NEW YORK—Multiple myeloma survival is improving dramatically with the introduction of novel therapeutic agents and combination approaches, but no one therapy or modality fits all patients, according to two myeloma experts who squared off in a debate at the Great Debates and Updates in Hematologic Malignancies meeting.
Both experts agreed achieving minimal residual disease (MRD) negativity is important, although the clinical implications require further investigation, and they strongly encouraged practicing oncologists to enroll multiple myeloma patients into ongoing clinical trials.
Edward A. Stadtmauer, MD: Upfront Transplant As a Standard of Care?
The goals of the ideal initial treatment of the multiple myeloma patient are rapid symptomatic and biochemical response, rapid and prolonged correction of organ function abnormalities, low toxicities, long duration of remission, and they survival, said Edward A. Stadtmauer, MD, Professor of Medicine at the Hospital of the University of Pennsylvania, Philadelphia.
“I agree that no one size fits all. Since no particular regimen or sequence has been shown to be optimal, all options need to be considered. The approach, regimens, and goals must be individualized based on a patient's age, organ function, risk assessment, and personal factors,” Stadtmauer said.
The best results have been seen with primary or induction therapy followed by high-dose melphalan and autologous stem cell transplantation (ASCT), followed by maintenance therapy. “All patients should be considered for this sequence until deemed unable to proceed,” he said, noting that since no therapy is curative, all patients should be encouraged to participate in ongoing clinical trials.
Some studies using high-dose melphalan have shown improved overall survival compared with standard-dose therapy in the past, while others have not. The phase III IFM 2009 study compared lenalidomide-bortezomib-dexamethasone (RVD) with or without ASCT in 700 newly diagnosed younger multiple myeloma patients. ASCT was associated with a 31 percent reduced risk of progression, improved time to progression and rate of MRD negativity, and similar low rate of mortality, Stadtmauer said.
Progression-free survival (PFS), the primary endpoint, was prolonged with high-dose melphalan by approximately nine months. There was no difference in four-year overall survival (OS), and while longer follow-up is required to make any conclusions about overall survival, the OS was 83 percent for the non-ASCT arm versus 80 percent for early ASCT.
“The authors concluded that ASCT should remain a standard of care for eligible patients with myeloma,” he said. A similar parallel trial, the so-called Determination Trial (CTN 1304, Alliance, DFCI/IFM 2009), is ongoing in the U.S. with lenalidomide maintenance until progression, and this is a key difference.
Stadtmauer noted the likelihood of complete response or MRD negativity was higher in the ASCT group at all time points.
Another promising combination under investigation is carfilzomib-lenalidomide-dexamethasone with ASCT in newly diagnosed multiple myeloma, he said, although randomized data supporting its use are not yet available, in contrast to RVD where recent results from the SWOG phase III study show both PFS and OS advantage compared to controls.
“Multiple myeloma strategy for a cure includes induction or initial therapy, high-dose melphalan plus ASCT, immunotherapy plus anti-myeloma vaccines or consolidation therapy, and targeted maintenance therapy,” Stadtmauer said. “The best results incorporate high-dose melphalan and ASCT. We continue to show improvement with initial therapy using triplet drug combinations. A proteasome inhibitor, an immunomodulatory drug (IMiD), and dexamethasone win out over doublets.
“The role of stem cell transplantation (SCT) is clear—healthy patients under age 75 should be considered for initial therapy with ASCT and maintenance. The timing is also clear—as the first line of therapy,” Stadtmauer continued.
SCT will continue to improve with better stem cell collection and improved high-dose melphalan regimens, as well as with non-myeloablative allogeneic SCT and cellular immunotherapy.
Maintenance therapy also will continue to improve, including IMiDs or proteasome inhibitors in combinations with or without immunotherapy with monoclonal antibodies (MABs), checkpoint inhibitors, and cellular therapies, he said.
Paul G. Richardson, MD: Not Every Patient Needs a Transplant
One size does not fit all, stated Paul G. Richardson, MD, RJ Corman Professor of Medicine at Harvard Medical School, Boston. “We have seen continued improvement in survival since the introduction of novel agents. Survival has improved over time, and also now in patients over age 65. In aggregate these data show novel agents are clearly making the difference,” said Richardson, who questioned the use of SCT for every transplant-eligible newly diagnosed multiple myeloma younger patient in the era of novel therapy.
“We have made progress in multiple myeloma in better understanding of disease biology and substantial improvements in outcome due to the availability of novel therapies. There is potential for multiple myeloma to become a chronic disease in most patients, and in some, to perhaps achieve a functional cure,” Richardson said.
He warned clinicians to therefore be careful about the long-term effects of therapies, particularly with toxicities. “Management of adverse events and comorbidities of intensive therapy, versus novel agents, need to be better understood to minimize the impact of genotoxic injury,” he said.
Richardson noted multiple myeloma remains incurable in the majority of patients. There is increasing symptom burden due to disease and cumulative effects of treatments, and late toxicities in particular, such as secondary acute myeloid leukemia. “The key is to balance disease control and quality of life. Does SCT benefit every eligible patient? What is its contribution to overall survival?” he asked.
“We are moving forward rapidly in novel therapies, with third-generation agents now making a difference,” he said. “The landscape is busy. New platforms that include combinations of MABs, proteasome inhibitors, IMiDs, and steroids with other small molecules are in development.”
He agreed an upfront triplet combination of RVD is an important platform and is generally well-tolerated. “Lenalidomide/bortezomib-based therapy is active in patients with adverse cytogenetics. Interestingly, hematologic toxicity is more severe with the addition of chemotherapy. In contrast, with RVD alone the risk of deep-vein thrombosis does not appear to be increased over lenalidomide/dexamethasone, and the risk of peripheral neuropathy is only moderately increased, but much more manageable with the use of subcutaneous bortezomib.”
When should transplant be used is another question. “For selected patients in my practice who are not in randomized trials, the stem cell option can be kept in reserve. For those with important lifestyle options, such as career changes or family events, it may be practical and holistic to wait for transplantation,” Richardson said.
Studies show there is no difference in OS for early or delayed ASCT. Lenalidomide maintenance seems to matter most, and a proteasome inhibitor is also needed to avoid an inferior outcome. Post-induction and post-transplant response rates are significantly higher with bortezomib pre-ASCT, according to the results of several meta-analyses, he said.
Richardson noted trials show lenalidomide maintenance buys 2.5 years of PFS as well as sustained OS benefit, while transplantation improves PFS by 8.8 months in the most recent IFM analysis, but with no OS advantage seen to date. He also pointed that, while transplantation is generally a safe procedure, there may be higher death rates than RVD therapy with ASCT kept in reserve, again as reflected by the IFM results, including a higher rate of mortality due to secondary AML.
He agreed current studies show a survival benefit with better MRD status over time, and in the IFM study this was achieved in both the non-ASCT and ASCT arms.
Successful salvage may be the most important determination of OS. “In my opinion, the quality of U.S. salvage therapy is some of the best in the world. I would argue that certainly autologous transplant is an important option for younger patients, but should every younger patient have one immediately, with the attendant risks both in the short and long term? I don't know yet as we await more results,” such as from The Determination Trial, Richardson said.
The future is very bright for novel therapies in myeloma, including combinations with carfilzomib and pomalidomide, MABs, histone deacetylase inhibitors such as panobinostat and AC 241, next generation IMiDs, BTK inhibition, novel cytotoxics that are less toxic, and the remarkable potential of checkpoint inhibitors, as well as other new cellular therapies, such as CAR T-cells.
“Novel agent-containing induction/consolidation regimens will improve the depth of response. Administration of consolidation and/or maintenance therapy results in an improvement in overall outcome, that is, PFS and overall survival in various settings and both with or without SCT,” Richardson said.
In conclusion, Richardson said “in the era of novel targeted therapy, we have improved classification of multiple myeloma and continued identification of targets in the myeloma cell and bone marrow microenvironment. Novel agents have been developed to target essential biological pathways, including proteasome inhibitors, IMiDs, other small molecule inhibitors, such as HDAC inhibitors, and now a variety of MABs.
“Rationally based combination therapies and effective salvage treatment have also been developed using proteasome inhibitors, IMiDs, steroids, HDAC inhibitors, and MABs. Other novel concepts to treat MRD include optimizing maintenance, the integration of vaccines, and immunological adjuvants, such as programmed death-1 blockade.”
Individualized treatment through gene expression profiling and other tools may become better predictors of outcome and risk, he added.
“Now, and in the future, early SCT is not required in every SCT-eligible patient. One size, therefore, does not fit all. SCT is and will be an option for younger patients, but is not a requirement, and participation in randomized, multi-center clinical trials is key,” Richardson said.
Mark L. Fuerst is a contributing writer.