Continued Progress in Treatment Options for Multiple Myeloma: From Past to Present and Future

This article is a review of Liposomal Doxorubicin(Drug information on doxorubicin) in Combination With Bortezomib(Drug information on bortezomib) for Relapsed or Refractory Multiple Myeloma

Following an era when a limited number of effective treatment options conferred poor outcome for almost all those diagnosed with multiple myeloma, the past 10 years have seen a dramatic improvement in prognosis following the introduction of a range of novel therapies.[1] On the one hand, the underlying genomic complexity of multiple myeloma has become increasingly understood,[2,3] and on the other, studies of the interaction of multiple myeloma cells in the bone marrow microenvironment have provided vital insights into disease biology.[4,5] Stromal cells, extracellular matrix proteins, and multiple cytokine pathways provide key mechanisms that support multiple myeloma tumor survival, proliferation, and drug resistance,[5,6] and in turn represent intriguing targets for novel therapies.

New Agents

The advent of thalidomide(Drug information on thalidomide) (Thalomid) as an effective treatment for relapsed and refractory multiple myeloma,[7] followed by its rapid incorporation into combination strategies,[8] ultimately led to its approval with high-dose dexamethasone(Drug information on dexamethasone) in the front-line setting.[9-11] Then, investigations with bortezomib (Velcade)[12] as a paradigm of new drug development in multiple myeloma resulted in its accelerated approval in 2003 for relapsed, refractory disease[13] and full approval in first relapse in 2005.[14,15] With these agents, the number of drugs available to clinicians to treat multiple myeloma effectively doubled. The approval of lenalidomide (Revlimid) in combination with dexamethasone for relapsed disease followed shortly thereafter,[16,17] and now the approval of liposomal doxorubicin (Doxil) in combination with bortezomib for relapsed or refractory multiple myeloma[18] constitutes the fourth approval in as many years.

This progress reflects a remarkable series of events that have collectively led to a dramatic improvement in outlook for our patients. First, the paradigm of bench-to-bedside development of novel agents has become clearly established, and second, the extraordinary partnership between academia, pharma, patient advocacy, the National Institutes of Health/National Cancer Institute, and the US Food and Drug Administration has resulted in the rapid approval of new drugs for the treatment of an incurable malignancy for which there has been an urgent unmet medical need.[19]

Large Body of Research

Under the leadership of Dr. Richard Pazdur, Dr. Yang-Min Ning and colleagues present in their approval summary a highly concise and informative paper that encompasses a large body of work. First, the observation that bortezomib in preclinical in vitro models could potently sensitize myeloma cells to anthracyclines (doxorubicin) or alkylating agents—even in cases of myeloma cells resistant to either of these drug classes given alone[20,21]—led to the rapid translation through phase I/II clinical studies of the combination, showing its ability to overcome resistance in patients with manageable toxicity, and establishing an appropriate dose and schedule for the two agents.[22]

This was followed by the pivotal phase III international study described herein and led by Dr. Robert Orlowski and colleagues, which compared the efficacy and safety of a combination of pegylated liposomal doxorubicin plus bortezomib with bortezomib monotherapy in patients with relapsed and refractory multiple myeloma.[18] A total of 646 patients were randomly assigned to receive bortezomib (1.3 mg/m²) on days 1, 4, 8, and 11 per 21-day cycle or the same bortezomib regimen with pegylated liposomal doxorubicin given at 30 mg/m² on day 4. The median time to progression (the primary endpoint of this study) was increased from 6.5 months for bortezomib alone to 9.3 months with the pegylated liposomal doxorubicin plus bortezomib combination (P = .00004). Moreover, the 15-month survival rate for the combination was also significantly superior to that for bortezomib alone.

At the time of submission of this study at interim analysis, the complete-plus-partial response rate for monotherapy vs the combination was not significantly different. However, further analysis has confirmed superiority,[18] an observation supported in the initial analysis, where responding patients were shown to have a longer median duration of response with the combination at 10.2 months, compared to 7 months with bortezomib alone.

It is important to note that adverse reactions occurred more frequently with the combination therapy. As compared to bortezomib alone, more frequent grade 3/4 adverse reactions with the combination included neutropenia and thrombocytopenia. Additional frequent all-grade adverse reactions also included anemia, fatigue, pyrexia, nausea, vomiting, diarrhea, mucositis, and hand-foot syndrome. However, there was no significant increase in the rate of heart failure, which remained low at 3% in both groups. Furthermore, rates of peripheral neuropathy were not significantly different and remained manageable in both arms. The absence of any thrombosis and the ability of a steroid-sparing regimen to prove highly active were observations especially relevant to current practice.[18]