Weekly bortezomib in the treatment of patients (pts) with previously treated multiple myeloma: A phase II trial of the Minnie Pearl Cancer Research Network

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7547-7547 ◽  
Author(s):  
F. A. Greco ◽  
D. R. Spigel ◽  
J. H. Barton ◽  
C. Farley ◽  
M. T. Schreeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Research Network ◽  
High Dose ◽  
Weekly Schedule ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Previously Treated ◽  
Grade 3

7547 Background: Bortezomib, administered on a twice-weekly schedule, is now a standard part of treatment for patients with multiple myeloma. Weekly bortezomib schedules have shown activity in other cancer types, and are more convenient than twice weekly schedules. In this multicenter, community-based phase II trial, we evaluate the feasibility, toxicity, and efficacy of weekly bortezomib in pts with previously treated multiple myeloma. Methods: Eligibility criteria included a diagnosis of multiple myeloma treated with 1 or 2 previous systemic regimens (only 1 if first-line therapy included high-dose therapy); ECOG PS 0–2; creatinine < 2.0 mg/dL; WBC ≥ 3000/μL; ANC > 1000/μL; platelets ≥ 50,000/μL; no peripheral neuropathy > grade 1; informed consent. All pts received bortezomib 1.6mg/m2 IV on days 1, 8, 15, and 22 of each 5-week cycle. Pts were reevaluated at 10-week intervals; treatment continued for 8 cycles (40 weeks) or until myeloma progression. Results: Between 5/04 and 12/05, 37 pts entered this trial. Pt characteristics: median age 70 years; male/female, 20/17; 24 pts (65%) had received 2 previous regimens (previous high dose therapy, 2 pts); elevated β-2 microglobulin, 27 pts (73%). Of 26 pts evaluated, 13 pts (50%) had major responses, 11 pts (42%) stable disease, and 2 pts (8%) had progression. After a median follow-up of 7 months, projected median PFS is 9.6 months; overall survival at 1 year is 81%. Weekly bortezomib was well tolerated by most pts. Grade 3/4 toxicities included fatigue (21%), diarrhea (11%), neutropenia (7%), thrombocytopenia (4%), all others < 5%. No grade 3/4 neuropathy occurred. Only 1 pt required bortezomib dose reduction during treatment, and 2 pts discontinued treatment because of toxicity (myelosuppression, 1; fatigue/dehydration, 1). Conclusions: Weekly bortezomib is a convenient, well tolerated treatment for pts with previously treated multiple myeloma. Overall response rates with this schedule are similar to those previously reported with the standard twice-weekly schedule. Further followup is necessary to better evaluate the duration of response and the incidence of cumulative toxicities. [Table: see text]

A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2309-2309
Author(s):  
Manish Sharma ◽  
Peter Thall ◽  
Xuemei Wang ◽  
Chitra Hosing ◽  
Floralyn L Mendoza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
High Dose ◽  
Randomized Phase Ii ◽  
Preparative Regimen ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Abstract 2309 Poster Board II-286 Background There is a role for novel preparative regimens in multiple myeloma to improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto HCT). Bortezomib is an active agent in newly diagnosed or relapsed multiple myeloma, and has synergistic activity with melphalan. We conducted a randomized phase II trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA) and melphalan. Methods auto HCT, with preparative regimen melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3(arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Primary endpoints were complete response (CR), NCI grade 4 toxicity, and overall survival (OS). Results In arms 1, 2 and 3, median intervals between diagnosis and auto HCT were 12.2, 9.6 and 8.8 months; median follow up in all surviving patients was 20 months (range 10 to 31). CR+near CR rates in arms 1, 2 and 3 were 35%, 30% and 25%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84%, 70% and 95% of patients in arms 1, 2 and 3. Median time to neutrophil engraftment (ANC >500/dl) was 10 days in each arm. Median OS has not been reached in any of the 3 arms. Median progression-free survival (PFS) times were18.6, 13.2 and 17.5 months. OS was significantly shorter in patients with relapsed disease (0.00001) and cytogenetic abnormalities at auto HCT (0.0002). Conclusions Adding bortezomib to a preparative regimen of ATO, AA and high dose melphalan is safe and well tolerated in patients with multiple myeloma. There was no significant impact of adding bortezomib at either dose on the CR rate, grade 3-4 toxicity or OS. Disclosures: Shah: Celgene, Amgen, Novartis, Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Qazilbash:Cephalon: Speakers Bureau.

Bortezomib in Combination with Pegylated Liposomal Doxorubicin and Thalidomide (VDT), An Effective Steroid Independent Regimen for Previously Untreated Multiple Myeloma Patients: Final Result of a Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 618-618
Author(s):  
Taimur Sher ◽  
Kena C Miller ◽  
Sikander Ailawadhi ◽  
Debbie Manfredi ◽  
Margaret Wood ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Pegylated Liposomal Doxorubicin ◽  
High Dose ◽  
Advisory Committees ◽  
Significant Toxicity ◽  
Grade 3

Abstract Abstract 618 Introduction: Steroids have been an important component of multiple myeloma (MM) therapeutics. High doses steroids as used in MM are associated with significant toxicity and morbidity. Development of steroid independent or steroid-lite regimens remains an important area of investigation in MM. Orlowski et al combined Doxil (D) with bortezomib (V) and showed enhanced anti-myeloma activity. In a phase II study in relapsed refractory MM patients, we observed further improvement in clinical efficacy with addition of thalidomide (T) to VD combination (VDT regimen). Encouraged by high response rates of this steroid sparing novel combination we investigated VDT regimen in treatment naïve MM patients. Final results of this phase II trial are reported here. Methods: Patients with previously untreated MM were eligible for this phase II trial. VDT regimen (V 1.3mg/m2 on days 1, 4,15,18; D 20mg/m2 on days 1,15 and T 200 mg daily continuously) given on a 4-week cycle for a maximum of 8 cycles. Acyclovir (400 mg BID) and weight adjusted low-dose warfarin (1 or 2mg for absolute body weight <70kg or ≥70kg, respectively) was given for prophylaxis of herpes zoster and deep vein thrombosis (DVT), respectively. Response was assessed using the modified Blade criteria. Results: Forty patients (26 males, 14 females; median age 60.5, range 40-80 yrs) were enrolled on this study. Among these 58%(n=23) had stage III (Durie-Salmon) disease with a median b2 microglobulin of 3.7 (range 1.6-16.5 mg/L) and median LDH of 443 (range 152-129 IU/L). Thirty-nine patients are eligible for response evaluation (1 too early for assessment). Overall response rate (CR/nCR+PR) was 79.4% (n=31) with 38% (n=15) patients achieving CR/nCR. The median progression free (PFS) and overall survival (OS) has not been reached. At 1 year the PFS and OS is 81% and 97%, respectively (1 patient died from disease progression to leukemic phase). Toxicity: Neutropenia was the most significant hematological toxicity with grade 3 and 4 neutropenia observed in 22.5% and 2.5% of the patients, respectively. Only 1 (2.2%) patient had febrile neutropenia. Clinically significant neuropathy (grade ≥2) was seen in 20% while grade ≥2 palmer planter erythrodysesthesia was seen in 15% (n=6) of the patients. Other grade 3 non-hematological toxicities included pneumonia (20%), pleural effusion (10%), pulmonary embolism (2%), DVT (2%), congestive heart failure (5%) and interstitial pneumonitis (2%). Conclusion Although effective, steroid based treatment regimen can be associated with significant toxicity especially among patients with concurrent co morbid conditions such as hypertension and diabetes mellitus. Furthermore, recent investigations demonstrate that decreasing steroid doses may actually improve PFS and OS despite a comparatively low initial ORR. In this clinical trial we hypothesized that rational combination of novel myeloma agents may actually preclude the need to rely on high-dose steroids without significantly compromising ORR. Consistent with our expectations, the VDT regimen has ORR comparable to some of the steroid-inclusive triple drug combinations. The toxicity profile of this combination was acceptable and the regimen was well tolerated. Thus we note that VDT is an effective and well tolerated steroid-independent induction regimen for MM patients. Disclosures: Off Label Use: A Phase II study of a novel combination in newly diagnosed myeloma patients. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Centocor Ortho Biotech: Research Funding. Sood:Celgene: Stock. Chanan-Khan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy

2004 ◽  
Vol 34 (3) ◽  
pp. 235-239 ◽  
Author(s):  
S Kumar ◽  
M A Gertz ◽  
A Dispenzieri ◽  
M Q Lacy ◽  
L A Wellik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Value ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy

Total Therapy With Tandem Transplants for Newly Diagnosed Multiple Myeloma

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 55-65 ◽  
Author(s):  
B. Barlogie ◽  
S. Jagannath ◽  
K.R. Desikan ◽  
S. Mattox ◽  
D. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Remission Induction ◽  
Comprehensive Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Total Therapy ◽  
Macrophage Colony ◽  
Intent To Treat

Abstract Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.

Delphi-Panel Analysis of Appropriateness of High-Dose Therapy and Bone Marrow Autotransplants in Newly Diagnosed Multiple Myeloma

1999 ◽  
Vol 33 (5-6) ◽  
pp. 511-519 ◽  
Author(s):  
Robert Peter Gale ◽  
Rolla Edward Park ◽  
Robert W. Dubois ◽  
Kenneth C. Anderson ◽  
William M. Audeh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Delphi Panel ◽  
High Dose ◽  
Panel Analysis ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy

A Phase II Trial of Doxil, Vincristine and Reduced Schedule Dexamethasone (DVd) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2415-2415 ◽  
Author(s):  
Paul Masci ◽  
Mary A. Karam ◽  
Luba Platt ◽  
Steven Andresen ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Liposomal Doxorubicin ◽  
Phase Ii Trial ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Response Rates ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Grade 3

Abstract Patients with newly diagnosed multiple myeloma (MM) typically have responses to initial cytotoxic or steroid based therapy. Disease relapse occurs in all patients. As high as 90% of patients with relapsed or refractory disease will have over-expression of the multi-drug resistance (MDR) gene. Pharmacokinetic data suggest that prolonged exposure to high concentrations of doxorubicin can overcome MDR. Pegylated liposomal doxorubicin can theoretically achieve this goal as the angiogenic activity of the MM bone marrow is significantly increased. We proceeded with a phase II trial to evaluate the response rate of patients with relapsed or refractory MM (R/R-MM) to the DVd regimen. Eligible patients had clinically active R/R-MM following at least one prior cytotoxic based treatment regimen. Patients received intravenous (IV) pegylated liposomal doxorubicin 40 mg/m2 day 1, vincristine 2 mg day 1 and oral or IV dexamethasone 40 mg daily days 1–4. Cycles were repeated every 28 days for a minimum of 6 cycles and 2 cycles after best response. Myeloma parameters were measured at the start of each cycle. SWOG criteria were used to determine response. Thirty-five patients (21 male and 14 female) with R/R-MM clinically active disease were enrolled. Median age was 59 years (range 43–87). Patients received a median of 2 (range 1–4) prior cytotoxic based treatments. All patients received at least one cycle of treatment (median=5; range 1–12) and were evaluable for response. Ten (29%) patients responded to therapy; 5 partial responses (PR &gt; 50%) and 5 responses (R &gt; 75%) were observed after a median of 2 cycles (range 1–9). Median progression free survival of responding patients (PR + R) was 4.5 mos. (range 0.67–44.8). Patients achieving R had a median progression free survival of 32.5 mos. (3.0–44.8). Thirteen (37%) patients had stable disease (SD) for a median of 1.4 mos. (range 0.8–9.9). Twelve (34%) patients had progressive disease after a median of 1 cycle (range 1–5). The most common toxicities were hematologic; there were four occurrences of febrile neutropenia. Three patients experienced grade 3 constipation and one grade 3 palmar-plantar erythrodysethesia was observed. This study suggests that in patients with R/R-MM, DVd alone yields response rates similar to bortezomib with patients achieving an R experiencing a durable plateau phase. Ongoing studies of DVd in combination with thalidomide or CC-5013 in patients with R/R-MM have resulted in higher and better quality response rates (comparable to autologous SCT) translating to a durable progression free survival. We would not recommend the DVd regimen in patients with R/R-MM without the addition of an immune modulator such as thalidomide.

Transplant Outcomes after Topotecan-Melphalan-Cyclophosphamide (TMC) Conditioning for Autologous Stem Cell Transplantation for Multiple Myeloma. Comparison to Melphalan 200 mg/M2 (MEL200).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1177-1177
Author(s):  
Michele Donato ◽  
Ana Aleman ◽  
Donna Weber ◽  
Michael Wang ◽  
Muzaffer Qazilbasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
High Dose ◽  
Transplant Outcomes ◽  
Transplant Program ◽  
Preparative Regimen

Abstract Background: Topotecan at modest doses has activity in multiple myeloma (MM). The combination of high-dose topotecan, melphalan, and cyclophosphamide (TMC) has been used as a conditioning regimen for autologous SCT in patients with MM. We report the results of a phase II trial with this combination and perform a retrospective analysis comparing TMC to a standard preparative regimen of melphalan 200 mg/m2 (MEL200). Patients and Methods: Between 10/99 and 3/04, 55 patients with newly diagnosed MM were treated on a Phase II trial of topotecan 3.5 mg/m2 daily for 5 days in combination with cyclophoshamide 1 gm/m2 daily for 3 days, and melphalan 70 mg/m2 daily for 2 days followed by autologous SCT. Patient characteristics are summarized in table 1. In brief, median age was 55 (range, 37–67), median time to transplant was 6 months (range, 2-59); median B2M @diagnosis 3.3 (range, 1.4–17.2); 76% of patients had chemosensitive disease prior to transplant. Results: No treatment related deaths were observed, the regimen was well tolerated with grade 2 Bearman mucositis and diarrhea the most common toxicities, and no grade 3 or 4 toxicities observed. When compared to a group of patients who received MEL 200 the overall response rate was lower 75% vs 82% and a lower CR rate 11% vs 36%, but a similar median time to disease progression (14 m vs 13 m), with a trend towards a better 3 yr overall survival (87% vs 77%; p=.05) (Table 2 and Figure 1). Conclusion: TMC is a well tolerated conditioning regimen for myeloma, our results suggests that although no more effective than MEL200 as a single preparative regimen for MM, it warrants exploring as part of a tandem transplant program. Patient Characteristics TMC MEL200 N 55 157 Median Age (range) 55(37-67) 56(29-75) Median B2M @Dx 3.3 (1.4 - 17.2) 4 (0.5 - 49.8) % Abn Cytogenetics 15% 22% CR/PR @ SCT 4%/73% 10%/89% % 1ry Refractory 24% 27% Transplant Outcomes TMC MEL200 p ORR/CR conversion 75%/11% 82%/36% Non Relapse Mortality 0 2 Median OS NR 52 months .05 Figure Figure

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