Responding to the assertion that bortezomib (Velcade)/lenalidomide (Revlimid)/low-dose dexamethasone induction followed by continuous lenalidomide/dexamethasone is potentially a new standard of care in newly diagnosed multiple myeloma, Sagar Lonial, MD, Chief Medical Officer of Winship Cancer Institute of Emory University and Professor of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta, agreed, suggesting that the triple regimen of a proteasome inhibitor, immunomodulatory drug, and steroid has “come of age” as the best initial treatment.
“In my view, the take-home message from ASH 2015 is that three-drug induction is optimal, and the [immunomodulatory drug]/proteasome inhibitor combination is likely the best regimen to use in newly diagnosed patients,” he said.
Dr. Lonial commented that with the results of SWOG S0777, “We have now established in the induction therapy setting that three drugs are better than two, for most patients across the board.” Essentially the only persons who might be exceptions to this new standard are frail patients, he added.
In contrast to some earlier studies of different drugs, triplets of novel agents have now been shown in a large randomized trial to significantly improve response rates, progression-free survival, and overall survival, he said.
Synergistic Combinations
“In the era of novel agents, we now have the ability to give non–cross-resistant drugs in synergistic combinations,” he said.
Combinations of immunomodulatory drugs and proteasome inhibitors lead to deeper and more durable responses and also add benefit by potentially suppressing resistant clones. At the time of diagnosis, the average myeloma patient has approximately 60 different mutations, and this number only increases as the disease worsens. Resistant clones may thrive under the weaker power of sequential therapy, but they can be squelched with combinations that work through different mechanisms of action, he said.
In addition to the existence of mutations at diagnosis, genomic instability and the existence of subclones are at play from the start. With subsequent lines of treatment, this genomic instability and the number of subclones grow—and this is true not only for patients with high-risk cytogenetics but also for some standard-risk patients. High-risk patients, however, do especially benefit from triplets, which appear to overcome negative adverse features, such as the t(4;14) translocation, he pointed out.
“This pushes the idea of using combination therapy to attack the genomically unstable, clonally heterogeneous disease at the time of initial presentation,” he concluded. “The best shot of eliminating or suppressing the disease is at the very beginning.… It’s the best way to embark on curative or suppressive therapy.”
Cautionary Notes
While Dr. Lonial said that he might combine three to five drugs, he does not use novel agents in combination with chemotherapy. “This does not enhance efficacy; it only enhances toxicity,” he cautioned.
He also emphasized that the triplet he advocates involves an immunomodulatory drug, proteasome inhibitor, and dexamethasone. While the combination regimen of cyclophosphamide, bortezomib, and dexamethasone may be less expensive, he acknowledged, it is not the optimal triplet. ■
Disclosure: Dr. Lonial is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx, and Janssen.
