Randomized Phase III Study of Pegylated Liposomal Doxorubicin Plus Bortezomib Compared With Bortezomib Alone in Relapsed or Refractory Multiple Myeloma: Combination Therapy Improves Time to Progression

2007 ◽  
Vol 25 (25) ◽  
pp. 3892-3901 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Arnon Nagler ◽  
Pieter Sonneveld ◽  
Joan Bladé ◽  
Roman Hajek ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
International Study ◽  
Phase Iii ◽  
Combination Group ◽  
Time To Progression ◽  
Refractory Multiple Myeloma ◽  
Grade 3

PurposeThis phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma.Patients and MethodsSix hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m2on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m2on day 4.ResultsMedian time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome.ConclusionPLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.

The Prolonged Time to Progression with Pegylated Liposomal Doxorubicin + Bortezomib Versus Bortezomib Alone in Relapsed or Refractory Multiple Myeloma Is Unaffected by Extent of Prior Therapy or Previous Anthracycline Exposure.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 410-410 ◽  
Author(s):  
Joan Blade ◽  
Jesus San Miguel ◽  
Arnon Nagler ◽  
Pieter Sonneveld ◽  
Andrew Spencer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Phase Iii ◽  
Time To Progression ◽  
Total Study Population ◽  
Refractory Multiple Myeloma ◽  
Prior Therapy ◽  
Heterogeneity Test

Abstract Recently, a significant improvement in time to progression (TTP) was reported for pegylated liposomal doxorubicin (PLD) + bortezomib combination therapy vs. bortezomib monotherapy in a phase III randomized trial in relapsed or refractory multiple myeloma (RRMM) (Orlowski, JCO 2007). This pre-specified analysis assessed the efficacy of PLD+bortezomib in RRMM based on the number of prior lines of therapy and previous anthracycline exposure status. Patients with ≥1 prior therapy were randomized to receive PLD at 30 mg/m2 on day 4 and bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least 2 cycles beyond CR, or optimal response unless disease progression, or unacceptable toxicities occurred. The baseline beta-2 microglobulin levels were comparable between the subgroup with ≥2 prior treatments and that with 1 treatment (median 3.98 vs. 4.01 mg/L), as well as between anthracycline-exposed and -naïve patients (median 3.91 vs. 4.55 mg/L). The improved TTP reported previously with PLD+bortezomib over bortezomib in the total study population was similarly observed in all four subgroups of patients (patients with ≥2 lines of prior therapy or 1 prior therapy, anthracycline-exposed (median 144 mg/m2 in both treatment arms) or -naïve groups (Table)), indicating a consistent therapeutic benefit favoring the PLD+bortezomib combination. Furthermore, TTP was comparable for the PLD+bortezomib combination between groups with ≥2 lines of prior therapy vs. 1 prior therapy (heterogeneity test, p=0.523), as well as patients who were anthracycline-exposed or -naïve (heterogeneity test, p=0.716). Incidence of treatment-related SAEs, grade 3/4 neuropathy, and symptomatic cardiac events was comparable between treatment arms in each subgroup (Table). PLD-related hand-foot syndrome was also <10% in all PLD+bortezomib subgroups. These results demonstrate that PLD+bortezomib combination therapy significantly improves TTP compared to bortezomib alone, regardless of the number of prior lines of therapy, or anthracycline exposure.

Effect of the combination of pegylated liposomal doxorubicin and bortezomib on time to progression (TTP) and overall survival of patients with relapsed/refractory multiple myeloma compared with bortezomib alone

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8002-8002 ◽  
Author(s):  
J. L. Harousseau ◽  
A. Nagler ◽  
P. Sonneveld ◽  
J. Bladé ◽  
R. Hajek ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Combination Therapy ◽  
Liposomal Doxorubicin ◽  
Randomized Study ◽  
Pegylated Liposomal Doxorubicin ◽  
Proteasome Inhibition ◽  
Phase Iii ◽  
Combination Group ◽  
Refractory Multiple Myeloma

8002 Background: Proteasome inhibition with bortezomib is a standard of care for patients with relapsed/refractory multiple myeloma (MM). Recently, we reported the results of an interim analysis for the DOXIL-MMY-3001 study, a large multi-national, phase III, randomized study of patients with previously treated MM demonstrating that the combination of pegylated liposomal doxorubicin (PLD) and bortezomib resulted in a 45% risk reduction of experiencing disease progression over bortezomib alone (Orlowski et al, 2006 ASH Meeting, Abstract #404). The improvement in TTP was associated with an overall survival (OS) trend favoring the combination therapy (P=0.113; hazard ratio[HR], 1.48, 95% Confidence Interval [CI], 0.91 to 2.41). We now present an updated survival analysis with a median follow up of 11 months. Methods: 646 patients at 123 centers in 18 countries received either intravenous bortezomib, 1.3 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, or the same bortezomib regimen with PLD, 30 mg/m2, on day 4. Results: As previously reported, median TTP was improved from 6.5 months for bortezomib alone to 9.3 months for the PLD+bortezomib combination (P=0.000004; HR, 1.82; 95% CI, 1.41 to 2.35). The complete+partial response rate was 43% for bortezomib and 48% for PLD+bortezomib (P=0.251). Median duration of response was increased from 7.0 months (95% CI, 5.9 to 8.3) to 10.2 months (95% CI, 10.2 to 12.9) with combination therapy (p=0.0008). Updated OS analysis showed PLD+bortezomib significantly improved OS (p<0.05; HR, 1.41, 95% CI, 1.002 to1.97). Both groups received a median of 5 cycles of treatment. The safety profile of the combination was consistent with the known toxicities of the two agents. Grade 3/4 adverse events were more frequent in the combination group primarily due to increase in myelosuppression and GI toxicities. Conclusions: PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed/refractory MM. [Table: see text]

Effect of Disease Stage and Time Since Diagnosis on Time to Progression for Pegylated Liposomal Doxorubicin + Bortezomib vs Bortezomib Alone in Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2740-2740
Author(s):  
Heather J. Sutherland ◽  
Joan Blade ◽  
Jesus San Miguel ◽  
Arnon Nagler ◽  
Pieter Sonneveld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Staging System ◽  
Risk Groups ◽  
Phase Iii ◽  
Disease Stage ◽  
Time To Progression ◽  
Total Study Population ◽  
Refractory Multiple Myeloma

Abstract A recent report of a phase III randomized trial with pegylated liposomal doxorubicin (PLD)+bortezomib vs. bortezomib alone in relapsed or refractory multiple myeloma (RRMM) demonstrated improved time to progression (TTP) with PLD+bortezomib (Orlowski, JCO 2007). The present post-hoc analyses evaluated the efficacy of PLD+bortezomib according to International Staging System (ISS) disease stage, and time since initial myeloma diagnosis (TSD). Patients with ≥1 prior therapy were randomized to receive PLD at 30 mg/m2 on day 4 and bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least 2 cycles beyond CR, or optimal response unless disease progression or unacceptable toxicities occurred. The improved TTP reported previously with PLD+bortezomib over bortezomib alone in the total study population was also observed in the higher risk groups based on disease stage (ISS 2 & 3; Table). TTP was also significantly longer with PLD+bortezomib vs. bortezomib for TSD >2 yrs despite more protracted disease. The therapeutic advantage of prolonged TTP with the PLD+bortezomib combination was maintained consistently across subgroups (heterogeneity tests: ISS 1 vs. 2 vs. 3, p=0.407; TSD ≤2 yrs. vs. >2 yrs., p=0.946). Incidence of grade 3/4 neuropathies was low (<10%) in the two treatment arms in all subgroups. PLD-related hand-foot syndrome was also <10% in all PLD+bortezomib subgroups. Despite high-grade disease or protracted disease history, the PLD+bortezomib combination shows significantly improved TTP as compared to bortezomib alone. Also, the combination therapy was well-tolerated.

The Effect of Bone Marrow Involvement on the Efficacy of Pegylated Liposomal Doxorubicin + Bortezomib Vs Bortezomib Alone in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5192-5192
Author(s):  
Jatin Shah ◽  
Joan Blade ◽  
Jesus San Miguel ◽  
Pieter Sonneveld ◽  
Donghan Luo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Liposomal Doxorubicin ◽  
Bone Marrow Involvement ◽  
Pegylated Liposomal Doxorubicin ◽  
Tumor Burden ◽  
Phase Iii ◽  
Rank Test ◽  
Time To Progression ◽  
Refractory Multiple Myeloma

Abstract Background: Patients with relapsed/refractory multiple myeloma (RRMM) often have a large tumor burden with significant bone marrow involvement, conferring a poor prognostic feature. Those patients with significant bone marrow involvement may benefit from combination regimens with increased activity. Orlowski et al. reported a phase III randomized trial with pegylated liposomal doxorubicin (PLD) + bortezomib (B) vs. B alone in RRMM, which demonstrated improved time to progression (TTP) with the combination of PLD+B. (Orlowski, JCO 2007) We investigated the effect of bone marrow involvement on overall response rates and time to progression (TTP) of PLD+ B versus B alone in patients with RRMM. Methods: Eligible patients were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n=322) or to the same B regimen plus IV PLD 30 mg/m2 on day 4 (n=324) of each cycle. The subsets of patients with bone marrow involvement and those with &gt;30% involvement were analyzed retrospectively. Results: A total of 379 patients had bone marrow involvement and 349 patients had &gt;30% bone marrow involvement compared with 259 with no bone marrow involvement. Time to disease progression (TTP) and complete response (CR) + partial response (PR) rates for PLD+B vs B alone in patients with or without any bone marrow involvement or &gt;30% bone marrow involvement are listed in the table. PLD+B B P valueb Hazard Ratioc a. Based on Kaplan-Meier product-limit estimates. b. Based on stratified Log-rank test. c. A hazard ratio &gt;1 indicates an advantage for PLD+B. d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment. No bone marrow involvement, N 132 127 TTP, Median days (95% CI)a 251 (212, 282) 198 (162, 227) 0.0134 1.69 (1.11, 2.57) Total CR+PR, n/evaluable (%) 49/118 (42) 43/124 (35) 0.2887d Any bone marrow involvement, N 188 191 TTP 311 (264, 354) 197 (169, 222) .0001 1.91 (1.37, 2.67) Total CR+PR 94/183 (51) 88/182 (48) .5187d &gt;30% bone marrow involvement, N 172 177 TTP 276 (221, 415) 183 (158, 211) .0005 1.83 (1.30, 2.58) Total CR+PR 82/168 (49) 69/170 (41) .1446d Regardless of bone marrow involvement or extent of bone marrow involvement, there was a statistically significant benefit in TTP for PLD+B vs. B alone. Safety profiles for the 2 regimens in the subsets of patients with or without bone marrow involvement were consistent with the known toxicities of the 2 agents. Conclusions: These data suggest that the combination of PLD+B is an active salvage therapy and superior to B alone in patients with RRMM, regardless of the presence or extent of bone marrow involvement. Patients with significant bone marrow involvement and associated poor risk due to increased tumor burden may benefit from the addition of PLD.

The Combination of Pegylated Liposomal Doxorubicin and Bortezomib Significantly Improves Time to Progression of Patients with Relapsed/Refractory Multiple Myeloma Compared with Bortezomib Alone: Results from a Planned Interim Analysis of a Randomized Phase III Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 404-404 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Sen H. Zhuang ◽  
Trilok Parekh ◽  
Liang Xiu ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Interim Analysis ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Time To Progression ◽  
Free Survival ◽  
Refractory Multiple Myeloma

Abstract Introduction: Proteasome inhibition with bortezomib (VELCADE®) is a standard of care for patients with relapsed/refractory multiple myeloma (MM) who have received at least one prior therapy. Pre-clinical studies have shown that bortezomib acts synergistically with anthracyclines, and clinical trials have shown encouraging evidence of enhanced anti-myeloma activity for the combination of bortezomib with pegylated liposomal doxorubicin (PLD; DOXIL®). We therefore sought to test the hypothesis that the bortezomib/PLD regimen would improve clinical outcome measures in this patient population. Methods: Between December, 2004 and March, 2006, 646 patients with relapsed or refractory MM after at least one prior line of therapy were randomized on the DOXIL-MMY-3001 study conducted at 144 sites in 18 countries. Patients were eligible if they had not previously received bortezomib, progressed on an anthracycline-containing regimen, or received more than 240 mg/m2 of doxorubicin, or the equivalent amount of another anthracycline. Subjects were randomized in a 1:1 ratio to receive either bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle, or the same dose and schedule of bortezomib but with the addition of PLD at 30 mg/m2 given on day 4 of each cycle. Treatment was to continue for up to a total of 8 cycles unless a complete response (CR) was attained, or disease progression occurred, or unacceptable treatment-related toxicity was noted. Exceptions included patients achieving CR at any time, who were treated with an additional two cycles, and patients experiencing a continued paraprotein response after 8 cycles, who were allowed to continue for as long as treatment was tolerated, and they continued to respond. Disease assessments were to occur at the start of each cycle, beginning at cycle 2, and were made according to the stringent criteria recommended by the European Group for Blood & Marrow Transplantation. Subjects who did not progress after the initial 42-week period were assessed every 6 weeks until disease progression was documented. Results: During the course of the study, an Independent Data Monitoring Committee (IDMC) reviewed safety data every 3 months, and a planned interim analysis (IA) was performed after at least 230 progression events were collected. Upon review, the IDMC concluded that, based on the IA, there was a significant benefit to patients randomized to the bortezomib/PLD arm of the trial in the primary study endpoint, time to progression, as well as in progression-free survival. No survival advantage had yet been demonstrated to date. While there was an increase in adverse events associated with the combination therapy, this increase was judged to be acceptable in the context of the benefits. In light of these results, the IDMC recommended that study results be communicated. Toxicity, time to progression, and progression free survival data will be available for presentation at the time of the annual meeting. Conclusions: At the IA, PLD plus bortezomib was significantly more effective than bortezomib monotherapy for patients with previously treated multiple myeloma.

Early Normalization of Serum Free Light Chain Is Associated with Prolonged Time to Progression Following Bortezomib ± Pegylated Liposomal Doxorubicin Treatment of Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2735-2735 ◽  
Author(s):  
Robert Orlowski ◽  
Heather Sutherland ◽  
Joan Bladé ◽  
Jesús San Miguel ◽  
Roman Hájek ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Response Rates ◽  
Free Light Chain ◽  
Time To Progression ◽  
Serum Free ◽  
Refractory Multiple Myeloma ◽  
Serum Free Light Chain

Abstract Multiple myeloma (MM), like other monoclonal gammopathies, frequently causes impairment of the κ/λ serum free light chain (sFLC) ratio. Based on a short serum half-life of FLC as compared to the complete immunoglobulin (hours versus days), early normalization of κ/λ could predict for response to treatment. As part of a randomized, controlled study, we examined the association between normalization of the κ/λ ratio after one or two 21-day cycles of treatment with bortezomib (B) ± pegylated liposomal doxorubicin (PLD) among patients with relapsed/refractory multiple myeloma. Patients with ≥1 prior therapy were randomized to receive PLD 30 mg/m2 on day 4 and B 1.3 mg/m2 on days 1, 4, 8, and 11, or B alone for up to eight 21-day cycles, or at least 2 cycles beyond complete response (CR) or optimal response, unless disease progression or unacceptable toxicities occurred (Orlowski, JCO 2007). κ/λ measurements were carried out prior to the start of therapy and at the end of each cycle through the entire study period using an immunoassay (Freelite, The Binding Sites, Birmingham, UK). Serial sFLC κ/λ measurements were available on sera from 487 patients with baseline values out of a total of 646 study patients. At baseline, 458/487 patients (94%) had an abnormal κ/λ ratio (<0.26 or >1.65). The percentage of patients with normal κ/λ ratio increased from 6% at baseline to 12% after cycle 1, 17% after cycle 2 and 23% by the end of the study. Among patients with a normal κ/λ ratio after cycle 1 (n=54), the median time to progression (TTP) was 345 days compared to 225 days in patients with abnormal ratios (n=395, p=0.0005, HR=0.47 favoring normalization). Following cycle 2, TTP was 325 days vs. 224 days (p≤0.001) in patients with normal (n=72) vs. abnormal (n=348) ratios, respectively. Additionally, patients with normalized sFLC ratios showed significantly higher overall response rates as compared to those with persistently abnormal ratios (≥ partial response [PR] 73% vs. 47%, p=0.001 following cycle 1, and 77% vs. 48%, p<0.0001 following cycle 2, respectively). Similarly, CR + very good PR rates were significantly higher among patients with normalized sFLC ratios after cycles 1 and 2 (p<0.0001 and p<0.001 respectively). As reported previously, both treatments, B + PLD and B alone, were well tolerated (Orlowski, JCO 2007). Normalization of the sFLC ratio as early as after cycle 1 of B + PLD, or B alone, was associated with a prolonged TTP and higher response rates. Additional analyses are undertaken to evaluate whether Freelite data: predict treatment outcome earlier than electrophoresis, and correlate with 24-hour urine M-protein.

The Effect of Paraprotein Heavy Chain and Free Light Chain Types on the Efficacy of Pegylated Liposomal Doxorubicin + Bortezomib Versus Bortezomib Alone in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5190-5190
Author(s):  
Jatin Shah ◽  
Joan Blade ◽  
Pieter Sonneveld ◽  
Jesus San Miguel ◽  
Donghan Luo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Heavy Chain ◽  
Light Chain ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Complete Response ◽  
Phase Iii ◽  
Rank Test ◽  
Absolute Increase ◽  
Refractory Multiple Myeloma

Abstract Background: Many factors influence the choice of salvage therapy in relapsed/refractory multiple myeloma (RRMM), including various disease characteristics such as light chain and heavy chain subtypes. Patients with light chain only myeloma are a biologically and phenotypically distinct subset of patients from those with IgG, IgA, IgM, or IgD disease. Evidence exists that the presence of different paraprotein heavy and light chain subtypes may affect treatment outcomes. We investigated the effect of the presence of paraprotein heavy and light chain types on the efficacy and safety of pegylated liposomal doxorubicin (PLD) + bortezomib (B) versus B alone based on the phase III randomized trial of PLD+B vs. B alone in RRMM, which demonstrated improved time to progression (TTP) with PLD+B (Orlowski, JCO 2007). Methods: Eligible patients were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n=322) or to the same B regimen plus IV PLD 30 mg/m2 on day 4 (n=324) of each cycle. The subsets of patients with light chain and heavy chain multiple myeloma subtypes were analyzed retrospectively. Results: The presence of light chain myeloma was observed in 77 patients. Few patients had IgM/IgD subtype myeloma (4 and 6 patients, respectively), while the majority of patients had IgG (n=379) or IgA (n=265) subtypes. Time to disease progression (TTP) and complete response (CR) + partial response (PR) rates for PLD+B vs B alone in patients with light chain, IgG, and IgA myeloma subtypes are listed in the table. PLD+B B P valueb Hazard Ratioc a. Based on Kaplan-Meier product-limit estimates. b. Based on stratified Log-rank test. c. A hazard ratio &gt;1 indicates an advantage for PLD+B. d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment. Light chain, N 40 37 TTP, Median days (95% CI)a 276 (171, n/a) 117 (85, 173) .003 3.09 (1.42, 6.73) Total CR+PR, n/evaluable (%) 22/39 (56) 10/33 (30) .030d IgG subtype, N 182 197 TTP 282 (221, 331) 199 (170, 222) .002 1.67 (1.20, 2.31) Total CR+PR 70/173 (41) 81/194 (42) .915d IgA subtype, N 88 77 TTP 250 (218, n/a) 205 (177, 236) .506 1.22 (0.68, 2.18) Total CR+PR 46/79 (58) 39/72 (54) .723d Results showed that the combination of PLD+B had significant benefit over B alone in TTP (PLD+B led to longer TTP than B alone) for IgG paraprotein and light chain subtypes. Safety profiles for the 2 regimens in these subsets of patients with heavy or light chain myeloma were consistent with the known toxicities of the 2 agents used. Conclusions: These data demonstrate that the combination of PLD+B is an important treatment option in patients with RRMM. Patients with light chain only disease had the largest incremental benefit from the addition of PLD with an absolute increase in TTP of 159 days as well as an increase in the overall response rate from 30% to 56%.

Relapsed or Refractory Multiple Myeloma: Prospective Study with Bortezomib, Non-Pegylated Liposomal Doxorubicin and Dexamethason (PAD Regimen)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5032-5032
Author(s):  
Antonietta Pia Falcone ◽  
Grazia Sanpaolo ◽  
Giovanni Rossi ◽  
Carlo Bodenizza ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Prospective Study ◽  
Median Time ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Hemopoietic Stem Cell ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Grade 3

Abstract Abstract 5032 Introduction. Combining bortezomib with pegylated liposomal doxorubicin for the treatment of Multiple Myeloma (MM) may reciprocally increase their efficacy in vitro and appears to offer higher overall response rates in vivo. With the aim to verify the synergistic interaction towards myeloma cells we planned a prospective study with bortezomib, non-pegylated liposomal doxorubicin and dexamethason in patients with relapsed/refractory multiple myeloma (R/R MM). In this setting of patients, showing a poor outcome because of multi-drug resistance, low-performance status and toxicity to previous chemotherapy, bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to doxorubicin and overcome drug-resistance. Thus, to improve outcome minimizing therapy-related toxicity, bortezomib was added to non-pegylated liposomal doxorubicin and dexamethason (PAD regimen). Patients and Methods. From November 2005 and January 2012, 50 patients with R/R MM (relapsed n= 37 and refractory n= 13) referred to the our Institution received PAD regimen. Male/Female ratio: 27/23; Median age: 61 years (range 34–79); median time from diagnosis: 32 months (range 4–121); median of previous therapy lines: n= 3 (range 1–5); patients previously underwent to autologous and allogeneic hemopoietic stem cell transplantation (auto- and allo-HSCT): 22 and 5, respectively. Planned treatment: bortezomib 1, 3 mg/mq iv days 1, 4, 8, 11; non-pegylated liposomal doxorubicin 30 mg/mq on day 1 and dexamethason 40 mg days 1–4 of a 28-day cycle up to 6 cycles. Results. Forty patients (80%) received the planned treatment schedule whereas 10 patients did not complete it because of toxicity (1 patients) and resistant or progressive disease (9 patients). Median time to best response was 3 months (range 2–6). The overall response rate was 74% with 10 CR (20%), 15 vGPR (30%) and 12 PR (24%). Fifteen of the responder patients underwent HSCT (auto-HSCT: 9; allo-HSCT: 6). The previous use of anthracyclines (35 patients) and bortezomib (3 patients) did not seem influence the response. Median duration of response was 24 months (range 6–57 months). After a median follow-up of 58 months, 14 (28%) patients were alive and, of these, 7 (14%) in Continue CR. The safety profile was manageable: the hematologic grade 3/4 toxicity (neutropenia, thrombocytopenia and anemia) was 28%; non-hematologic grade 3/4 toxicity (sensory or motor neuropathy, infections, fever, fatigue, diarrhea) was 36%. Despite heavy previous treatments, including anthracycline-based, no significant cardiac toxicity was observed. Conclusion. According to our study, the PAD regimen appears feasible and effective in both elderly and heavily pre-treated R/R MM patients. In fact a significant improved clinical outcome in our cohort of patients was observed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Vorinostat, Bortezomib, Cyclophosphomide, Thalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5773-5773 ◽  
Author(s):  
Charise Gleason ◽  
Jonathan L. Kaufman ◽  
Ajay K. Nooka ◽  
Kelly Valla ◽  
Leonard T Heffner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Combination Therapy ◽  
Clinical Benefit ◽  
Research Funding ◽  
Response Rates ◽  
Phase Iii ◽  
Refractory Multiple Myeloma ◽  
Heavily Pretreated ◽  
Grade 3

Abstract The combination of vorinostat, a histone deacetylase (HDAC) inhibitor, is synergistic with proteasome inhibitors and IMIDs based upon preclinical and clinical data. Phase III trials with vorinostat in relapsed myeloma failed to demonstrate benefit due to excess toxicity that precluded chronic administration of the agent allowing patients to realize the clinical benefits. Herein we report on our experience combining vorinostat, or adding vorinostat to current treatments in the context of refractory myeloma. Methods: Forty RRMM pts that received vorinostat (V) (200mg orally daily on days 1-14) and bortezomib (B) (1.3 mg/m2 IV/SQ days 1,4,8, and 11) combinations, every 28 days from May 2008 until May 2014 at Emory University were reviewed. Cohort 1 consisted of 22 RRMM pts that received VBCyTD regimen (V,B, cyclophosphamide (Cy) (300 mg orally flat dose days 1, 8 and 15), thalidomide (T) (100 mg daily) and dexamethasone (D) 40 mg orally weekly), while cohort 2 consisted of 18 RRMM pts that received other combinations (VBCyD+lenalidomide (R): 4 pts; VBRD: 4 pts; VBCyD: 2 pts; VBD: 4 pts; VBTD: 4 pts and VCyTD+carfilzomib (Ca): 2 pts). The objectives are response assessment by IMWG criteria, progression-free survival (PFS) and overall survival (OS). Drug related adverse events (AEs) ≥grade 3 (CTCAE v3.0) were summarized. Results: Twenty-one males and nineteen females (median age at diagnosis: 56 years [range 28-89], median age at initiation of V treatment: 62 years [range 33-91]) that were heavily pretreated (median lines of therapy: 7 [range 3-14] were included in the analysis. Ninety-five percent of pts were B refractory and 85% pts were R refractory; 97.5% and 15% of pts underwent prior autologous and allogeneic SCT, respectively. High risk cytogenetic abnormalities were seen in 40% of pts. Time from diagnosis to initiation of V combination therapy is 58.5 months (range 18-138). The overall clinical benefit rate (≥SD) was 72.5%. Figure 1 illustrates response rates from both cohorts. Median PFS for cohort 1 is 3 months (95% CI 0.5-5.51) and for cohort 2 is 2 months (95% CI 0.8-3.2), respectively. At a median follow-up of 26 months from the time of V initiation, median OS for cohort 1 is 6 months (95% CI 0-13.6) and for cohort 2 is 3 months (95% CI 1.4-4.7). Median overall survival from diagnosis for these cohorts is 80 months (95% CI 70.2-89.8) and 70 (95% CI 55.6-84.4) months, respectively. ≥Grade 3 AEs include fatigue (15%); generalized weakness (12.5%); neutropenia (15%); and thrombocytopenia (35%). Conclusions: In heavily pretreated relapsed/refractory multiple myeloma patients with limited therapeutic options, vorinostat and bortezomib combination therapy offers clinical benefit with good response rates and acceptable tolerability, likely due to lower doses of vorinostat used. This data further supports the activity of HDAC inhibitors in the context of refractory myeloma. Figure 1 Figure 1. Disclosures Gleason: Celgene: Consultancy; Novartis: Consultancy. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document