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

By John A. Zoidis, MD
Published: Thursday, Jun 10, 2010
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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

1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin. 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.

3. Kyle RA, Gertz MA, Witzig TE, et al: Review of 1,027 patients with newly diagnosed multiple myeloma. Mayo Clin

    Proc
2003;78:21-33.

4. NCCN practice guidelines for multiple myeloma. National Comprehensive Cancer Network. Oncology (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.

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, P = 0.009).


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