Anthracyclines Survive Targeted Therapy

In this issue of ONCOLOGY, Ning and colleagues at the US Food and Drug Administration (FDA) provide the approval summary for doxorubicin HCl liposome (liposomal doxorubicin; Doxil) in combination with bortezomib (Velcade) in patients with relapsed or refractory myeloma who have received at least one prior therapy with a non–bortezomib-containing chemotherapy regimen. The FDA approval was based on one phase III open-label, randomized, multicenter trial of liposomal doxorubicin plus bortezomib vs bortezomib monotherapy. This study showed a significant improvement in time to disease progression of 9.3 months in the combination arm compared to 6.5 months with bortezomib monotherapy. Although the response rate was similar, and overall survival data are preliminary, it was felt that the 3-month absolute improvement in time to progression was relevant in this study population.

There is currently no curative therapy available for multiple myeloma, and most patients typically receive an average of four different regimens during the course of their disease. The treatment of multiple myeloma has received a significant boost over the past decade with the introduction of more targeted and less toxic agents. Despite this, relapsed and refractory disease continues to be a major problem. In vitro data have shown synergy between the newer targeted therapies and some traditional chemotherapy drugs.[1] There are therefore many clinical trials investigating the optimal approach to combining conventional chemotherapeutic agents and new agents such as bortezomib and lenalidomide (Revlimid).

 Evolving Role of Doxorubicin

Although as single agents anthracyclines have minimal efficacy in multiple myeloma (with response rates of only about 5% to 10%), they have been employed in several combination chemotherapy regimens used to treat the disease for many years. For example, doxorubicin is an integral part of the VAD regimen (vincristine, doxorubicin [Adriamycin], dexamethasone), which until 5 years ago was one of the most commonly used initial therapies for myeloma in patients eligible for stem-cell transplantation.[2] The use of VAD diminished greatly after the introduction of oral thalidomide (Thalomid) plus dexamethasone, mainly due to concerns about vincristine-induced neuropathy and the cumbersome nature of the regimen, which requires continuous intravenous infusion.

Liposomal doxorubicin has shown activity in myeloma both as a single agent and in combination with other drugs (VDD [vincristine, doxorubicin, dexamethasone]).[3,4] Liposomal doxorubicin may be less cardiotoxic compared with doxorubicin, and may be more active in myeloma.

Following the promising activity seen in uncontrolled phase I/II investigations, Orlowski et al studied the role of liposomal doxorubicin in combination with bortezomib in patients with relapsed or refractory myeloma in this pivotal trial.[5] The median time to progression was 6.5 months for bortezomib vs 9.3 months with the liposomal doxorubicin plus bortezomib combination. Although the combination arm had greater toxicity, most adverse events were manageable and did not significantly affect treatment.

This is the first randomized study to demonstrate the benefit of anthracyclines in myeloma. Although the improvement in time to progression is modest, it is of clinical significance, particularly when one considers the nature of the patient population studied. Evidence suggests a positive correlation between time to progression and overall survival in multiple myeloma, but in many recent trials it has become difficult to document improvements in overall survival because of crossover. In this regard, the interim overall survival results reported by Orlowski et al, showing a 15-month survival rate of 76% with liposomal doxorubicin plus bortezomib vs 65% for bortezomib alone (P = .03), should not be overlooked.[5]

 Clinical Implications

What is the role of this new regimen in clinical practice? In our opinion, the regimen may have particular value in patients with aggressive relapse, such as those relapsing within 12 months of stem-cell transplantation in whom emerging data suggest that this combination may have more activity than bortezomib alone (Shaji Kumar, MD, personal communication). Liposomal doxorubicin can also be combined with other active antimyeloma agents, such as lenalidomide and thalidomide, but more data are needed to determine the specific additive value of the drug in such settings. There is no standard approach to the treatment of relapsed refractory myeloma, and in general it is better to enroll such patients in clinical trials.

In this era of targeted therapy, the role of older traditional chemotherapy drugs in combination with novel drugs should be evaluated further. These combinations tend to have more side effects, but the improvement in response rates, time to progression, and overall survival may justify their continued use-as has already been demonstrated with regimens such as MPT (melphalan [Alkeran], prednisone, thalidomide) and MPV (melphalan, prednisone, bortezomib).

-Francis K. Buadi, MD
-S. Vincent Rajkumar, MD

References:

1. Mitsiades N, Mitsiades CS, Richardson PG, et al: The proteasome inhibitor ps-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: Therapeutic applications. Blood 101:2377-2380, 2003.

2. Barlogie B, Smith L, Alexanian R: Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310:1353-1356, 1984.

3. Hussein MA, Wood L, Hsi E, et al: A phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer 95:2160-2168, 2002.

4. Mohrbacher AF, Gregory SA, Gabriel DA, et al: Liposomal daunorubicin (daunoxome) plus dexamethasone for patients with multiple myeloma. A phase II international oncology study group study. Cancer 94:2645-2652, 2002.

5. 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. J Clin Oncol 25:3892-3901, 2007.