In the Journals

Bortezomib-pegylated liposomal doxorubicin combination fails to improve survival in multiple myeloma

The addition of bortezomib to pegylated liposomal doxorubicin did not extend OS in patients with relapsed or refractory multiple myeloma, according to a randomized, phase 3 trial.

Although patients with multiple myeloma usually respond to initial therapy, most will eventually relapse and become refractory to treatment.

“With the advent of new and more effective drugs for the treatment of multiple myeloma, both alone and in combination with established anti-multiple myeloma agents, there is now a rapid increase in the number of therapeutic options available to patients with multiple myeloma, particularly in the relapsed or refractory setting,” Robert Z. Orlowski, MD, PhD, department chair ad interim of the department of lymphoma/myeloma at The University of Texas MD Anderson Cancer Center, and colleagues wrote.

Robert Orlowski

Robert Z. Orlowski

Orlowski and colleagues randomly assigned 645 patients with relapsed or refractory multiple myeloma who had previously received one or more lines of therapy to receive IV 1.3 mg/m² bortezomib (Velcade, Takeda/Millennium) alone (days 1, 4, 8 and 11 of every 21-day cycle; n = 322) or with IV pegylated liposomal doxorubicin (30 mg/m2 on day 4; n = 324).

An interim analysis of the study demonstrated that the bortezomib-pegylated liposomal doxorubicin combination reduced the risk for disease progression by 45%, prolonged the median time to progression by 3 months and showed an early OS benefit (HR = 1.41; 95% CI, 1-1.97).

The protocol-defined, long-term survival analysis occurred after a median follow-up of 8.6 years.

During that time, 78% of patients assigned the combination therapy and 80% assigned bortezomib monotherapy died.

Median OS was 33 months in the combination arm compared with 30.8 months in the monotherapy arm, which was not statistically different (HR = 1.04; 95% CI, 0.88-1.25).

Many patients in the combination and monotherapy arms received salvage therapy, the most common of which included dexamethasone (47% vs. 51%), thalidomide (Thalomid, Celgene; 31% vs. 31%), cyclophosphamide (26% vs. 31%), melphalan (24% vs. 22%), lenalidomide (Revlimid, Celgene; 23% vs. 21%), bortezomib (23% vs. 18%) and doxorubicin (6% vs. 11%).

“The inability to sustain the observed early survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect differences in long-term OS,” Orlowski and colleagues wrote.

Sagar Lonial, MD

Sagar Lonial

Combinations of two novel agents for multiple myeloma may have better efficacy than novel agents combined with cytotoxic drugs due to their “alternate mechanisms of additive/synergistic cell death and overpowering potential resistant clones,” Ajay K. Nooka, MD, MPH, assistant professor of hematology and medical oncology at Winship Cancer Institute at the Emory University School of Medicine, and Sagar Lonial, MD, professor and chair of the department of hematology and medical oncology at Winship Cancer Institute, as well as a HemOnc Today Editorial Board member, wrote in an accompanying editorial.

“Combining cytotoxic agents and even novel agent cytotoxic agent combinations have failed us in the past and continue to fail us now,” they wrote. “Although we bid farewell to the routine use of cytotoxic combinations in patients with relapsed myeloma, it is time to realize that not all combination therapies have the same efficacy, and the agents in the combinations do matter.” – by Kristie L. Kahl

Disclosures: Orlowski reports research funding, personal fees and grants from Abbott Laboratories, Amgen, Array BioPharma, Bio-Theryx, Bristol-Myers Squibb, Celgene, Cephalon, Forma Therapeutics, Genentech, Incyte, Janssen-Cilag, Janssen Research and Development, Millennium Pharmaceuticals, Novartis, Onyx Pharmaceuticals and Spectrum Pharmaceuticals. Nooka reports personal fees from Novartis, Onyx and Spectrum Pharmaceuticals. Lonial reports personal fees from Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis and Onyx. Please see the full study for a list of all other researchers’ relevant financial disclosures.

The addition of bortezomib to pegylated liposomal doxorubicin did not extend OS in patients with relapsed or refractory multiple myeloma, according to a randomized, phase 3 trial.

Although patients with multiple myeloma usually respond to initial therapy, most will eventually relapse and become refractory to treatment.

“With the advent of new and more effective drugs for the treatment of multiple myeloma, both alone and in combination with established anti-multiple myeloma agents, there is now a rapid increase in the number of therapeutic options available to patients with multiple myeloma, particularly in the relapsed or refractory setting,” Robert Z. Orlowski, MD, PhD, department chair ad interim of the department of lymphoma/myeloma at The University of Texas MD Anderson Cancer Center, and colleagues wrote.

Robert Orlowski

Robert Z. Orlowski

Orlowski and colleagues randomly assigned 645 patients with relapsed or refractory multiple myeloma who had previously received one or more lines of therapy to receive IV 1.3 mg/m² bortezomib (Velcade, Takeda/Millennium) alone (days 1, 4, 8 and 11 of every 21-day cycle; n = 322) or with IV pegylated liposomal doxorubicin (30 mg/m2 on day 4; n = 324).

An interim analysis of the study demonstrated that the bortezomib-pegylated liposomal doxorubicin combination reduced the risk for disease progression by 45%, prolonged the median time to progression by 3 months and showed an early OS benefit (HR = 1.41; 95% CI, 1-1.97).

The protocol-defined, long-term survival analysis occurred after a median follow-up of 8.6 years.

During that time, 78% of patients assigned the combination therapy and 80% assigned bortezomib monotherapy died.

Median OS was 33 months in the combination arm compared with 30.8 months in the monotherapy arm, which was not statistically different (HR = 1.04; 95% CI, 0.88-1.25).

Many patients in the combination and monotherapy arms received salvage therapy, the most common of which included dexamethasone (47% vs. 51%), thalidomide (Thalomid, Celgene; 31% vs. 31%), cyclophosphamide (26% vs. 31%), melphalan (24% vs. 22%), lenalidomide (Revlimid, Celgene; 23% vs. 21%), bortezomib (23% vs. 18%) and doxorubicin (6% vs. 11%).

“The inability to sustain the observed early survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect differences in long-term OS,” Orlowski and colleagues wrote.

Sagar Lonial, MD

Sagar Lonial

Combinations of two novel agents for multiple myeloma may have better efficacy than novel agents combined with cytotoxic drugs due to their “alternate mechanisms of additive/synergistic cell death and overpowering potential resistant clones,” Ajay K. Nooka, MD, MPH, assistant professor of hematology and medical oncology at Winship Cancer Institute at the Emory University School of Medicine, and Sagar Lonial, MD, professor and chair of the department of hematology and medical oncology at Winship Cancer Institute, as well as a HemOnc Today Editorial Board member, wrote in an accompanying editorial.

“Combining cytotoxic agents and even novel agent cytotoxic agent combinations have failed us in the past and continue to fail us now,” they wrote. “Although we bid farewell to the routine use of cytotoxic combinations in patients with relapsed myeloma, it is time to realize that not all combination therapies have the same efficacy, and the agents in the combinations do matter.” – by Kristie L. Kahl

Disclosures: Orlowski reports research funding, personal fees and grants from Abbott Laboratories, Amgen, Array BioPharma, Bio-Theryx, Bristol-Myers Squibb, Celgene, Cephalon, Forma Therapeutics, Genentech, Incyte, Janssen-Cilag, Janssen Research and Development, Millennium Pharmaceuticals, Novartis, Onyx Pharmaceuticals and Spectrum Pharmaceuticals. Nooka reports personal fees from Novartis, Onyx and Spectrum Pharmaceuticals. Lonial reports personal fees from Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis and Onyx. Please see the full study for a list of all other researchers’ relevant financial disclosures.