Pegylated Liposomal Doxorubicin in Salvage Chemotherapy for Multiple Myeloma Patients

2013 ◽  
Vol 9 (1) ◽  
pp. 1-7
Author(s):  
Alessandra Romano ◽  
Giuseppina Uccello ◽  
Paolo Spina ◽  
Rosario Cunsolo ◽  
Calogero Vetro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Salvage Chemotherapy

Pegylated Liposomal Doxorubicin in Salvage Chemotherapy for Multiple Myeloma Patients

2013 ◽  
Vol 9 (1) ◽  
pp. 1-7
Author(s):  
Alessandra Romano ◽  
Giuseppina Uccello ◽  
Paolo Spina ◽  
Rosario Cunsolo ◽  
Calogero Vetro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Salvage Chemotherapy

scholarly journals A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4774-4774
Author(s):  
James R. Berenson ◽  
Laura V. Stampleman ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
Leonard M Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

Bortezomib in Combination with Pegylated Liposomal Doxorubicin for the Treatment of Multiple Myeloma

2007 ◽  
Vol 1 (1) ◽  
pp. 68-73
Author(s):  
Rami Manochakian ◽  
Kena C. Miller ◽  
Asher Alban Chanan-Khan
Keyword(s):  
Multiple Myeloma ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin

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 > 50%) and 5 responses (R > 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.

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.

An Open-Label Study of Pegylated Liposomal Doxorubicin, Vincristine and Reduced-Dose Dexamethasone Combination Therapy in Newly Diagnosed Multiple Myeloma Patients in Chinese Population.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4816-4816
Author(s):  
Yang Shen ◽  
Zhixiang Shen ◽  
Bin Jiang ◽  
Jian Hou ◽  
Rong Zhan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chinese Population ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Combination Regimen ◽  
Newly Diagnosed ◽  
Open Label ◽  
Open Label Study ◽  
Reduced Dose

Abstract BACKGROUND: Pegylated liposomal doxorubicin (CAELYX®) is a liposomal formulation of doxorubicin sterically stabilized by the grafting of segments of polyethylene glycol (PEG) onto the liposomal surface. Given the demonstrated efficacy of VAD (vincristine and doxorubicin and oral dexamethasone) in Multiple Myeloma (MM) patients and the potential for CAELYX® to extend the duration of bone marrow exposure to therapeutic levels of doxorubicin, a combination regimen of CAELYX®, vincristine, and reduced-dose dexamethasone (DVD) has been actively investigated in MM patients. Studies showed that substituting CAELYX® for doxorubicin in the VAD regimen and reducing the dose of dexamethasone in MM patients improves the safety profile and convenience of the treatment regimen without compromising efficacy. Due to potential differences in metabolism of these patients, safety and efficacy results may vary. Thus, we carried out this study in 82 newly diagnosed MM patients in China, in order to demonstrate the efficacy and safety profiles of DVD. METHODS: Patients (n=82) from 15 sites were recruited in this study. CAELYX® (40mg/m2) was infused intravenously over 60-minutes, administered every 28 days. Vincristine (2.0mg) was administered intravenously on Day 1 of each cycle. Dexamethasone (40 mg) was administered from Day 1- Day 4 of each cycle orally or intravenously. The treatment was repeated every 28 days for 4 cycles. RESULTS: Upon ITT analysis, the overall response rate was approximately 68% (56/82); 11% of the patients achieved complete remission (CR), 40% achieved partial response (PR), 17% achieved minimal response; 15% had stable disease (SD), and 12% o had progressive disease (PD) after the treatment. The cumulative 4-month progression-free survival (PFS) was 88%. The incidence of all the adverse events was 46%. The most common non-hematological toxicities were palmar-plantar erythrodysesthesia (13.4%) and stomatitis (6.1%), respectively. CONCLUSION: Pegylated liposomal doxorubicin, vincristine and reduced dose dexamethasone combination (DVD) regimen is an effective and safe regimen in newly diagnosed multiple myeloma patients in Chinese population.

Impact of Baseline Free Light Chain Ratio (rFLC) On Clinical Outcomes and Change in rFLC During Treatment in Patients with Relapsed/Refractory Multiple Myeloma Treated with Pegylated Liposomal Doxorubicin Plus Bortezomib or Bortezomib Alone.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4778-4778
Author(s):  
Valeria Magarotto ◽  
Anil Londhe ◽  
Keith C. Lantz ◽  
Colin Lowery ◽  
Pieter Sonneveld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Outcomes ◽  
Light Chain ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Free Light Chain ◽  
Controlled Study ◽  
Employment Equity ◽  
Ortho Biotech ◽  
Equity Ownership

Abstract Abstract 4778 Background The serum immunoglobulin-free light chain (sFLC) assay measures levels of free κ and » immunoglobulin light chains. In multiple myeloma (MM), similar to other plasma cell dyscrasias, a secretory dysfunction causes an abnormal sFLC (κ/») ratio (rFLC). The rFLC (normal range: 0.26-1.65) is a requirement for documenting stringent complete remission (sCR) and can be a prognostic indicator in newly diagnosed multiple myeloma (Dispenzieri et al. for the International Myeloma Working Group, Leukemia, 2009). As part of a randomized controlled study in MM (Orlowski et al., JCO 2007), we previously have shown that the normalization of rFLC after the first 2 cycles of pegylated liposomal doxorubicin (PLD) + bortezomib (B) or B alone is associated with a prolonged time to progression (TTP) and higher response rate (RR) among patients with relapsed/refractory MM (Orlowski et al., Blood 2007, abstract #2735). In this analysis, we examined how baseline ratios of sFLC impacted clinical outcomes (TTP and RR), and if sFLC ratios changed over the course of treatment in patients receiving PLD + B or B alone. Methods Patients with ≥1 prior therapy were randomized to receive PLD at 30 mg/m2 on day 4 with B at 1.3 mg/m2 on Days 1, 4, 8, and 11, or B alone on this same dose and schedule, 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. Serial serum κ/» measurements were made prior to the start of therapy and at the end of each cycle throughout the entire study using an immunoassay (Freelite, The Binding Sites, Birmingham, UK). Results Sera from 491 patients were available for these analyses: 31 patients (6.3%) had a normal baseline rFLC, while 460 patients (93.6%) had an abnormal baseline rFLC (<0.26 or >1.65). Among patients with a normal baseline rFLC, 14 received B and 17 received PLD + B. The RR (≥partial remission) was 5/14 (35.7%) and 5/17 (29.4%), respectively (P=0.73). Mean TTP was 297 days for B vs. not reached for PLD + B (P=0.93, HR 0.92, CI 95%). In patients with an abnormal baseline rFLC, 232 received B and 228 received PLD + B. The RR was 95/232 (40.9%) and 107/228 (46.9%), respectively (P=0.19). TTP was longer and statistically significant for patients who received PLD + B (282 days) vs. B alone (180 days; P=0.001, HR 1.76, CI 95%). For the overall population, TTP was 297 vs. 218 days (P=0.11, HR 0.51, CI 95%) and RR was 10/31 (32.3%) vs 202/460 (43.9%) for normal vs abnormal baseline rFLC groups, respectively. During the course of therapy, there was a trend for an increase in the percentage of patients in whom the baseline rFLC changed from abnormal to normal (Table). This trend occurred in earlier treatment cycles and reached a plateau in later cycles. When only patients who had completed at least 4 cycles of therapy were examined, the same trend was observed (not shown). Conclusion This study showed a correlation between the baseline rFLC and outcomes (TTP and RR) in patients with relapsed/refractory MM treated with PLD + B or B alone. Similar to the overall study results, combination therapy demonstrated better outcomes over B alone in patients with abnormal rFLC at baseline. Regardless of treatment, patients with normal rFLC at baseline had longer TTP but lower RR than patients with abnormal rFLC at baseline, which was possibly due to the small number of patients with normal rFLC at baseline. Disclosures: Londhe: Centocor Ortho Biotech Services, LLC: Employment, Equity Ownership. Lantz:Centocor Ortho Biotech Services, LLC: Employment. Lowery:Centocor Ortho Biotech Services, LLC: Employment, Equity Ownership. Sonneveld:Johnson & Johnson: Consultancy. Bladé:Johnson & Johnson / Janssen-Cilag: Honoraria; Schering-Plough: Honoraria.

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