Hollywood, FL—The National Comprehensive Cancer Network (NCCN) Panel for Multiple Myeloma reported its annual update to the NCCN Clinical Practice GuidelinesTM at the 2012 NCCN Conference.
Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston, who chairs the NCCN myeloma panel, and panel member William Bensinger, MD, of Fred Hutchinson Cancer Research Center, Seattle, WA, reported only minor changes, but put these into context for the clinicians in attendance.
“It really is a new world in multiple myeloma,” said Dr Anderson. “Whether patients are young or old, they all benefit from novel therapies in combination, and we are learning how to use them in the induction, transplant, and maintenance settings. Our hope is that with continued progress, multiple myeloma will be a chronic illness, with sustained complete responses achieved by a significant fraction of patients.”
According to Dr Anderson and Dr Bensinger, the key take-home messages were:
- Novel drug combinations have become the standard of care for newly diagnosed transplant-eligible patients
- High-dose melphalan, followed by autologous transplant, improves depth of remission, regardless of induction regimens, and this translates into prolonged remissions
- After transplant, maintenance with lenalidomide prolongs remission
- Patients who are ineligible for transplant also derive survival benefits from novel drugs combined with older agents
- Novel agents with different mechanisms of action represent the future treatment of myeloma.
Initial Treatment Recommendations
Optimal treatment remains predicated on the patient’s disease stage, cytogenetic profile, and eligibility for autologous stem-cell transplant (ASCT). “I want to underscore the importance of cytogenetics and fluorescence in situ hybridization as part of the evaluation of new patients per the NCCN guidelines. I emphasize this because we still see patients who come for consultation who have not had these tests done,” said Dr Bensinger.
Patients who are eligible for transplant remain fortunate, because transplant “does add value in terms of major responses,” Dr Bensinger said. “Even with a suboptimal regimen you can upgrade responses with transplant. Regardless of whether patients achieve a complete response, there appears to be an advantage for transplant in terms of progression-free survival [PFS],” he noted.
Transplant eligibility is based on physiologic age, performance status, and comorbidities. The NCCN guidelines have been updated to list “preferred” initial treatment regimens, with a category 1 recommendation given to the following 4 regimens:
- Bortezomib/dexamethasone
- Bortezomib/doxorubicin/dexamethasone
- Bortezomib/thalidomide/dexamethasone
- Lenalidomide/dexamethasone.
Triple-drug combinations are recommended based on the fact that they generally produce higher response rates; 4-drug combinations do not seem to add additional value. Combinations of the newer drugs not only enhance the possibility for near-complete responses initially, but they further enhance responses after transplant, Dr Bensinger added.
After high-dose therapy and ASCT, maintenance therapy is an option, as is allogeneic stem-cell transplant, but only within the context of a clinical trial because of contradictory data, he suggested.
Therapy for Transplant-Ineligible Patients
Patients who are ineligible for transplant also have improved survival when novel agents are combined with conventional drugs, Dr Bensinger continued. Therefore, for transplant-ineligible patients, the NCCN guidelines give category 1 recommendations to melphalan/prednisone in combination with bortezomib, lenalidomide, or thalidomide, and to lenalidomide/dexamethasone.
Maintenance Therapy
Maintenance therapy after transplant can significantly reduce the risk of relapse. Trials of maintenance therapy have consistently shown improvements in complete responses, PFS, and overall survival, at least in patients without high-risk cytogenetics, Dr Anderson said.
The NCCN guidelines now list several “preferred” agents for maintenance. Although thalidomide currently has the sole category 1 recommendation, lenalidomide will soon be upgraded to a category 1 recommendation as well, Dr Anderson predicted. Bortezomib has been added to this list; however, supporting data come only from nonrandomized studies at this point.
Although there are concerns about an increased risk for secondary cancers with lenalidomide maintenance, Dr Anderson argued, “the risk of progression and death from myeloma are far outweighed by the overwhelming benefit of lenalidomide.”
Salvage Treatments
The recommended treatment for patients with relapsed/refractory disease includes 3 regimens with a category 1 classification: bortezomib, bortezomib/liposomal doxorubicin, and lenalidomide/dexamethasone. A variety of other agents and novel combinations are also acceptable.
The 2012 NCCN Clinical Practice GuidelinesTM have eliminated single-agent dexamethasone, lenalidomide, and thalidomide, and have updated several regimens to category 2A recommendations. Weekly administration of bortezomib, as opposed to twice weekly, is recommended based on the sharp reduction in neuropathy. Subcutaneous bortezomib will soon be added to the recommendations, because it has shown equivalent efficacy with significantly less neuropathy, Dr Anderson said.
The Future of Myeloma Treatment
Rapidly moving from bench to bedside are a host of new drugs in a variety of classes, some with completely novel mechanisms of action, Dr Anderson noted. These include immune therapies (ie, vaccine and adoptive immunotherapy) and novel agents targeting the myeloma cell in the bone marrow microenvironment. New, rational-based combinations will be employed, and genomics will be used to better classify patients and personalize treatment.
“Remarkably for multiple myeloma, we have a long list of agents in late-stage development,” Dr Anderson said. The following drugs are now in phase 3 clinical trials:
- Carfilzomib, a proteasome inhibitor
- Pomalidomide, an immunomodulatory drug
- Siltuximab, a monoclonal anti–interleukin-6 antibody
- Elotuzumab, a humanized monoclonal anti-CS1 antibody
- Perifosine, an Akt inhibitor
- Vorinostat, a histone deacetylase (HDAC) inhibitor
- Panobinostat, an HDAC inhibitor.
Finally, efforts are under way to identify mutations in myeloma that will help drive targeted therapies, according to Dr Anderson. Sequencing of the myeloma genome has revealed mutations in protein homeostasis, NF-ĸB signaling, IRF-4, Blimp-1, histone-methylating enzymes, and BRAF. Because mutations of an individual patient may change along the disease continuum, more than 1 genetic assay (when these become available) will likely be necessary to molecularly classify the patient.