based Combinations

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Efficacy and Safety of Three Bortezomib-Based Combinations in Elderly, Newly Diagnosed Multiple Myeloma Patients: Results From All Randomized Patients in the Community-Based, Phase 3b UPFRONT Study

Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 478

Ruben Niesvizky, MD 1, Ian W. Flinn, MD, PhD 2, Robert Rifkin, MD 3, Nashat Gabrail, MD 4, Veena Charu, MD 5, Billy Clowney, MD 6, James Essell, MD 7, Yousuf Gaffar, MD 8, Thomas A. Warr, MD, FACP 9, Rachel Neuwirth, MS 10, Deyanira Corzo, MD 10, and James Reeves, MD11

1. Medicine and Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA,
2. Sarah Cannon Research Institute; Tennessee Oncology, PLLC, Nashville, TN, USA,
3. Rocky Mountain Cancer Center, Denver, CO, USA,
4. Gabrail Cancer Center, Canton, OH, USA,
5. Pacific Cancer Medical Center, Anaheim, CA, USA,
6. Santee Hematology/Oncology, Sumter, SC, USA,
7. Sarah Cannon Research Institute and Oncology Hematology Care, Inc., Cincinnati, OH, USA,
8. St. Joseph Medical Center, Towson, MD, USA,
9. Clinic Cancer Care, Great Falls, MT, USA,
10. Millennium Pharmaceuticals, Inc., Cambridge, MA, USA,
11. Sarah Cannon Research Institute and Florida Cancer Specialists, Fort Myers, FL, USA

Abstract 478

Background:

The US community-based, phase 3b randomized, open-label, multicenter UPFRONT trial compares the efficacy and safety of three bortezomib (VELCADE®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by weekly Vc maintenance, in elderly, newly diagnosed, transplant-ineligible multiple myeloma (MM) patients. This is the first phase 3 study of VcD and VcTD in this patient population.

Methods:

Patients with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc as before; T 100 mg/day, days 1–21; D as before); VcMP: Vc as before; M 9 mg/m2 and P 60 mg/m2, days 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly Vc 1.6 mg/m2, days 1, 8, 15, 22. Patients in the VcTD arm received concomitant prophylaxis with aspirin, full-dose warfarin, or low-molecular weight heparin unless medically contraindicated. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR)/near CR (nCR) and very good partial response (VGPR) rates, overall survival (OS), and safety. Best confirmed responses were assessed by investigators per modified International Myeloma Working Group (IMWG) criteria. Adverse events (AEs) were graded by NCI-CTCAE v3.0. PFS and OS were estimated by Kaplan–Meier methodology. For the first time, we report results from the entire cohort of 502 randomized patients (VcD, n=168; VcTD, n=167; VcMP, n=167), who completed up to a maximum of 13 cycles of treatment.

Results:

Patients in the VcD, VcTD, and VcMP arms had a median age of 74.5, 73.0, and 72.0 years, respectively, and 71%, 62%, and 72% had ISS stage II/III disease. Patients received a median of 8 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles; 50%, 38%, and 42% of patients, respectively, received Vc maintenance. Response and safety data are summarized in the table. All three Vc-based induction regimens exhibited substantial activity, with ORR of 73% (VcD), 80% (VcTD), and 69% (VcMP) during the treatment period. After a median follow-up of 21.8 months, no significant difference in PFS was observed between the treatment arms; median PFS was 13.8 months (VcD), 14.7 months (VcTD), and 17.3 months (VcMP), respectively (Figure). 1-year OS estimates were 87.4% (VcD), 86.1% (VcTD), and 88.9% (VcMP). Rates of grade 3 AEs, serious AEs (SAEs), and discontinuations due to AEs during the treatment period were highest for the VcTD arm. The most common grade 3 AEs across all three arms during the treatment period were neuropathy peripheral (23%), fatigue (10%), and diarrhea (9%). Grade 3 pneumonia was reported in 10% (VcD), 6% (VcTD), and 6% (VcMP) of patients. AEs of deep vein thrombosis/pulmonary embolism were reported in 8% (VcD), 7% (VcTD), and 2% (VcMP) of patients. Compared with rates during induction, Vc maintenance produced little additional toxicity; across all three treatment arms, only 5% of patients experienced grade 3 peripheral neuropathy during cycles 9–13. One second primary malignancy (lung neoplasm) was reported in the VcMP arm.

Conclusions:

VcD, VcTD, and VcMP induction followed by weekly Vc maintenance produced similar activity in elderly, newly diagnosed, transplant-ineligible MM patients. Patients in the VcD doublet arm appear to have similar long-term outcomes to patients in the VcTD and VcMP triplet arms.

Disclosures:

Niesvizky: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Flinn: Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin: Celgene: Speakers Bureau; Amgen: Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charu: GSK: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership; Pfizer: Equity Ownership. Neuwirth: Millennium Pharmaceuticals, Inc.: Employment. Corzo: Millennium Pharmaceuticals, Inc.: Employment.

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Continued Overall Survival Benefit After 5 Years' Follow-up with Bortezomib-Melphalan-Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial

Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 476

Jesús F San Miguel, MD PhD 1, Rudolf Schlag, MD 2, Nuriet K Khuageva, MD 3, Meletios Athanasios Dimopoulos, MD 4, Ofer Shpilberg, MD, MPH 5, Martin Kropff, MD 6, Ivan Spicka, MD, PhD 7, Maria T Petrucci 8, Antonio Palumbo, MD 9, Olga S Samoilova, MD 10, Anna Dmoszynska 11, Kudrat M Abdulkadyrov, Prof 12, Michel Delforge, MD, PhF 13, Bin Jiang 14, María-Victoria Mateos, MD, PhD 1, Kenneth C. Anderson, MD 15, Dixie-Lee Esseltine, MD, FRCPC 16, Kevin Liu, PhD 17, William M Deraedt, PhD 18, Andrew Z Cakana, MD, FRCPath 19, Helgi van de Velde, MD, PhD 18 and Paul G. Richardson, MD 20

1. Hospital Clinico Universitario, Salamanca, Spain,
2. Praxisklinik Dr. Schlag, Würzburg, Germany,
3. SP Botkin Moscow City Clinical Hospital, Moscow, Russia,
4. Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece,
5. Institute of Hematology, Rabin Medical Center, Petah Tikva, Israel,
6. University of Muenster, Muenster, Germany,
7. Charles University, Prague, Czech Republic,
8. University La Sapienza, Rome, Italy,
9. Myeloma Unit, Division of Hematology, University of Torino, AOU S. Giovanni Battista, Torino, Italy,
10. Nizhnii Novgorod Region Clinical Hospital, Novgorod, Russia,
11. Medical University of Lublin, Lublin, Poland,
12. St Petersburg Clinical Research Institute of Hematology & Transfusiology, St Petersburg, Russia,
13. Myeloma Study Group Belgian Hematological Society, Brussels, Belgium,
14. Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China,
15. Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,
16. Millennium Pharmaceuticals, Inc., Cambridge, MA, USA,
17. Janssen Research & Development, Raritan, NJ, USA,
18. Janssen Research & Development, Beerse, Belgium,
19. Janssen Research & Development, High Wycombe, United Kingdom,
20. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Abstract 476

Background:

Data from the initial report of the international, multicenter, phase 3 VISTA trial demonstrated that VMP was superior to MP across all efficacy endpoints, including response rates, time to progression, and overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy. Following this report, centralized assessment of response/progression was stopped and, per protocol, patients were followed for up to 4.5 years post-last patient in date for survival and the use of subsequent anti-MM therapy only. An updated analysis, conducted after a median follow-up of 36.7 months, demonstrated a continued significant OS benefit with VMP. Here we report the final updated OS analysis of VISTA after 5 years of follow-up, including an exploratory analysis of the risk of second primary malignancies (SPMs), an important issue for MM patients receiving long-term therapy.

Methods:

Patients were randomized (1:1) to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, days 1, 8, 22, and 29, cycles 5–9; melphalan 9 mg/m2 days 1–4, prednisone 60 mg/m2, days 1–4, all cycles) or MP (N=338) alone. Patients were followed at least every 12 weeks for survival and subsequent therapy use. Data on SPMs were collected during February 2011 by surveying all study sites to capture information for 655 (96%) patients.

Results:

After median follow-up of 60.1 months, with only 5% of patients lost to follow-up, median OS was 56.4 versus 43.1 months for patients randomized to VMP compared to MP (HR 0.695, p=0.0004), reflecting a 31% reduced risk of death with VMP (Figure); 5-year OS rates were 46.0% and 34.4%, respectively. This compares favorably with the 6.6-month increase in median OS in a meta-analysis of six phase 3 trials of MP-thalidomide vs MP (Fayers et al, Blood 2011). The OS benefit with VMP was seen across patient subgroups, including those aged 75 years (median 50.7 vs 32.9 months, HR 0.71), patients with ISS stage III MM (median 42.1 vs 30.5 months, HR 0.67), and those with creatinine clearance <60 mL/min (median 56.8 vs 36.7 months, HR 0.70), but no significant difference was observed in the small subgroup of patients with documented high-risk cytogenetics (n=46). At data cut-off (March 24, 2011), 63% of VMP and 73% of MP patients had received subsequent MM therapies; use of subsequent therapies was generally similar between arms, except for a higher proportion of MP patients receiving subsequent bortezomib (43% vs 22%). Time to next treatment (median 27.0 vs 19.2 months; HR 0.557, p<0.0001) and treatment-free interval (median 16.6 vs 8.3 months, HR 0.573, p<0.0001) were superior with VMP vs MP. Among all patients who had received subsequent therapies, OS was superior with VMP vs MP (median 55.7 vs 46.4 months; HR 0.745, p=0.0162). A 30-month landmark OS analysis demonstrated superior survival from landmark among all VMP patients (median not reached) and among VMP patients who had received any subsequent therapy (median 28.2 months) vs MP patients who had received subsequent bortezomib (median 23.0 months). Taking into account the longer observation period due to prolonged survival on the VMP arm, analyses of SPM risk (Table) showed no difference in incidence proportions or ‘exposure'-adjusted incidence rates between arms. Rates on both arms (VMP 0.0166, MP 0.013 per patient-year) were consistent with background incidence rate in the general population aged 65–74 years (0.019, SEER database).

Conclusions:

VMP resulted in a substantial long-term OS benefit vs MP (13.3-month increase in median), which was seen across patient subgroups and regardless of extensive subsequent therapy. There was no increased risk of SPMs identified with VMP vs expected background rates.

Disclosures:

San Miguel: Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Dimopoulos: Millennium Pharmaceuticals, Inc.: Honoraria; Ortho Biotech: Consultancy, Honoraria. Kropff: Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Spicka: Janssen-Cilag: Honoraria; Celgene: Honoraria. Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska: Janssen-Cilag: Research Funding. Delforge: Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mateos: Janssen-Cilag: Honoraria; Celgene: Honoraria. Anderson: Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Esseltine: Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Liu: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. de Velde: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Richardson: Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy.

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Maintenance Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus Prednisone (VP) In Elderly Myeloma Patients Included In the GEM2005MAS65 Spanish Randomized Trial

Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 477

María-Victoria Mateos, MD, PhD 1, Albert Oriol 2, Ana-Isabel Teruel 3, Enrique Bengoechea 4, Montse Pérez 5, Javier López 6, Joaquín Díaz-Mediavilla 7, Jose Mariano Hernández 8, Felipe de Arriba 9, Yolanda Gonzalez 10, Joan Bladé, MD 11, Juan José Lahuerta 12, and Jesðs F. San Miguel 13

1. Hospital Clinico Universitario, Salamanca, Spain,
2. PETHEMA Group. Spanish Society of Hematology, Badalona, Spain,
3. Hospital Clinico Universitario de Valencia, Valencia,
4. Hematology, Hospital Osakidetza, San Sebastian, Spain,
5. Hematology, Hospital Virgen de la Concha, Zamora, Spain,
6. Hematology, hospital ramón y cajal, Madrid, Spain,
7. Hematology, Hospital Clinico de Madrid, Madrid, Spain,
8. Hospital General de Segovia, Segovia, Spain,
9. Hospital Morales Messeguer, Murcia, Spain,
10. ICO Dr Josep Trueta, Girona, Spain,
11. Hospital Clinic, Barcelona, Spain,
12. Hospital 12 de Octubre, Madrid, Spain,
13. Hematology, Hospital Universitario de Salamanca, Salamanca, Spain

Abstract 477

In 2005, Spanish Myeloma Group (GEM/Pethema) activated a two-stage, randomized trial including 260 elderly untreated myeloma patients. In the first stage, patients received induction therapy based mainly on a once per week dosing of bortezomib in combination with prednisone plus either melphalan (VMP) or thalidomide (VTP). The results of this first stage were already published (Mateos et al. Lancet Oncology 2010) and among all the 260 patients included in the trial, VMP and VTP as induction regimens yielded similar overall responses rate (80% and 81%, respectively). Patients completing the six induction cycles, in absence of disease progression or toxicity, moved to the second stage, in which each of the arms were equally randomly assigned to maintenance therapy with bortezomib plus prednisone (VP) or bortezomib plus thalidomide (VT). Maintenance consisted of one conventional cycle of bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) every 3 months, plus either oral prednisone 50 mg every other day or oral thalidomide 50 mg daily, for up to 3 years. We report the results of this second stage of the trial comparing VT with VP for up to three years as maintenance following induction with VMP or VTP.

178 out of 260 patients were randomized to receive VT or VP. Concerning baseline characteristics, both groups were well balanced, including the response status at the moment of randomization to maintenance (23% of patients were in CR in VT arm and 20% in VP arm). Median follow-up after randomization to maintenance therapy was 34 months (8–54). Overall, maintenance therapy resulted in an improvement of the depth of response and the IF-CR rate was increased from 24% after induction up to 42%. Although no significant differences were observed between VT and VP, the IF-CR rate was slightly higher for VT versus VP (46% versus 39%). For all patients receiving maintenance therapy, the median progression free survival (PFS) from initiation of treatment was 35 months (95% CI 29–39) and the median overall survival (OS) 60 months (95%C CI 51–69). From the randomization to maintenance therapy, the median PFS was 30 months (95% CI 21–39) for patients receiving VT and 24 months (95% CI 15–33) for those receiving VP (p=0·1). The slight benefit of VT versus VP as maintenance was independent of the type of induction therapy (VMP or VTP) (p=0·9). No differences in overall survival from this timepoint for VT and VP arms were observed (HR 1·4, 95% CI 0·8–2·4). Concerning safety profile, grade 3 or higher hematological toxicity was recorded only as neutropenia in one patient (1%) in each arm and grade 1–2 occurred in less than 5% of patients (3% and 2% of patients in VT arm developped neutropenia and thrombocytopenia, respectively; and 1% of anemia in VP arm). Concerning non-hematological toxicity, although more of the side effects were of grade 1–2 in both arms, their incidence was superior for VT as compared with VP arm (p=0·0001). Of note, seven patients (7%) in VT arm developped cardiac events, consisting on bradycardia (2 pts), tachycardia (2 pts), heart attack (2 pts) and cardiac failure (1 pt), while only one patient in VP arm. Gastrointestinal toxicity, as constipation or paralitic ileus, was reported in 11 patients (11%) in VT and 3 patients (3%) in VP arm. Grade 3–4 peripheral neuropathy was observed in 9 patients (9%) in VT and 3 (3%) in VP arm.

In summary, VT or VP as maintenance therapy resulted in a substantial increase in complete response rate, from 24% after induction to 42%, which can not be attributed to thalidomide or prednisone single agents but to their combination with bortezomib. In terms of CR, PFS and OS, although no significant differences between VT and VP were observed, a trend to better outcome for VT patients was observed, with a PFS that is one of the longest so far reported for elderly MM patients (39 months from diagnosis). However, VT arm was also associated with a higher incidence of non-hematological toxicity. These regimens, including bortezomib-based induction schemes that use weekly dosing of bortezomib, followed by bortezomib-maintenance schemes represent a platform for further optimisation of the treatment for elderly patients with multiple myeloma through use of lenalidomide instead of thalidomide by reducing adverse events and potentially improving the efficacy.

Disclosures:

Mateos: Celgene: Honoraria; Janssen-Cilag: Honoraria. Off Label Use: BORTEZOMIB, THALIDOMIDE AND PREDNISONE ARE NOT APPROVED FOR THE MAINTENANCE THERAPY.