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Pegylated Liposomal Doxorubicin (Doxil) and Drug Combinations in Multiple Myeloma

OBTN, June 2008, Volume 2, Issue 6

Current treatment approaches for mutiple myeloma focus on improving progression-free and overall survival. Although five-year survival rates have increased significantly over the past ten years, the prognosis of the disease is generally poor. The availability of several promising new therapies offers clinicians treatment options to further improve response rates, especially through the development of new combination regimens.

An Overview of Clinical Studies Presented at the American Society of Hematology’s 49th Annual Meeting

An estimated 19,900 new cases of multiple myeloma (MM) were diagnosed in the United States in 2007, and nearly 11,000 died from the disease during the year.1 Although five-year survival rates have increased significantly over the past 10 years (with median survival increasing from approximately 2—3 years in 1998 to approximately 5–7 years in 2005), the prognosis of the disease is generally poor.1—3 The availability of several promising new therapies offers clinicians treatment options to further improve response rates, especially through the development of new combination regimens.

Current treatment approaches for MM focus on improving progression-free and overall survival. Generally, treatment is selected based on whether there is a need for immediate action and whether the individual patient is an appropriate candidate for high-dose chemotherapy and stem-cell transplantation.4 Recently, studies with novel agents such as bortezomib (Velcade) or the immunomodulatory drugs thalidomide and lenalidomide have shown promise in improving overall response rates when combined with dexamethasone. The following four studies, which discuss pegylated liposomal doxorubicin (PLD) (Doxil) in combination with bortezomib, were presented at this year’s 49th ASH Annual Meeting in Atlanta in December 2007.

PLD is a unique doxorubicin formulation in which a polyethylene glycol layer surrounds a doxorubicin-containing liposome. The pegylation process protects the liposome from detection by the immune system, thereby increasing the plasma half-life relative to conventional doxorubicin. Use of the PLD formulation provides several advantages. First, the extended half-life prolongs drug exposure of tumor cells, mimicking continuous infusion. This prolonged cellular exposure with PLD (combined with the slow rate of myeloma cell division) has been suggested to overcome multidrug- resistance—gene overexpression within plasma cells, thereby increasing antitumor potential and improving clinical response. Also, the size of the doxorubicin-containing vesicles allows leakage of the drug through the abnormally permeable tumor vessels, resulting in preferential concentration of doxorubicin at the tumor sites. In addition, PLD appears to have an improved cardiac safety profile compared with that of the conventional formulation.

The landscape of MM treatment continues to evolve as research results accumulate from trials of conventional and new therapies and from studies on risk factors and side effects.

References

Cancer J Clin.

1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA 2007; 57:43-66.

2. Durie BG. New approaches to treatment for multiple myeloma: Durable remission and quality of life as primary goals.

Clin Lymphoma Myeloma

2005;6:181-190.

Mayo Clin

Proc

3. Kyle RA, Gertz MA, Witzig TE, et al: Review of 1,027 patients with newly diagnosed multiple myeloma. 2003;78:21-33.

Oncology

4. NCCN practice guidelines for multiple myeloma. National Comprehensive Cancer Network. (Williston Park)

1998;12:317-351.

Pegylated Liposomal Doxorubicin in Combination With Bortezomib May Provide Therapeutic Advantage for High-Risk Multiple Myeloma Patients Relapsing Within 12 Months of Stem-Cell Transplantation

Shaji Kumar, MD, Division of Hematology, Mayo Clinic, Rochester, Minnesota, presented results of a retrospective analysis of a large, phase III study (DOXIL-MMY3001; please see reference below), which demonstrated that the combination of pegylated liposomal doxorubicin (PLD) (Doxil) plus bortezomib (Velcade) improved time to progression (TTP), compared with B monotherapy, in patients with multiple myeloma (MM) who relapse within 12 months of autologous stem-cell transplantation (SCT).

The present analysis examined the 12-month post-randomization survival of 646 patients who had early (<12 months) vs late (≥12 months) relapse following SCT, as well as the effect of PLD plus bortezomib vs bortezomib alone in patients who had relapsed early. Patients received intravenous bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle with or without PLD, or the same bortezomib regimen with PLD 30 mg/m2 on day 4.

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Of the 359 patients who had previously received SCT, 114 (32%) relapsed within 12 months. The median age, gender distribution, time from diagnosis at trial enrollment, baseline measures of disease burden (M-Protein levels and B2M), and renal function were comparable between the early- and laterelapse groups. There was no difference in overall response rates (complete partial response [CR PR]) or very good partial response (VGPR) rates between the two groups, or between treatment arms within each group. There was no significant difference in TTP between early- vs late-relapse groups (hazard ratio = 0.94). Twelve-month survival from randomization was significantly lower in the early-relapse group compared with that in the late-relapse group (83% vs 92% respectively, = 0.009).

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However, within the early-relapse group, the 12-month post-randomization survival rate was significantly superior following treatment with PLD plus bortezomib compared with that in the group receiving bortezomib alone (52 of 56 patients [93%] vs 43 of 58 patients [74%] respectively, = 0.01). Correspondingly, TTP was better in the group treated with PLD plus bortezomib, compared with that in the group receiving bortezomib alone (276 days vs 205 days, respectively, = 0.13). Overall, the toxicity profiles of the combination regimen and bortezomib monotherapy were comparable regardless of early or late relapse following SCT.

According to the conclusions of study researchers, these results demonstrate that the combination of PLD plus bortezomib may provide an important therapeutic advantage for high-risk MM patients who experience early relapse following SCT.

Reference

J Clin Oncol

Orlowski RZ, Nagler A, Sonneveld P, et al: 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;25:3892-3901.

Pegylated Liposomal Doxorubicin Plus Bortezomib Yields Improved Time-to-Progression vs. Bortezomib Alone in Patients With Relapsed or Refractory Multiple Myeloma and High-Grade or Protracted Disease

post-hoc

A recently reported phase III randomized trial comparing pegylated liposomal doxorubicin (PLD) (Doxil) plus bortezomib (Velcade) with bortezomib alone in relapsed or refractory multiple myeloma (MM) demonstrated improved time to progression (TTP) with the combination regimen (please see reference below). Following-up on this report, Heather J. Sutherland, MD, Department of Medicine, University of British Columbia, Vancouver, BC, Canada, presented the results of a analyses evaluating the efficacy of PLD plus bortezomib according to International Staging System (ISS) disease stage, and time since initial myeloma diagnosis (TSD).

Patients with at least one 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 two cycles beyond complete response (CR), or optimal response unless disease progression or unacceptable toxicities occurred.

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The improved TTP reported previously with PLD plus bortezomib over bortezomib alone in the total study population was also observed in the higher-risk groups based on disease stage (ISS 2 and 3). TTP was also significantly longer with PLD plus bortezomib compared with bortezomib alone for TSD of >2 years despite more protracted disease. The therapeutic advantage of prolonged TTP with the PLD plus bortezomib combination was maintained consistently across subgroups (heterogeneity tests: ISS 1 vs. 2 vs. 3, = 0.407; TSD ≤2 years vs. TSD >2 years, = 0.946).

The incidence of grade 3/4 neuropathies was low (<10%) in the two treatment arms in all subgroups. The incidence of PLD-related hand—foot syndrome was also <10% in all PLD-plus- bortezomib subgroups.

Results of the analysis demonstrated that, despite high-grade disease or protracted disease history, the PLD-plus-bortezomib combination shows significantly improved TTP compared with bortezomib alone. In addition, the combination therapy was shown to be well tolerated.

Reference

J Clin Oncol

Orlowski RZ, Nagler A, Sonneveld P, et al: 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;25:3892-3901.

Early Normalization of Serum Free Light Chain Is Associated With Prolonged Time to Progression Following Bortezomib With or Without Pegylated Liposomal Doxorubicin Treatment of Relapsed or Refractory Multiple Myeloma

Robert Orlowski, MD, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, presented the results of a randomized, controlled study examining the association between normalization of the κ/λ ratio after one or two 21-day cycles of treatment with bortezomib (Velcade) with or without pegylated liposomal doxorubicin (PLD) (Doxil) among patients with relapsed or refractory multiple myeloma (MM).

Multiple myeloma, like other monoclonal gammopathies, frequently causes impairment of the κ/λ serum free light chain (sFLC) ratio. Based on a short half-life of sFLC as compared with the complete immunoglobulin (hours vs. days), early normalization of κ/λ could predict treatment response.

Patients with at least one prior therapy were randomized to receive PLD 30 mg/m2 on day 4 and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least two cycles beyond complete response (CR) or optimal response, unless disease progression or unacceptable toxicities occurred (please see reference below). The κ/λ measurements were carried out before 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 enrollees).

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At baseline, 458 of 487 patients (94%) had an abnormal κ/λ ratio (<0.26 or >1.65). The percentage of patients with a 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 with 225 days in patients with an abnormal ratio after cycle 1 (N = 395, = 0.0005, HR=0.47). Following cycle 2, TTP was 325 days vs. 224 days ( ≤ 0.001) in patients with normal (N = 72) vs abnormal (N = 348) ratios, respectively.

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In addition, patients with normalized sFLC ratios showed significantly greater overall response rates as compared with those with persistently abnormal ratios (≥ partial response [PR], 73% vs. 47%, [ = 0.001] following cycle 1, and 77% vs. 48%, [ < 0.0001] following cycle 2, respectively). Similarly, CR plus very good partial response (VGPR) rates were significantly greater among patients with normalized sFLC ratios after cycles 1 and 2 ( < 0.0001 and < 0.001, respectively). As reported previously, both treatment regimens—the combination of, PLD plus bortezomib and bortezomib alone— were well tolerated (please see reference below).

This study demonstrated that normalization of the sFLC ratio as early as after cycle 1 of either PLD plus bortezomib or bortezomib alone was associated with a prolonged TTP and greater response rates.

Reference

J Clin Oncol

Orlowski RZ, Nagler A, Sonneveld P, et al: 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;25:3892-3901.

Prolonged Time to Progression with Pegylated Liposomal Doxorubicin Plus Bortezomib With Bortezomib Alone in Relapsed or Refractory Multiple Myeloma Unaffected by Extent of Prior Therapy or Previous Anthracycline Exposure

Joan Blade, MD, Hospital Clinic i Provincial, Barcelona, Spain, presented alpha-prespecified analysis that assessed the efficacy of pegylated liposomal doxorubicin (PLD) (Doxil) plus bortezomib (Velcade) in relapsed or refractory multiple myeloma (MM) based on the number of prior lines of therapy and previous anthracycline exposure status.

Patients with at least one 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 two cycles beyond complete response (CR), or optimal response unless disease progression or unacceptable toxicities occurred. The baseline beta-2 microglobulin levels were comparable between the subgroup with 2 or more prior treatments and that with 1 prior 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).

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The improved time to progression (TTP) reported previously with PLD plus bortezomib vs. bortezomib alone in the total study population of patients with relapsed or refractory MM (please see reference below) was similarly observed in all four subgroups of patients (patients with ≥2 lines of prior therapy, those with 1 line of prior therapy, anthracycline-exposed patients, and anthracycline-naïve patients), indicating a consistent therapeutic benefit favoring the PLD-plusbortezomib combination. Furthermore, TTP was comparable between the PLD-plus-bortezomib combination between the groups with ≥2 lines of prior therapy and those with 1 line of prior therapy ( = 0.523), as well as between those who were anthracycline-exposed or -naïve ( = 0.716). The incidence of treatment-related serious adverse events, grade 3/4 neuropathy, and symptomatic cardiac events was comparable between treatment arms in each subgroup. The incidence of PLD-related hand—foot syndrome was also <10% in all PLD-plus-bortezomib subgroups.

These results demonstrate that combination therapy with PLD plus bortezomib significantly improves TTP compared with bortezomib alone, regardless of the number of prior lines of therapy, or anthracycline exposure.

Reference

J Clin Oncol

Orlowski RZ, Nagler A, Sonneveld P, et al: 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;25:3892-3901.