Although upfront therapy can achieve remission in multiple myeloma, most patients will ultimately relapse. Newer targeted therapies and genomic analysis are moving the management of relapsed/refractory multiple myeloma forward, according to Kenneth C. Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Center/Brigham and Women’s Cancer Center, and Kraft Family Professor of Medicine, Harvard Medical School, Boston. Dr. Anderson discussed management of relapsed/refractory multiple myeloma at the National Comprehensive Cancer Network (NCCN) 8th Annual Congress on Hematologic Malignancies, held recently in New York.1
Decade of Progress
“There are many protocols of novel immune and targeted agents that show promise alone and in combination. Genomic analyses are both defining the basis for evolution of disease leading to relapse and identifying new targets for therapeutic approaches,” he explained.
Over the course of the past decade, progress has come from U.S. Food and Drug Administration (FDA) approval of bortezomib (Velcade), lenalidomide (Revlimid), thalidomide (Thalomid), liposomal doxorubicin, carlfilzomib (Kyprolis), and pomalidomide (Pomalyst) in the treatment of multiple myeloma.
“These drugs were first tested in advanced and relapsed disease, but more recently have shown efficacy as initial, consolidation, and maintenance therapy. These drugs target both the tumor and the microenvironment and can overcome resistance to conventional therapies,” Dr. Anderson said.
Experience has shown that bortezomib, the first proteasome inhibitor to be FDA-approved for multiple myeloma, can be given more safely once a week in a subcutaneous administration, instead of twice a week with intravenous administration. This strategy retains the efficacy of the drug, but causes significantly less peripheral neuropathy.
Newest Drug Approvals
Carlfilzomib and pomalidomide are the most recent drugs to be granted accelerated FDA approval for multiple myeloma. Carlfilzomib has improved antitumor activity with consecutive-day dosing and does not cause neurotoxicity in animal models. Durable responses lasting 8 months have been reported in relapsed/refractory multiple myeloma patients without attendant peripheral neuropathy.
“These findings were in patients who had run out of other options,” Dr. Anderson said.
Going forward, the ASPIRE trial, which is now fully enrolled, is evaluating the combination of carlfilzomib with lenalidomide and dexamethasone in relapsed multiple myeloma.2 Moreover, overall response rate after 12 cycles of carfilzomib, lenalidomide, and dexamethasone as initial treatment was 100%, with an 80% rate of complete response or near-complete response.
Pomalidomide, the second new drug recently approved, is a potent stimulator of autologous T cells and natural killer cells. The drug directly targets regulatory T cells and enhances the immune response. Pomalidomide with low-dose dexamethasone is now FDA-approved for treatment of relapsed/refractory multiple myeloma. The triple combination of pomalidomide/bortezomib/low-dose dexamethasone shows promise, with a 73% response rate in relapsed multiple myeloma, including rapid and ongoing responses even in patients with adverse cytogenetic features. This triple combination is being studied in a phase III trial.
Experience shows that second-generation drugs are difficult, if not impossible, to dose-escalate, he continued. “These agents are stronger than first-generation agents, and it is difficult to escalate and maintain a therapeutic index,” Dr. Anderson said. “Although we have made progress to date, patients still relapse and new treatments are therefore urgently needed,” he added.
Novel Approaches
Elotuzumab and daratumumab are two monoclonal antibodies being evaluated in multiple myeloma. Dr. Anderson expects FDA approval of a three-drug regimen of elotuzumab, lenalidomide, and dexamethasone in the future, and early studies of daratumumab are ongoing.
A promising immune approach entails a vaccine that fuses a patient’s own myeloma cells with their dendritic cells. This strategy triggered an anti-myeloma immune response and disease stabilization in 70% of patients with relapsed/refractory myeloma.3
New proteasome inhibitors and new immunomodulatory drugs are also under study.
Patients who don’t respond to bortezomib may respond to new agents that include the chymotryptic oral proteasome inhibitors ixazomib and oprozamib, Dr. Anderson noted. Marizomib is a broader proteasome inhibitor that has also achieved response rates in advanced multiple myeloma, even in the setting of bortezomib/lenalidomide resistance.
Two new classes of drug under investigation for multiple myeloma include Bruton’s tyrosine kinase inhibitors and BET bromodomain inhibitors. Experimental studies of these agents show promising activity, and they are being studied clinically. Finally, combinations such as proteasome inhibitors with histone deacetylase inhibitors are demonstrating promise.
Genomic Studies
“In multiple myeloma, whole-genome sequencing has identified mutations consistent with myeloma cell biology. A new and surprising finding is that BRAF mutations found in malignant melanoma were also present in 4% of multiple myeloma patients,” Dr. Anderson told the audience. Preliminary studies of BRAF inhibitors in multiple myeloma patients with this mutation have achieved responses.
“We have learned [from genomic sequencing] that a newly diagnosed multiple myeloma patient has multiple abnormalities, various mutations, and marked clonal heterogeneity even at the outset. As the disease evolves, the situation becomes more complex, with new mutations, copy number changes, and translocations occurring. When we talk about personalized medicine, we need to characterize genomics not only at the time of diagnosis, but also at the time of relapse. We should learn from our lymphoma colleagues and use drug combinations at the outset to prevent resistance from developing,” Dr. Anderson stated.
“Once we have defined active combination novel targeted therapies, we will need to move to very early in the disease to make an impact on outcomes,” he noted. ■
Disclosure: Dr. Anderson is on the advisory board for Millennium Takeda.
References
1. Anderson KC: Management of relapsed/refractory multiple myeloma. NCCN 8th Annual Congress: Hematologic Malignancies. Presented September 21, 2013.
2. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012.
3. Rosenblatt J, Vasir B, Uhl L, et al: Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood 117:393-402, 2011.
