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Last decade brought progress in treatment of multiple myeloma
Increasing prolongation of life may lead to a chronic disease classification for the condition.
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Major strides have been made in the treatment of multiple myeloma in the last decade, with the advent of new agents such as thalidomide, lenalidomide and bortezomib in conjunction with high-dose chemotherapy and stem-cell rescue. However, the optimal combination and sequencing of these new drugs with the transplant schema have yet to be determined.
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Photo by Al Hayashi, Loyola University Health System |
Although the new drugs have allowed successful salvage of relapsed disease, many oncologists have argued that it is not clear if the survival of patients has improved. Conversely, researchers have found improved outcomes in patients with myeloma in recent years, both in the relapsed setting as well as at diagnosis, according to a 2007 study published in Blood.
“At present, we are striving to establish myeloma as a chronic disease — one that patients can live with for many years, similar to our medical care with other chronic diseases such as hypertension or diabetes,” David Vesole, MD, PhD, FACP, director of Loyola University Health System’s Blood and Marrow Transplant program, told HemOnc Today.
An estimated 20,000 new multiple myeloma cases will be diagnosed in the United States this year, with about 11,000 Americans dying from the disease, according to the American Cancer Society. Though a relatively uncommon cancer, multiple myeloma carries a five-year survival rate of 34%.
So with time of the essence, and the progress that’s been made in the last decade, is it feasible for oncologists to expect a cure in the next 10 years? HemOnc Today spoke with several leaders in multiple myeloma research to discuss the controversies surrounding the impact of the new agents and whether oncologists can be optimistic about the future.
“Until we can eradicate the myeloma stem cell, it will be difficult to cure the disease,” said Vesole.
Proper handling
Bart Barlogie, MD, PhD, director of the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences, Little Rock, said the reason proper handling of treatment, sequencing and combinations has been difficult to resolve is because of a lack of data.
“Naturally, as the permutations are vast and robust data on new agent combination outcomes beyond three to four years are lacking, clear directions are only now beginning to emerge,” Barlogie said.
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“Few, if any, of the novel agent trials provide breakdown by key prognostic factors such as metaphase cytogenetic abnormalities, or better yet, gene expression profiling-derived molecular subgroups or risk categories, which impact outcomes enormously,” Barlogie said. He noted that several pivotal trials are underway worldwide, including one in the Southwest Oncology Group (S0777) that compares lenalidomide (Revlimid, Celgene) plus dexamethasone vs. lenalidomide plus dexamethasone plus bortezomib (Velcade, Millenium).
Vesole said a possible reason the optimal sequencing has yet to be determined in well-designed clinical trials is because the regimens currently utilized are usually based upon the treating physician’s experience with the agent(s).
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“Many of the myeloma specialists are utilizing regimens that are risk-based,” Vesole said. “For example, patients with renal insufficiency are treated with bortezomib-based regimens since these do not have to be adjusted based on renal function; patients with neuropathy are receiving lenalidomide-based regimens since these do not cause neuropathy,” Vesole said.
Guido Tricot, MD, PhD, director of the Utah Blood/Marrow Transplant and Myeloma Program at the University of Utah School of Medicine, said that the novel agents mentioned above are only moderately effective when given alone or in combination and have not resulted in median survivals exceeding four years. These agents will be much more effective when introduced at a stage of minimal residual disease after tandem autologous transplants, Tricot said.
“If such a sequence of treatments is given, it is likely that median survivals of 10-plus years will be achieved,” he said. “The question is not whether patients should be treated with the novel agents or transplantation. In my opinion, the best results will be obtained by combining both treatments in the right sequence.”
Chung-Che (Jeff) Chang, MD, PhD, director of hematopathology service at the Methodist Hospital, Houston, Texas, said the only way to figure out how to properly handle these agents is to rely on carefully designed clinical trials.
“A national or worldwide collaborative program will be needed to recruit enough patients to these trials,” Chang said.
Induction therapy relapse
The management of refractory disease continues to be a challenge in treating the patients with myeloma. Despite the aggressive and improved treatments, most patients with myeloma will eventually have resistance to therapy or relapse, according to an article published recently in the Journal of Managed Care Pharmacy.
“I disagree entirely with this notion,” Barlogie said. “When I look at long-term outcome data of our frontline Total Therapy (TT) protocols, 15% of 231 patients enrolled in TT1 (cross resistant induction polychemotherapy, melphalan-based tandem transplants, interferon maintenance) can be cured, as they have remained in continuous remission beyond 10 years and as far out as 18 years,” he said.
In TT2, Barlogie and his research team introduced post-tandem transplant consolidation therapy and evaluated, in a phase-2 randomized trial design, the role of thalidomide (Thalomid, Celgene). Among all 668 patients enrolled, TT2 significantly extended the median durations of event-free survival from three years in TT1 to five years, and overall survival from six years in TT1 to nine plus years. Patients randomly assigned to thalidomide enjoyed superior 10-year event-free and overall survival rates of 40% and 60% respectively, compared with 25% and 45% for the control arm, according to Barlogie.
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With the addition up front of both bortezomib and thalidomide in TT3, approximately 80% of 303 patients enrolled achieved near-complete remission, 90% of whom have not relapsed four years later, according to Barlogie.
“This bodes well for a high-cure percentage that we estimate to reach 60% at 10 years,” Barlogie said.
Amrita Krishnan, MD, director of the Multiple Myeloma Program at City of Hope’s division of hematology & hematopoietic cell transplantation, Duarte, Calif., said that although these new agents have increased response rates and complete remission rates in both the up front setting and relapsed setting, physicians are still evaluating how best to combine or sequence these agents to achieve the best response with the least toxicity.
“Reasons for relapse of myeloma are probably multifactoral and relate directly to mechanisms of resistance in the myeloma cells,” Krishnan said. “Also some of the side effect profiles of the medications may preclude our ability to deliver optimal doses of therapy to patients.”
Objective of therapy
“The cure is no longer an elusive goal in myeloma,” Barlogie said.
“The results in our sequential Total Therapy protocols, incorporating all active treatment ingredients up front to target a maximum of potential disease escape mechanisms, strongly attest to the curability of patients with myeloma if — and this is key — if cure is made the objective of therapy,” Barlogie said.
Unlike many other hematologic malignancies, Barlogie said, myeloma is characterized by a profound genomic instability so that even at diagnosis, a dozen chromosomal abnormalities on average can be recognized in an individual patient.
Based on molecular genetic insights, a spectrum of myeloma entities is now recognized. These share abundant survival and resistance signaling pathways, negating the prospect of success from interventions directed at a single target. This view is supported by the ever-increasing frequency of and shorter time to complete remission, observed when both new and old agents, especially melphalan, are combined up-front, according to Barlogie.
“The critical cure surrogate, however, is not the incidence of CR, but its sustained duration,” Barlogie said. Among the 85% of patients with gene array-defined low-risk myeloma treated in TT3, 95% of those attaining CR status have not relapsed 5 years later.
“We would be hard pressed at this point to improve upon these significant results,” Barlogie said. In contrast, Barlogie noted, the median event-free survival in high-risk myeloma is only three years.
Disease manageability
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With the progress that has been made in the last decade, hematologists and oncologists cannot help but wonder what the next 10 years will bring. Many of the researchers HemOnc Today spoke with said disease manageability is the next step.
“Disease control is definitely a realistic goal, and in many cases we are already there,” said Melissa Alsina, MD, associate professor and myeloma specialist in the Blood and Marrow Transplant Program at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla.
According to Alsina, how patients with standard risk cytogenetics respond to therapy, including both high-dose chemotherapy and PSCT, has been a positive. Patients with poor risk cytogenetics are still a challenge but bortezomib therapy, for example, may be able to overcome some of the poor risk factors.
Even with all patients still relapsing, there continues to be new drugs in clinical trials with significant activity in myeloma — such as carfilzomib — that are showing promise, Alsina said.
“The fact that the new agents are able to induce more profound and durable responses makes us feel hopeful that we are indeed closer to a cure,” Alsina said. “We need to develop more sensitive techniques to evaluate response and also develop trials to better evaluate the role of allogeneic transplantation in myeloma as a modality with potential cure for this disease,” Alsina said.
“We should never be happy with where we are and should always strive to improve outcomes for our patients,” Tricot said.
“However, we have now come as far as we can go with the available treatments. Further progress needs to come from research trying to provide a better understanding of drug resistance in myeloma by systematically examining the remaining myeloma cells surviving our treatments or by finding treatment modalities that are not cross-resistant with our current treatments, such as immunologic destruction of myeloma cells, which again will work best after debulking the myeloma load. Immunotherapy works best in conditions of minimal residual disease.”
Chang said that if physicians can prolong the lives of patients long enough, oncologists may be able to make myeloma a chronic disease such as hypertension or diabetes. As far as a cure, “we’re still not able to address the root of the problem,” Chang said.
Targeting stem cells
“We probably will not be able to cure myeloma before we address the myeloma stem cells,” Chang said. “However, disease control will be a realistic goal with all the agents currently available if we can find out the best combination through new clinical trials. Most of the drugs are designed to target the mature neoplastic cells but not the myeloma stem (precursor) cells. For a long-term cure, how to eliminate the myeloma stem cell and how to disturb the myeloma stem cells and their niches will be key issues to be addressed.”
Tricot said he believes physicians need to better understand the make-up of the drug-resistant myeloma cells so that they can be targeted.
“If we can do so, we have a realistic chance of curing myeloma,” Tricot said.
“We have yet to delineate the myeloma stem cell,” said Vesole.
Although a combination of older and newer drugs has increased the median survival from three to four years, Tricot said this could be improved by applying the most effective treatment — tandem transplants — up front and then providing maintenance therapy with the newer drugs.
“It is realistic to achieve 10-year median survivals with such an approach,” he said.
Tricot said that with the TT2 protocol, which provided thalidomide to only half of the patients and did not include Velcade, the median survival was eight years, which is twice as long as with the best available non-transplant approach.
“The current treatments target either the differentiated, end-stage malignant plasma cell, the bone marrow microenvironment or both,” Vesole said. “Thus, newer treatments provide the patients with more targeted therapy, resulting in improved response rates and significantly longer remission durations and survival. However, the myeloma stem cell remains elusive.”
Another bright spot in the horizon, according to Vesole, is that current technology is rapidly advancing with microgene arrays. These microarrays will allow clinicians to better understand each individual’s risk and determine which treatments are best suited for the individual. With this approach, there is hope in the near future to provide an “operational cure,” where the disease will be contained in a quiescent state with remission durations and survival exceeding 10 years.
“The future is promising that these goals will come to fruition within the next 10 years,” Vesole said. – by Angelo Milone
What problems do
oncologists face on the road to a cure for multiple myeloma?
For more information:
- Barlogie B, Jagannath S, Desikan KR, et al. Total Therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93: 55-65.
- Barlogie B, Tricot GJ, Vesole D, et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol. 2006;135:158-164.
- Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008. 111: 2516-2520.
- Schwartz RN and Vozniak M. Current and emerging treatments for multiple myeloma. J Manag Care Pharm. 2008;14(suppl S): S12-S18.