scholarly journals High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program

2009 ◽  
Vol 144 (2) ◽  
pp. 169-175 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Andrew R. Belch ◽  
H. Miles Prince ◽  
Maria Nambo Lucio ◽  
Angelo Maiolino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rate ◽  
High Response Rate ◽  
High Response ◽  
Refractory Multiple Myeloma ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Access Program

Expanded Access Program (EAP) for Lenalidomide (Revlimid®) Plus Dexamethasone in over 1400 Subjects with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3556-3556 ◽  
Author(s):  
Christine Chen ◽  
Donna E. Reece ◽  
David Siegel ◽  
Ruben Niesvizky ◽  
Ralph Vincent Boccia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Iii ◽  
Advocacy Groups ◽  
Refractory Multiple Myeloma ◽  
Expanded Access ◽  
Prior Therapy ◽  
Expanded Access Program ◽  
The Us ◽  
Grade 3 ◽  
Access Program

Abstract Background: Lenalidomide (Revlimid®) in combination with dexamethasone was approved in the US on June 29, 2006 for the treatment of subjects with multiple myeloma who had received at least one prior therapy. On February 28, 2005 based upon a positive interim analysis of two pivotal placebo-controlled Phase III studies, an independent Data Safety Monitoring Board recommended the studies be unblinded and all subjects in both studies be given access to lenalidomide. In April 2005, the FDA in association with myeloma patient advocacy groups requested Celgene establish an expanded access program to make lenalidomide plus dexamethasone available to subjects with relapsed or refractory multiple myeloma while the treatment was awaiting approval. Aim: To provide lenalidomide to multiple myeloma subjects with a high likelihood of benefit and to obtain additional safety data. Methods: Subjects with relapsed or refractory multiple myeloma that received at least 1 prior therapy were eligible. Subjects received 25 mg lenalidomide plus high-dose dexamethasone in 4-week cycles until disease progression was documented, study drug was discontinued, or lenalidomide became commercially available for this indication. Results: Between September 8, 2005 and July 25, 2006, approximately 1400 subjects in the US and Canada were enrolled into the study. A data snapshot taken March 17, 2006 demonstrated that 746 subjects had been enrolled, median age was 63 years, 60% were male, and 66.5% had Stage III disease. Median time on study was 7.1 weeks (0.1–24.4) and median daily dose was 20.5 mg. At least one Grade 3 or 4 adverse event was reported in 261 (35%) of the 746 subjects. Most commonly reported Grade 3–4 events were neutropenia (7.9% of subjects), thrombocytopenia (6.0%), fatigue (3.6%), anemia (3.5%), pneumonia (3.1%) and hyperglycemia (2.0%). These most commonly reported Grade 3–4 adverse events were the same as those found in the previous pivotal studies, however, their frequencies of occurrence were lower in the current study probably due to ongoing data collection and differences in study maturity. Likewise, the most commonly reported adverse events (all grades) were the same as those reported in the two previous pivotal studies. Conclusion: Preliminary data from this expanded access program in over 1400 subjects with multiple myeloma are consistent with results from two earlier Phase III pivotal studies. The EAP of lenalidomide plus dexamethasone in multiple myeloma represents a model of how government, advocacy groups, healthcare providers and industry can work together to quickly provide treatment to subjects in need while a clearly active treatment regimen is awaiting approval.

Response to Tositumomab and Iodine 131I-Tositumomab (BEXXAR) Based on International Prognostic Index (IPI) Score.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4630-4630
Author(s):  
Sridhar E. Pal ◽  
Eric S. Winer ◽  
Kevin Chin ◽  
Alisa Dungy ◽  
Beth Higgins ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Response Duration ◽  
Overall Response ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Access Program

Abstract Purpose: The therapeutic efficacy of Bexaar (tositumomab and131I tositumomab) in the treatment of follicular lymphoma patients who have relapsed or had refractory disease after rituximab has been demonstrated. A retrospective review has reported durable complete responses in patients who were both rituximab refractory and naive.1 Results of an expanded access program reported a 59% overall response rate with a median duration of 15 months in patients with relapsed or refractory NHL.2 We report results on 33 patients treated in the expanded access program and have attempted to identify patient characteristics predictive of response or outcome. Methods: From April 1999 to November 2001, 33 patients with refractory NHL were enrolled in an IRB-approved expanded access trial at Tufts New England Medical Center. Patients were dosed with 450 mg of tositumomab and a total body exposure of 75cGy with 131I-tositumomab. Results: Of 33 treated patients, 24 had follicular lymphoma, 6 had transformed to diffuse large cell lymphoma, and 3 had small lymphocytic lymphoma. Median prior therapies was 2 (range 1–6), with 18 rituximab refractory and 15 rituximab naïve. Of 33 evaluable patients, the overall response rate was 67%, with 59% (13/22) of responders achieving CR. Median progression free survival (PFS) of the responders was 19 months, compared to a median PFS of 4 months with their last therapy. Median overall survival was 44 months in the 22 responders compared to 23 months in non-responders (p=.002). Among all patients, 28 of 33 eventually developed progressive disease, and 17 deaths had occurred during this study period. Median time to ANC nadir was 41 days and PLT nadir occurred at a median of 34 days. Two patients developed AML/MDS, and no patient required long term treatment for thyroid dysfunction. When prognostic factors were considered, 15 patients had an International Prognostic Index (IPI) score of 4–5. The median survival in this group was 24 months, while patients with Intermediate risk IPI scores of 2–3 (18 pts) had not yet reached median survival at 42+ months. Duration of response was 12 months in the high-risk IPI group compared to 42 months in the intermediate-risk group (p=.0017). Prior rituximab was also an independent predictor of outcome, with a median response duration of 12 months in rituximab exposed vs 38 months in rituximab naïve patients (p=.03), although there was not a statistically significant difference in response rates between the two groups. Because or number of transformed patients was small, it was impossible to correlate response based on histology. Conclusions: We report an overall response rate of 67% with a response duration of 19 months in responders. Median overall survival for responders was in excess of 44 months. Response duration was higher for patients with low -intermediate IPI scores and in rituximab naïve patients. A response duration of 12 months in the high IPI group in this retrospective analysis suggests that Bexaar therapy may be associated with an improved outcome compared to other therapies. Further prospective studies stratifying patients based on IPI score are underway.

Doxil (D), Vincristine (V), Reduced Frequency Dexamethasone (d) and Revlimid(R) (DVd-R) Results in a High Response Rate in Patients with Refractory Multiple Myeloma (RMM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2559-2559 ◽  
Author(s):  
Rachid Baz ◽  
Toni K. Choueiri ◽  
Rony Abou Jawde ◽  
Bridget McGowan ◽  
Yvette Ellis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Progressive Disease ◽  
Response Rate ◽  
Median Number ◽  
High Response Rate ◽  
High Response ◽  
Chemotherapeutic Regimen ◽  
Best Response ◽  
Grade 3

Abstract Background: The combination of DVd with Thalidomide (T) results in a high response rate (greater than 80% with about 50% of patients achieving a CR or NCR) in multiple myeloma. Revlimid, an immunomodulatory drug (IMiD) is active in patients with MM. We previously reported on a phase I trial of DVd-R in patients with MM, in which the maximum tolerated dose of R was 10mg daily. Methods: The DVd-R regimen was given as follows: on day 1 D was given at 40 mg/m2 IVPB; V at 2 mg IVP; d at 40 mg PO daily for 4 days, R was started at 10mg daily. R was given for 21 days consecutively. For the first cycle R was started 7 days prior to chemotherapy, while it was started on day 1 on subsequent cycles (cycle 1 was 35 days). DVd was planned every 28 days for 2 cycles after best response or a minimum of 4 cycles. Maintenance therapy consisted of R +/− Prednisone 50 mg Qod. All patients received amoxicillin, acyclovir and aspirin 81mg prophylactically. Responses were assessed based on the criteria set forth by SWOG. Patients: The study accrued 58 patients to date (36 refractory and 22 relapsed patients), 45 are evaluable for response. The median patient age at the start of the study is 62 years and 74% are males. The median number of prior chemotherapeutic regimen is 3 (range 1–7), 67% of patients had progressed after a Thalidomide containing regimen, 70% had received a VAD like regimen and 17% had received a prior autologous stem cell transplant. The median time from diagnosis to study entry is 39 month (range 5–182). Eighty six percent had Durie Salomon stage III. The mean serum B2microglobin was 6.6mg/dL (s.d.4.2). Results: The median number of cycles of DVd-R delivered was 4. Of evaluable patients, 6 patients had a CR (13%), 5 had a NCR (11%), 16 had a PR (35%), 11 had stable disease (24%), and 7 had progressive disease (15%) as their best response. The median time to best response was 38 days. After a median follow up of 7.3 month (range 0–24 months), 23 patients had progressive disease and 16 patients had died. Fifty two percent of refractory patients (19/36) had a response on DVd-R. Grade 3 and 4 leukopenia occurred in 24% and 15% respectively, however febrile neutropenia occurred in only 1 patient. Grade 3 and 4 infections occurred in 26% and 3% respectively (all but one were pneumonia). Grade 3 thrombocytopenia occurred in 20%. Venous thromboembolic events occurred in 5 patients (9%) (2 patients with pulmonary embolus and 4 with deep venous thrombosis). Grade 3 neuropathy occurred in 3 patients (no patients had grade 4 neuropathy). Two patients developed grade 3 tumor lysis syndrome. Conclusion: DVd-R is an effective chemotherapeutic regimen in patients with RMM who progressed or did not respond to VAD like regimens or to Thalidomide containing regimens, produces a high response rate among chemotherapy resistant patients, and has a manageable toxicity profile. The results will be updated at the time of the meeting.

Doxorubicin and Dexamethasone Followed by Thalidomide and Dexamethasone (AD-TD) as Initial Therapy for Symptomatic Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2409-2409 ◽  
Author(s):  
Hani Hassoun ◽  
Lilian Reich ◽  
Virginia M. Klimek ◽  
Tarun Kewalramani ◽  
Madhav Dhodapkar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
High Response Rate ◽  
High Response ◽  
Stage Ii ◽  
Thromboembolic Complications ◽  
Overall Response ◽  
Β2 Microglobulin ◽  
Low Incidence

Abstract Several drug combinations have been designed for the initial treatment of multiple myeloma. Although none has been shown to be superior, a regimen that leads to a high response rate in association with low incidence of major adverse events is highly desirable. We report response rates and complications - specifically thromboembolic complications- with the combination of doxorubicin, thalidomide and dexamethasone for patients with Durie-Salmon stage II and III symptomatic multiple myeloma. Methods: In this regimen, the drugs are used in a sequential fashion with the intent to reduce the high incidence (up to 28%) of venous thromboembolic complications known to be associated with this combination of drugs (NEJM2001; 344:1951–2; Blood2001;98:1614–5; Blood2002;100:1168–71). Doxorubicin and dexamethasone (AD; A=9mg/m2/day, Days 1–4; D=40mg/day, Days 1–4, 9–12, 17–20) are given for 3 months followed by thalidomide and dexamethasone (TD; T=200mg nightly; D=as above) for 2 months with prophylactic antibiotics and daily aspirin (81 mg/day). At any point during therapy patients achieving a complete response (immunofixation negative) are permitted to forgo further induction therapy and proceed with autologous stem cell transplantation. Results: As of 8/04, we have enrolled 38 patients ( 22 men, 16 women) with a median age of 59 years (range, 35–82). Median β2 microglobulin level was 2.5 mg/L (ND-12.5) and median albumin level 3.95 g/dL. Fluorescent in situ hybridization (FISH) studies of baseline bone marrows, searching for abnormalities of chromosomes 11, 13 and 14, are available for 36 patients. Among those, 22 patients have abnormal findings. Three patients have been removed from study, one for a DVT that occurred during cycle 5, one for a myocardial infarction after cycle 1, and one for refusing further therapy. Five patients are currently receiving treatment. Therefore response data are available for 30 patients. Among those, 26 have responded to therapy (86.6 %), including 6 complete responses (20%), 8 very good partial responses (26.6%) and 12 partial responses (40%). Two patients (6.6 %) have stable disease while two patients (6.6 %) have progression of disease. When patients are stratified according to the International Staging System using β2 microglobulin and albumin levels, the response rate is not influenced by stage, as overall response rate is 81% for stage I (n=22), 100% for stage II (n=7) and 100 % for stage III (n=1). Likewise, the presence of Δ13 does not appear to affect overall response rate (82% for patients with no Δ13 and 100 % for patients with Δ13). Among patients who completed the treatment and those removed from study because of DVT, only three developed DVT (3/31; 9.6 %). All other patients tolerated the treatment well and completed therapy with no major adverse event. Conclusion: These results indicate that the regimen consisting of doxorubicin, dexamethasone, and thalidomide used in a schedule that allows sequential administration of the drugs as described and DVT prophylaxis with low dose aspirin is well tolerated and results in a high response rate with a low incidence of therapy-related thromboembolic complications.

Reduced-Dosage of Three Drugs Combination of Cyclophosphamide, Bortezomib and Dexamethasone (reduced-CyBorD) Retains High Response Rate with Less Toxicities in Elderly Patients with Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1865-1865 ◽  
Author(s):  
Hideo Yagi ◽  
Ryosuke Fujiwara ◽  
Keigo Sano ◽  
Fujita Mariko ◽  
Takashi Iizuka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Elderly Patients ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
High Response Rate ◽  
High Response ◽  
High Dose ◽  
Weekly Schedule ◽  
High Dose Dexamethasone

Abstract Abstract 1865 Background: The three drugs combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) has been proven to be a powerful regimen for the treatment of the patients with multiple myeloma (MM). However, twice-weekly schedule of bortezomib and high dose dexamethasone has been shown to cause significant toxicities, including severe peripheral neuropathy (PN). Recently, once-weekly bortezomib induction therapy with CyBorD (modified-CyBorD) has shown less toxicity with high response rate equal to original regimen (Reeder, CB et al. Leukemia 2009). However, more than half of the patients developed bortezomib induced PN (BiPN) in modified-CyBorD. Thus it was still concerned adverse event for the transplant ineligible patients, especially frail elderly patients because it often caused interruption or withdrawal of the treatments, resulting in fewer efficacies. Under these circumstances, we introduced the reduced-dosage of CyBorD regimen (reduced-CyBorD) in the transplant ineligible patients with multiple myeloma for continuation of the treatment. Methods: The protocol consisted of bortezomib given intravenously at a dose of 1.3 mg/m2once a week on days 1, 8, 15, cyclophosphamide orally at a dose of 50 mg daily on days 1–21, and dexamethasone orally or intravenously at a dose of 20 mg daily on days 1,2,8,9,15,16 in 4-week cycles. Total of 20 patients, including 12 newly diagnosed and 8 refractory, were treated with reduced-CyBorD and evaluated its efficacy and safety. Results: The median age was 72 years (range from 62 to 81). 14 patients were more than 70 year-old (70%). A half of the patients were female. According ISS, 3 patients were classified in stage I, 6 were in II, and 11 were in III. The overall response was 86.6 % with 26.7 % CR/nCR (1 CR, 3 nCR, 5 VGPR and 4 PR). Hematological adverse events were neutropenia (35%; G1/2 n=7), lymphocytopenia (35%; G1/2 n=1, G3/4, n=1), thrombocytopenia (10%; G1/2 n=2). Non-hematological adverse events were pneumonia (20%; G2 n=2, G3 n=2), VZV infection (15%; G2 n=3), cerebral infarction (5%; G2 n=1). Importantly, only three patients (15%) developed grade 1 PN, and no patient reduced or discontinued bortezomib due to PN. Conclusions: Reduced-CyBorD with three times once-weekly bortezomib retained high efficacy seen in standard and modified CyBorD (4 times bortezomib administration). Furthermore, it was found that this regimen obviously revealed less toxicity, especially BiPN compared with those previous regimens (See Table). Our results suggested that reduced-CyBorD might be safe and effective approach to the transplant ineligible patients, especially elderly frail patients with MM. Disclosures: No relevant conflicts of interest to declare.

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