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NEW YORK CITY-Allogeneic stem cell transplantation (SCT) remains a valid option for patients with high-risk multiple myeloma, as well as for younger patients with standard risk with very aggressive disease.
"For patients with standard-risk myeloma, treatment has improved so much that the risk-versus-benefit ratio needs to be balanced," Sergio Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memorial Sloan-Kettering Cancer Center, said in an interview here at the Lymphoma & Myeloma 2011 meeting.
"In very young patients with very aggressive disease, you may consider an allogeneic transplant for long-term disease control. But the availability of a donor is not a reason to do an allogeneic transplant."
Oncologists frequently see multiple myeloma patients in their practice who have achieved a stringent complete response (CR) after receiving several cycles of combination therapy, such as bortezomib plus thalidomide plus dexamethasone, followed by an autologous SCT. "These patients ask, 'Can I be cured? What is my life expectancy? Will my disease come back?'" Dr. Giralt said in his presentation at the meeting. "There is a chance these patients will be cured, but more likely the disease will come back and will be more difficult to control due to clonal evolution, and will be more difficult to control with chemotherapy."
The question for these patients is "would replacement of their bone marrow with the bone marrow and immune system of someone else be able to achieve long-term disease control? That is, can I do SCT and exploit the graft-versus-myeloma [GvM] effect that will prevent the disease from coming back. Is the risk of the procedure worth the benefit?"
Dr. Giralt noted that the bar for treatment of these patients has changed. "Traditionally we have been telling patients that high-dose chemotherapy and one autotransplant leads to an average remission rate of about 40% for around two to three years, with a progression rate of 90%. Only one-third of these patients would achieve a CR and stay in CR 10 years down the road. That data is no longer valid today. Some patients will live long enough to die of something else."
Clinical studies show where the bar for treatment stands today. Standard therapy for multiple myeloma patients includes induction therapy and lenalidomide maintenance for those who are not progressing. Patients who receive lenalidomide have a remission duration of approximately four years, compared with only about two years for those receiving placebo in clinical trials. "With standard therapy and one autologous transplant followed by maintenance, the average remission duration is four years. Survival data from clinical trials show that 80 to 90 percent of patients are alive at four years," Dr. Giralt said.
The goal of therapy is for the patient to achieve a complete response, which is a surrogate for long-term disease control. "Previously, patients who received allogeneic SCT with myeloablation therapy had a 30% mortality rate, which is high. With reduced intensity transplants, the mortality rate is down to 10-15%," said Dr. Giralt, noting that data from the University of Arkansas using a third tandem transplant using intensive induction following normal therapy show a reduction in the relapse rate.
New trials have compared allogeneic SCT versus autologous transplant in the upfront setting. "This is the question we face the most in the clinic," said Dr. Giralt. "A 55-year-old today has an expected life-span of 30 years. To say to a patient you have a seven-year lifespan, which is twice as high as it would have been 20 years ago, is still not that good."
He cited a North American trial (BMT-CTN 0102) that compared tandem autologous transplant with or without maintenance therapy (auto-auto) versus single autologous transplant followed by HLA-matched sibling non-myeloablative allogeneic transplant (auto-allo) for patients with standard-risk multiple myeloma.
The main groups compared had standard-risk disease and either had no sibling donor (436 patients auto-auto) or had an HLA-identifiable donor (189 patients auto-allo). This study was designed to evaluate patients with standard-risk disease who had no deletion 13 identified by conventional cytogenetics and a beta 2 microglobulin (B2M) of less than 4 mg/mL at diagnosis.
There is a tendency for oncologists to refer only high-risk patients to clinical trials, Dr. Giralt said: "In the community, we send only our worst-risk patients to a clinical trial. We don't want good-risk patients assigned to allogeneic transplant. Unfortunately, we still have one-quarter of patients referred to transplantation when B2M has not been done at diagnosis."
However, this is changing: "More patients are having a full workup as recommended by National Comprehensive Cancer Network guidelines," he said, adding that a proper workup involves tests of bone marrow, cytogenetics, and fluorescence in situ hybridization.
The results of the North American trial show that therapy failed for the same number of patients, about 15%, Dr. Giralt noted. The trial did not meet the primary endpoint - three-year progression-free survival (PFS) - which was similar in both groups (46% auto-auto, 43% auto-allo). Overall survival also was similar (80% auto-auto, 77% auto-allo).
A limitation in the study, though, he said, was that 30% of patients in the auto-auto arm who were randomized to receive thalidomide/dexamethasone refused to take the drugs. "They refused due to prior exposure to thalidomide and its side effects. Thalidomide maintenance was not considered acceptable by the patients in this trial."
The trial did demonstrate a GvM effect. Relapse rates were slightly higher, but the difference was not enough to overcome a higher transplant-related mortality in the auto-allo arm (12%) compared with the auto-auto arm (4%). The non-relapse mortality rates are acceptable but need to be improved upon, he said. "If we could exploit the GvM effect without decreasing the non-relapse mortality rate, we would have an instrument that could reduce the relapse rate by 50%."
The cumulative incidence of chronic graft-vs-host disease (GvHD) after allogeneic transplant was 54% at two years, he said. Chronic GvHD has an impact on disease progression and relapse for patients with standard-risk disease. Those who had no GvHD in the first 12 months had a higher incidence of disease progression at three years (42%) compared with those who did have a GvHD effect (20%).
Regarding high-risk patients, Dr. Giralt said that for patients who show deletion 13 by conventional cytogenetics or a high B2M, there was no improvement in either progression-free or overall survival. "There is a sign that patients who develop GvHD have lower risk of relapse in this group of patients, but if we look at auto-allo transplants, a significant number of patients are still dying of multiple myeloma. Despite getting donor cells, these cells can escape immune surveillance."
Dr. Giralt cited a recent study by a Nordic group that reported longer follow-up on a trial comparing tandem autologous/reduced intensity conditioning allogeneic SCT versus autologous transplantation (Bjorkstrand B et al:JCO 2011;29:3016-3022). The 357 patients in the trial received conventional modern induction high-dose therapy and were assigned to transplant or no transplant depending on the availability of an HLA-identical sibling.
"The bottom-line result showed as with the American trial, that the relapse rate decreased, but the researchers saw a significant benefit in PFS, and may be starting to show an overall survival benefit late in the course of the disease," Dr. Giralt said. "Survival was way below 60%, which when compared with modern autologous transplantation with maintenance seems to be significantly inferior." The non-relapse mortality was similar to the North American trial, about 12%.
"As we think about recommending transplantation to all patients with standard-risk disease, we need to recognize that we have to reduce the risk of non-relapse mortality," he said. "What we really need is a better way to define disease burden. If we could see the disease burden the same way we do in chronic myeloid leukemia using polymerase chain reaction, we could see that the tumor burden was increasing over time or that the tumor burden fell below a certain threshold that we knew maintenance therapy could not reduce, and we could then recommend aggressive therapy."
In summary, Dr. Giralt said, "current results with both autologous and allogeneic SCT justify the following patterns of care: in standard practice allogeneic SCT can be offered to patients with high-risk disease, or younger patients with standard risk disease who are highly motivated and well-informed. Allogeneic SCT as consolidation of a first remission should preferentially be performed under the auspices of a clinical trial. Autologous SCT remains the most reasonable consolidative therapy for myeloma patients today."
He added that approximately 15 to 20 percent of patients who receive a salvage allogeneic transplant achieve long-term disease control as long as they have increased clinical remission. "This is a reasonable strategy that should be performed in the context of a clinical trial," he said.
Morton Coleman, MD, Director of the Center for Lymphoma and Myeloma at Weill Cornell Medical College, commented on Dr. Giralt's presentation by saying that allogeneic transplant should be relegated only to a clinical trial or to young patients at high risk who are fully informed of the risks and benefits.
"This is not a routine procedure. The data do not show any genuine benefit using myeloablation or non-myeloablation allogeneic transplant. This is only for a subset of patients who are young with a poor prognosis."
And Brian Durie, MD, Chairman of the Board of the International Myeloma Foundation and the International Myeloma Working Group and an attending physician at Cedars-Sinai Samuel Oschin Cancer Center in Los Angeles, said, "Myeloma treatment starts before the patient has myeloma with smoldering disease. How should we treat a high-risk patient? Once identified, 50% will progress within two years."
The goal for low-risk patients is to extend survival and avoid unnecessary treatment, he continued. "We can't move away from early autologous transplant yet, because good-risk patients who receive a transplant early do amazingly well."
The role of double transplant, which is not yet a standard of care, may be best as consolidation for patients who do not attain very good partial response to induction therapy, he added. "The main thing is to balance toxicity and efficacy with what the physician thinks is best and what the patient wants to do when it comes to transplant."
Dr. Giralt summarized his view as follows, that current results with both autologous and allogeneic SCT justify the following patterns of care:
* In standard practice allogeneic SCT can be offered to patients with high-risk disease, or younger patients with standard-risk disease who are highly motivated and well-informed.
* Allogeneic SCT as consolidation of a first remission should preferentially be performed under the auspices of a clinical trial.
* Autologous SCT remains the most reasonable consolidative therapy for myeloma patients today.
Sensitive detection of resistant mutations after imatinib resistance via a mass spectrometry assay may be a new way to predict the outcome of subsequent therapy with a second-line tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML) patients, according to the results of a study in the November 10 issue of the Journal of Clinical Oncology (29;32:4250-4259).
Using a sensitive multiplexed mass spectrometry assay to detect BCR-ABL1 mutations, Australian researchers were the first to clearly demonstrate that low-level BCR-ABL1 mutations detected after imatinib failure in CML patients are clinically relevant.
"We found that a significant number of CML patients who have failed therapy with imatinib have low-level nilotinib - and/or dasatinib-resistant mutations that are detectable only using an assay that is more sensitive than conventional direct sequencing," lead author Wendy Parker, PhD, Research Officer in the Leukaemia Unit of the Department of Molecular Pathology at the University of Adelaide, said in an interview.
She and her co-researchers assessed the mutation status of 220 patients treated with nilotinib or dasatinib after they became resistant to imatinib. Mutations were detected by sequencing in 128 patients before commencing nilotinib or dasatinib therapy to switchover from imatinib. In 64 patients, 132 additional low-level mutations were detected by mass spectrometry alone. Fifty of the 132 mutations were resistant to nilotinib and/or dasatinib.
Nilotinib and/or dasatinib-resistant mutations were detected before starting nilotinib or dasatinib therapy after imatinib failure in 9% more patients using the sensitive mass spectrometry assay compared with conventional direct sequencing (32% vs 23%).
"Detection of low-level mutations that confer clinical resistance to nilotinib and/or dasatinib is highly predictive of their rapid clonal expansion under the selective pressure of nilotinib or dasatinib therapy and is associated with therapy failure," Dr. Parker said. "In patients who received the second generation TKI that retains sensitivity to the low-level mutation detected, the mutation rarely expanded."
When patients received the inhibitor for which the mutation confers resistance, 84% of the low-level resistant mutations rapidly became dominant clones detectable by sequencing, including 11 of 12 T315I mutations. Subsequent complete cytogenetic response rates were lower for patients with resistant mutations at switchover detected by sequencing (0%) or mass spectrometry alone (16%) compared with patients with other mutations or no mutations (41% and 49%, respectively).
The failure-free survival rates among the 100 patients with chronic phase CML when resistant mutations were detected at switchover by sequencing or mass spectrometry alone were 0% and 0% compared with 51% and 45% for patients with other mutations or no mutations.
The sensitive mutation assay may be used to detect nilotinib and/or dasatinib-resistant BCR-ABL1 kinase domain mutations that are present below the detection limit of conventional direct sequencing, she said. "Therefore, mutations that would aid informed decision making as to the most appropriate TKI therapy after imatinib failure may be detected in a greater number of patients than using conventional direct sequencing.
"If a nilotinib-resistant mutation (Y253H, E255K, E255V, F359V, F359C) was detected using the multiplex mass spectrometry assay, dasatinib would be preferred. If a dasatinib-resistant mutation (V299L, T315A, F317L, F317I, F317C, F317V) was detected using the multiplex mass spectrometry assay, nilotinib would be preferred."
If an inappropriate kinase inhibitor is selected, there is a high risk of treatment failure with clonal expansion of the resistant mutant, she added.
Patients with a T315I mutation, which confers resistance to both nilotinib and dasatinib, or multiple mutations resistant to both nilotinib and dasatinib, may benefit from stem cell transplantation or experimental therapy such as ponatinib, rather than nilotinib or dasatinib. If nilotinib or dasatinib-resistant mutations are not detectable, factors such as tolerance and disease phase should be considered when making therapeutic decisions, she said.
Dr. Parker said that currently, the mass spectrometry assay is being used to analyze samples of patients in three international clinical trials.
"The assay is also available upon request to clinicians in Australia. We are continuing to assess the clinical significance of sensitive mutation analysis in various clinical settings," she said.
The study's message, said Dr. Parker, is that "low-level BCR-ABL1 kinase domain mutations-i.e., present below the detection level of conventional direct sequencing-detected after imatinib failure are clinically relevant.
"Mutation analysis is essential to facilitate selection of appropriate therapy for CML patients who have developed resistance to imatinib. Sensitive mutation analysis before treatment with second-generation TKIs enables detection of clinically relevant mutations in more patients than using conventional direct sequencing, and therefore aids informed decision making for a greater number of patients."
Asked for his opinion for this article, Michael Mauro, MD, Associate Professor of Hematology at the Knight Cancer Institute, Center for Hematologic Malignancies, at Oregon Health & Science University, said that for a molecular test to be useful it has to be accessible in multiple locations, reproducible, and validated. "If a mass spectrometry assay could become a standard diagnostic marker we could clarify the question of low-level mutations."
Dr. Mauro noted that specifically at the time of switch-over from imatinib to another drug, "we need to better define the population at risk, who at the moment still may not get enough treatment. We haven't been able to make perfect sense of their mutations nor predict which mutations may arrive later in the course of the disease."
In current molecular analysis, a predictable number of patients show mutational resistance, he continued. "These are not the only patients who would be served by a mass spectrometry assay. If this test were widely available, it would increase the number of mutations identified and help to see mutations at a lower level, not only the mutations we see now but 'forecasting' those that may emerge later. It would help us tailor the choice of post-imatinib treatment with greater confidence and data."
At the moment, oncologists are left referencing in vitro sensitivity of mutations in Bcr-Abl if a patient does not respond to imatinib, he said.
"Ideally, we would need more clinical trial data of patients with different mutations on different therapies to best define which drug works best for which mutations. With better detection and prediction of mutations with this type of assay, we can move more efficiently to newer generations of selective drugs and better understand the performance of later generation kinase inhibitors in a proactive rather than entirely reactive manner."
He said that in the future, he foresees better ways to help choose optimal treatment for CML patients. "We will continue to look for early cytogenetic response because that matters and inquire early regarding any resistance to imatinib or to one of the second-generation TKIs. Our growing repertoire of knowledge and therapies will tell us what to do next.
"With identification of mutations present or predicted to emerge that we recognize we can shuttle patients to the best drug to subvert those mutations - for example, use ponatinib if a patient has evidence or risk of an emerging T315I mutation."
The achievement of a major molecular response (MMR) offers no advantage over complete cytogenetic response (CCyR) in defining long-term outcome in patients with newly diagnosed CML treated with second-generation tyrosine-kinase inhibitors (TKIs), according to a study in the November 10 issue of the Journal of Clinical Oncology (2011;29:4260-4265).
The use of second-generation TKIs as initial therapy in CML induces high rates of CCyR at early time points: "The European LeukemiaNet [ELN] definitions of response, which are based on front-line therapy with imatinib, are not applicable in this setting," said lead author Elias Jabbour, MD, Assistant Professor of Medicine in the Leukemia Department at the University of Texas MD Anderson Cancer Center.
"We propose that achievement of CCyR at six months should be considered an optimal response and a partial cytogenetic response at three months should be considered a suboptimal response."
Dr. Jabbour and his coauthors-Hagop M. Kantarjian, Susan O'Brien, Jianqin Shan, Alfonso Quintas-Cardama, Guillermo Garcia-Manero, Mary Beth Rios, and Jorge E. Cortes-treated 167 patients with newly diagnosed CML in chronic phase with second-generation TKIs in Phase II trials; 81 patients received nilotinib and 86 received dasatinib.
The patients were followed for a median of 33 months. Event-free survival (EFS) was measured from the start of treatment to the date of loss of complete hematologic response, loss of complete or major cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, progression to accelerated or blastic phases, or death at any time.
Overall, 155 patients (93%) achieved a complete cytogenetic response, including 146 patients (87%) who achieved a major molecular response. About one-quarter of the patients (28%) achieved a complete major response. Dr. Jabbour noted that according to the ELN definitions, the rates of suboptimal response were 2% or less up to 12 months of therapy. "There was no difference in event-free survival and CCyR duration between patients who achieved CCyR with and without MMR across all landmark times of three, six, 12, and 18 months."
Early responses seem to predict better outcomes. "Early response is important. We need to wait only six months, not 12, to see which patients are responding. What matters is that the patients who respond do really well."
He suggested starting all newly diagnosed chronic-phase CML patients on second-generation TKIs. "At six months, the large majority will respond and do better over the long-term. We can select good responders early on."
If bone marrow tests at three months indicate a partial response, the procedure should be to repeat the test again at six months, he said, cautioning though, that these new criteria have not yet been validated by others.
"If the patient achieves CCyR at six months, the outcome is good. If at six months the patient does not achieve a complete response, we don't have options at the moment," Dr. Jabbour said. He suggested monitoring these patients carefully, and if they still do not achieve a good response at 12 months, refer them to a clinical trial. "In the future, we may have new drugs coming to market for these patients."
The clinical message, said Dr. Jabbour, is "if patients do not achieve CCyR at six months, you have to follow them closely. If they do show CCyR, don't concern yourself so much with molecular testing. As long as they have CCyR, their outcome will be great. Once they hit CCyR, whether they have MMR or not, their outcome will be the same."
Asked for his opinion for this article, Michael Mauro, MD, Associate Professor of Hematology at the Knight Cancer Institute, Center for Hematologic Malignancies, at Oregon Health & Science University, called the study further evidence that supports that cytogenetic response is still the best predictor of clinical response, even with new therapeutic agents.
He noted that the role of early cytogenetic response as a delineator of subsequent outcomes is fairly firm. "This is one of the first reports synthesizing the data on faster cytogenetic responses with nilotinib and dasatinib into earlier predictive time points," said Dr. Mauro.
Patients treated with second-generation TKIs declare themselves as responders even faster than with imatinib therapy, Dr Mauro said. "Early cytogenetic response shows the optimal subset of treated patients, and it appears that delineation occurs earlier with second-generation TKIs.
The current CML literature "does not guide us much regarding suboptimal molecular responses. The follow-up may need to be longer to clarify the benefit of prompt molecular response in this data set [with second-generation TKIs].
"Molecular response is important, but is not as strong a predictor of risk reduction as cytogenetic response," Dr. Mauro continued.
"A patient with a three-month and six-month cytogenetic response is more likely to go to complete remission and stay in remission, and suboptimal cytogenetic response at early time points often leads to subsequent re-classification as treatment failure. Oncologists have to be more patient about their patients achieving a molecular response. The patient may need 12 or 18 months to show a molecular response."
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