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“Should all eligible patients with multiple myeloma receive autologous stem-cell transplant as part of initial treatment?”
Leukemia Research, 6, 36, pages 677 - 681
S. Vincent Rajkumar
Multiple myeloma is probably the only malignancy in which autologous stem cell transplantation (ASCT) is performed routinely without primary curative intent  . Randomized trials performed with ASCT in myeloma show no plateau in the survival curves, yet myeloma is the number one indication for ASCT in the United States. Although not curative, ASCT has become the mainstay of treatment for patients less than 65 based on improved median overall survival of approximately 12–18 months compared with chemotherapy alone in 2 randomized trials  and .
It is indeed intriguing that despite such a modest goal of therapy (prolongation of median survival, not cure) and the limited overall survival benefit (only 12–18 months, in some but not all randomized trials), ASCT has come to occupy such a key role in the overall treatment strategy. As I will discuss below this phenomenon is the result of a combination of factors including over-interpretation of positive trials, choosing to find fault with or ignoring negative trials , , , and , enthusiastic adoption of surrogate endpoints such as complete response (CR) and progression free survival (PFS) when overall survival benefits fail to materialize, failure to assign importance to quality of life, and a fundamental philosophical difference on where the burden of proof lies when adopting potentially toxic and expensive interventions  . Despite limitations, I think one could argue that it is reasonable to include upfront ASCT in hypothesis-generating clinical trials designed with the intent of developing a cure for myeloma. But the hope provided by improvement in surrogate endpoints or the anticipated results of such trials should not be the basis for advocating such treatment outside of trials. In other words, it is legitimate to offer ASCT outside of trials only based on the known, proven evidence in favor of such therapy. It should not be based on what one hopes to achieve in the future when such therapy is combined with “exciting” advances. The latter argument should be reserved for patients enrolling in clinical trials with informed consent. Since this article is to define the role of ASCT in current clinical practice outside of a trial setting, my arguments will be limited to the known evidence with ASCT, not what is anticipated to be shown in the future. I have no problems with the various trials testing ASCT with modern treatments in clinical trials; such trials are vital towards our drive for a cure and I support them fully. The arguments here are solely to define what the current role of ASCT is in clinical practice outside the setting of clinical trials.
Before I get into the details of the debate, it is worth defining the fundamentals. In general, “evidence” means proof of clinical benefit from randomized trials; data from phase II trials are interesting “hypothesis,” that need further testing, but not evidence. Clinical benefit is defined as improvement in overall survival or a validate patient reported quality of life outcome; prolonged PFS or higher response rates are imperfect surrogates, not necessarily indicative of clinical benefit, especially in myeloma. It is worth noting that the way progression is defined in myeloma is biochemical for most patients. It is, as defined in modern myeloma trials, often imperceptible to the patient but for the fact that a test was ordered to “check” for the event. So when we say “prolonged PFS” it is often (although admittedly not always) indicative of a “benefit” that the patient would not be aware of clinically, except for the monthly laboratory tests. So a longer PFS does not automatically mean that the patient had a better quality of life, since there are no data that a patient necessarily feels worse when the M protein is 1 g/dL compared with 1.5 g/dL. These are larger issues in this disease that require careful thought and reflection, and go beyond ASCT.
Role and timing of transplantation
In current clinical practice, and based on the evidence, my opinion is that although ASCT has an important role in the overall treatment strategy, it is not needed as part of initial therapy for all eligible patients with myeloma. ASCT is just one of many available options, and the decision on the need for ASCT and its timing must be tailored to meet the needs of the patient. A one-size-fits-all approach is no longer applicable in the disease  . There are very little data on the optimum sequence in which the various options for myeloma should be used. Most of the current recommendations are based on opinion, and the preference of the treating physician.
Two randomized trials showed a median survival prolongation with high-dose therapy followed by ASCT of approximately 12–18 months  and . These two trials are the principal sources of randomized data supporting early ASCT. But as I mentioned earlier, the improvements in terms of clinical benefit were modest; neither trial showed that ASCT was curative. These trials also did not study whether the same benefit can be obtained by delaying ASCT to the time of relapse. Thus the main message from these trials was that median overall survival can be improved in patients who added ASCT to their treatment strategy.
When should patients receive ASCT? Should all eligible patients get an ASCT as part of initial therapy? If we did not have additional trials, we can easily conclude that ASCT should be offered early to all eligible patients with myeloma as frontline therapy because that is the setting where the 2 randomized trials demonstrated an overall survival benefit  and . But we do have additional randomized trials that provide more data on the appropriate timing of ASCT. So we cannot ignore those results. So far, 3 randomized trials addressed the question of whether ASCT should be done as part of initial therapy or delayed until relapse , , and . None of these trials showed a survival benefit with early ASCT. In fact, there is not a single randomized trial conducted so far that shows that early ASCT results in better survival compared with delayed ASCT done at the time of relapse. The arguments in favor of early ASCT in the face of the above data have been predictable: “Early ASCT has better CR rates” “Early ASCT provides better PFS.” In my opinion, these considerations ignore the primary results. In fact, as long as overall survival has not been shown to be better with one approach over the other, and no validate patient reported quality of life studies have been done, the decision on what the appropriate timing is should be made based primarily on patient preference, not physician preference. It is the patients’ value on what is important to them in their life that should matter in this decision. Some argue that “time without therapy” (a presumed surrogate for quality of life) is longer with early ASCT. That is not true anymore. With many investigators promoting post-transplant maintenance therapy for all patients it is no longer possible to argue that “time without therapy” is longer with early ASCT. We need true quality of life comparison studies. If there is an advantage to one approach to the other it is actually in favor of delayed ASCT. Economically, for society and for the patient, delayed ASCT provides the same survival benefit with half as many transplants  . A delayed ASCT approach allows a person with newly diagnosed myeloma to live the younger years of their life without feeling like a cancer patient, and proceed to treatment that causes alopecia and makes it clear to them and their peers that they have a terrible malady that requires aggressive therapy. I am not against early ASCT; rather when data on survival are not iron clad, I would prefer to give the patient a choice between early and delayed ASCT.
The discussion above is critically important in framing ASCT as an imperfect but important option in myeloma. However, rapid changes in myeloma therapy are raising even more serious questions about the necessity of this procedure in the frontline setting. The two trials on the shoulders of which ASCT rests were both conducted prior to the arrival of lenalidomide and bortezomib. It was a time when CRs without ASCT were rare, and many patients failed to respond to standard chemotherapy. This is hardly the case today. Most patients are in excellent states of response within 4 months of starting standard dose therapy with modern drugs. Whether ASCT helps patients who respond well to initial therapy is a critical question that is on the minds of physicians and patients today. There is only one randomized trial that specifically looked at the efficacy of ASCT in patients responding well to their induction therapy  . Stunningly, this trial conducted in Spain found absolutely no benefit whatsoever when such patients responding well to initial therapy were randomized to ASCT versus continuing standard chemotherapy  . There are no randomized data that suggest that patients achieving excellent response to induction derive any survival benefit with early ASCT. Rather survival improvements with early ASCT come from trials conducted in an era where initial therapy of myeloma was much less effective. With modern treatment regimens, excellent response is the rule, and true non-responders to initial therapy are uncommon. Thus whether ASCT provides any benefit to these patients in the frontline setting is now in question.
In the United States there are additional questions than those discussed above. In Europe, the role of ASCT is largely restricted to the population tested in randomized trials, i.e., those less than 65. This approach was subsequently vindicated by the observation that oral therapy with melphalan, prednisone plus thalidomide (MPT) was superior to tandem ASCT with an intermediate dose melphalan in terms of overall survival in patients over 65  . In the United States, however, we have included non randomized data to support the use of ASCT well past the age of 70. While I do support this for various reasons, it is important to recognize that this approach is not based on randomized data.
Those in favor of a routine ASCT for all eligible patients suggest that the value of early ASCT is proven and that the burden of proof is on those who disagree with such a strategy to come up with randomized trials results to “disprove” the benefits of ASCT as initial therapy. The truth is quite the opposite. In medicine, the burden of proof is always on the more aggressive treatment strategy, and in this case, there are no randomized data that show that an early ASCT is superior to delayed ASCT in terms of clinical benefit. At Mayo Clinic, we follow a risk-adapted approach (msmart.org)  . The risk adapted approach is based on the principle that a patients preferences are guided by anticipated outcomes, and that offering patients a choice when there is no evidence that one approach is superior to another is not just logical, but requires no further justification. It is also grounded in the principle of primum non nocere.
We recognize that myeloma consists of many cytogenetic types with differing outcomes, and that treating all cytogenetic categories in the exact same manner is no longer acceptable. Thus, in standard-risk patients (∼75% of myeloma), the timing of ASCT (early versus delayed) is guided by patient choice (and other factors such as age and performance status). This requires that stem cells be collected and cryopreserved early in the disease course. Many patients wish to have this choice, and we respect that. I estimate that roughly 50% of eligible patients in the United States are currently deciding to adopt a delayed ASCT strategy. For intermediate-risk patients (∼10% of myeloma, characterized primarily by the t(4;14) translocation), induction with bortezomib-based regimen, early ASCT, and routine bortezomib-based maintenance is our preference and is supported by data from the Arkansas group  , as well as a randomized trial by Cavo et al. that such an approach brings their survival to outcomes similar to those seen in standard risk patients  . The role of ASCT in high-risk patients (∼15% of myeloma defined either by gene expression profiling, or presence of t(14;16), t(14;20), or 17p−) is totally unclear. High-risk patients appear to have a median survival of 2–3 years despite tandem ASCT. These patients are best treated on clinical trials as much as possible.
My goal is not to provide a “philosophical approach” to myeloma therapy for symptomatic patients. Instead, I will focus on evidence-based medicine and on reliable data generated from well-conducted trials performed both in the US and the EU, which support the routine use of high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) outside clinical trials in all young patients eligible for such a treatment.
Importantly, in order to avoid confusion in data interpretation, we must not mix data generated 20 years ago with those reported more recently. Indeed, when considering HDT and ASCT, we have to consider two distinct time periods, the first one before, and the second one after the introduction of novel agents. The former period, which corresponds to the 1990s, provided the proof-of-concept regarding the benefit of early ASCT and resulted in the procedure becoming the standard of care, whereas the introduction of the novel agents has led to the questioning of the role of this technique as part of frontline treatment. This comes at the very time when important advances in the understanding of the biology of the disease may lead some physicians to believe that a risk-adapted strategy should be routinely used, with biological parameters guiding treatment decisions in daily practice.
Considering first the 1990s, a literature search reveals that seven randomized trials investigated the use of conventional chemotherapy (CCT) versus HDT and ASCT in younger patients with de novo MM (reviewed in  ). In all of them, the response rate was in favor of ASCT, in 6/7 event-free survival (EFS) was in favor of ASCT, and in 3/7 there was an overall survival (OS) benefit associated with HDT and ASCT. Among the studies comparing CCT with ASCT, only one was specifically designed to address the question of early versus late ASCT  . On an intent-to-treat basis, the estimated median OS was 64.6 months in the early ASCT group and 64 months in the late group (P = .92), but the average time without symptoms, treatment and treatment toxicity was longer in the group of patients undergoing early HDT, indicating that the quality of life was improved in the early ASCT group. With the exception of this single trial, none of the randomized studies mentioned above evaluated the differences observed in quality of life between the two therapeutic options. Overall, the conclusions of the studies conducted in the 1990s were that ASCT results in improved response rates and better EFS with an OS benefit observed in some trials, which led to frontline ASCT becoming the standard treatment which since then has been systematically offered to young eligible patients in the EU.
In this last decade, two major advances occurred in the management of MM. First of all, thalidomide, bortezomib and lenalidomide were introduced into the therapeutic armamentarium, and secondly, major improvements have been made in the understanding of the disease biology, including the definition of important prognostic factors, based on cytogenetic and genomic characteristics. The novel agents have improved the rate of complete remission (CR) both before and after ASCT without substantially increasing toxicity, which has important implications as the achievement of high quality responses is a significant prognostic factor for outcome. The rate of very good partial responses (VGPR) increased from 15% following induction with the VAD regimen, the standard in the 1990s, up to 70% using triplet drug bortezomib-dexamethasone based combinations, which are further upgraded with melphalan 200 mg/m2 as the conditioning regimen prior to ASCT  . In addition, novel-agent based consolidation therapy following ASCT has resulted in the achievement of molecular complete responses, with some patients remaining long-term alive and free of disease, with a tumor-specific PCR negativity, compatible with a cure  . These unprecedented results were previously only achieved in the context of allogeneic transplantation, the routine use of which is not recommended in MM because of excessive transplant-related mortality. Recent data show that consolidation and maintenance strategies following HDT may significantly increase PFS by almost one year and a half , , and . Indeed, the implementation of an “optimal strategy”, consisting of novel agent-based induction, HDT and the use of novel agents in consolidation and maintenance, may result in a 5-year survival rate of 80%, which is, let us repeat again, unprecedented, and cure can be considered in a subset of patients who present with good prognostic features at the time of diagnosis.
The high efficacy of the novel agents has led some groups to test these agents upfront without ASCT and interesting results have been reported. Lenalidomide plus low-dose dexamethasone (Len/dex) as part of frontline therapy without ASCT yielded similar survival rates at two years as compared with Len/dex followed by ASCT in a non-randomized trial conducted by the ECOG  . Furthermore, in a non-randomized phase 2 trial of lenalidomide-bortezomib-dexamethasone in the upfront setting, in which the choice of proceeding to HDT or not was based on physician or patient preference, no difference in outcome was seen for the two approaches  . Based on these results, many colleagues have begun to consider the use of such novel agent-based therapies without the upfront application of ASCT as an alternative to early transplantation and the role of ASCT itself has become a matter of debate: should it be used upfront or as a salvage treatment at the time of progression in patients initially treated with novel agents? In 2011, we only have the preliminary data of a single study addressing this issue to try to solve this burning question. Boccadoro et al. reported in abstract form the results of the first prospective randomized study comparing CCT plus novel agents with tandem high-dose melphalan and ASCT in newly diagnosed MM patients  . 402 patients received four cycles of Len/dex as induction and were then randomized to melphalan-prednisone-lenalidomide (MPR) or tandem ASCT. After a median follow-up of 20 months, the 18-month PFS was 68% in the MPR and 78% in the tandem ASCT arm (p = 0.006), and was therefore in favor of the early HDT arm. At the time of the report, with a short follow-up time, OS was not significantly different between the two groups. Two other ongoing trials, one conducted by the European Myeloma Network ( NCT01208766 ) and one by the IFM plus a US consortium ( NCT01208662 ) are investigating the same issue and will enrol 1500 and 1000 patients, respectively. In both studies, reviewed by many experts and by ethical committees, the reference arm consists of early HDT, indicating that this strategy is considered the standard, and that delayed ASCT at the time of relapse after novel-agent based induction is the experimental option, and up to now, no prospective trial has demonstrated its superiority over early ASCT. Moreover, one cannot argue that early HDT increases the risk of death. ASCT is a routine procedure and is associated with a mortality rate of less than 2%, which is lower than that reported by physicians favoring continuous upfront therapy without ASCT, based for example on the lenalidomide-dexamethasone combination. Similarly, the argument of cost does not support the use of continuous novel agent-based therapy upfront in comparison with early ASCT, which is less expensive than two years of therapy including for example lenalidomide.
As mentioned previously, our understanding of the biology of the disease has increased markedly over the last years. Systematic cytogenetic evaluations in clinical trials have revealed critical adverse prognostic factors, including 17p deletion as one of the most important, while the application of genomics has enabled the segregation of patients into risk groups according to different gene signatures. Although we are progressing towards a consensus regarding the definition of high-risk disease, no cooperative group is currently able to propose a risk-adapted strategy based on well-defined initial biological and/or clinical characteristics. Additional correlative studies including genomic and cytogenetic analyses are being performed in the two ongoing prospective trials comparing upfront versus delayed ASCT mentioned above, with the specific goal of defining subgroups of patients that may benefit from the different therapeutic approaches, in order to develop a valuable risk-adapted strategy. In the US, two groups are currently applying risk-adapted therapy. The Little-Rock group in Arkansas proposes the application of total therapy 4 or total therapy 5 depending on the results obtained with gene-expression profiling (GEP), with the more intensive strategy being offered to the subgroup of patients who present with high-risk disease. This strategy relies on their very extensive and impressive single-center experience, however treatments are not randomized, with all patients receiving HDT and ASCT, and Barlogie et al. are not trying to solve the issue of upfront versus delayed ASCT. The second famous group, at the Mayo Clinic, Rochester, Minnesota, is proposing the mSMART (Mayo Stratification for Myeloma and Risk-adapted therapy) algorithm, a local consensus opinion taking into account genetically defined risk status, including cytogenetics, GEP and plasma cell labeling index. This classification allows for the definition of three risk groups, high, intermediate and standard, which determine the treatment approaches. The high and intermediate risk groups are routinely offered ASCT, whereas in the standard-risk group, the collection of stem cells after four cycles of induction is proposed, but ASCT is performed according to the patient's or the physician's choice. In following this approach, the Mayo group is also not trying to answer the unsolved and burning question of early versus late ASCT, and, according to Dr Rajkumar's personal data, roughly 50% of eligible patients are currently deciding to adopt a delayed ASCT strategy, to be able to enjoy “normal life”. These patients run a high risk of selecting the wrong option, a mistake induced by the concept of “primum non nocere”, which is wrong in this context, as discussed previously. At ASH 2010, Siegel et al. reported the important results on the outcome of Len/dex followed by early ASCT in the ECOG E4A03 study  . This trial randomized newly diagnosed MM patients to lenalidomide with high-dose dexamethasone (LD) vs lenalidomide with low-dose dexamethasone (Ld). Upon completing four cycles of therapy, patients had the option of proceeding to ASCT or continuing on the assigned therapy. In this post hoc retrospective analysis of patients under the age of 65 and including only those surviving the first four cycles of therapy, OS at 3-years was 94% with early ASCT and 78% in patients continuing protocol therapy. Although a direct comparison between patients undergoing early transplant versus those who did not was not possible because the assignment to early ASCT versus no early ASCT was not randomized, the survival with ASCT at 3-years appeared higher. The authors concluded that the strategy of lenalidomide plus dexamethasone induction followed by early ASCT had a remarkably good outcome in terms of OS and supported the continued role of early consolidative ASCT in newly diagnosed patients. To strengthen this point of view, I want to add that patients declining early ASCT should be informed that very few oral combinations lead to a VGPR rate of 70–80%. Continuous treatment with Len/dex yields only a 45% VGPR rate, with a median PFS of 25 months, which is not optimal. If the goal is to reach a 70–80% VGPR rate without ASCT, patients should receive combinations including bortezomib + dexamethasone + IMiDs or cyclophosphamide, which require frequent hospital stays over a period of at least 6–10 months, which is the same duration of therapy as for the application of induction + ASCT + consolidation. Outside of clinical trials, patients should also be informed that delaying ASCT carries the risk of the procedure becoming unfeasible due to refractory disease, deterioration of performance status, or comorbidity. In general, frontline ASCT is viable in more than 90% of cases, a rate which is significantly reduced in the relapse setting. This point was clearly demonstrated in the study by Fermand et al., in which only 77% of the patients of the late ASCT arm could actually receive the planned intensification at the time of relapse.
I am not against the possibility of restricting ASCT to a particular subgroup of patients, and I strongly support the idea of implementing a tailored approach for our patients in the future, based on individual risk factors in the same way as it has become standard in the treatment of acute leukemias. To date, regrettably, we have not reached that point in myeloma. In my view, the optimal approach to the treatment of MM is still to propose the most effective treatment for all patients, regardless of risk status and including the so-called “good risk” patients, and that this most effective treatment should involve the use of ASCT.
In summary, the last decade has seen significant advances in the setting of ASCT, which have resulted in substantial improvements in survival. My personal opinion is that ASCT, which is a cost-effective procedure that is associated with a low mortality rate, will remain the standard of care in the 2010s, and future studies should be focused on defining the groups of patients that will benefit most from this procedure.
S. Vincent Rajkumar, MD
Dr. Moreau has summarized the literature exceedingly well. His group, the IFM, has conducted phase III trials to address every important question one could think of in this context: ASCT versus no ASCT; early ASCT versus salvage ASCT; single ASCT versus double ASCT; ASCT versus allogeneic SCT, and so on. It would therefore be quite presumptuous to argue with the systematic way in which he has presented the rationale for his position or the data on which he has based his arguments on. Thus it is with some reluctance that I make three counter points to highlight some differences of opinion, but preface that with the caveat that these are situations in which the truth could the opposite of what either of us believes in, and can only be answered with additional scientific research, particularly because the field is evolving so rapidly.
First, it is not my intent to provide a philosophical point of view or an explanation that is counter to the data. Rather, my goal is simply to present what the data actually show, and how the interpretations can sometimes be well above what the actual randomized data are. For example, if one asks the question, “Does early ASCT make me live longer than delayed ASCT?” the only 3 randomized trials that have specifically addressed the question do not provide any evidence to support that. Second, I prefer to interpret a randomized trial based on what the randomization was specifically designed to answer. In other words results if a trial tests single upfront ASCT versus double upfront ASCT, it can only be used to answer whether 2 transplants are better than one. It cannot be used to interpret the role upfront versus delayed ASCT because that was not addressed by the trial. This seems very obvious, but a lot of the arguments on why ASCT is best done upfront are based on “phase II” type interpretations of trials in which the timing of transplant was not the randomized question. Thus although numerous randomized trials have found impressive benefits with treatment regimens that includes upfront ASCT, when the question is early versus delayed ASCT, these trials become mainly distractions; I have to fall back on the only 3 trials that specifically addressed this question. Finally, although the subject of this debate is ASCT in myeloma, my arguments apply equally well, if not even more, to the evaluation of new drugs in this disease, as well as other similar malignancies: we should be careful about trial-design, avoid over-interpretation of trial results, and wary of “superiority” based on surrogate endpoints.
P. Moreau, MD
Dr Rajkumar has nicely raised important issues on the role of early ASCT in multiple myeloma. To my opinion, the 2 most important ones are not yet solved. The first one is: are we able to offer our patients a tailored approach according to risk-factors at diagnosis?, and the answer is no. The second one is: do we have data supporting the systematic use of delayed ASCT at the time of relapse after novel-agent based induction?, and the answer is also no; ongoing trials are currently investigating this burning question.
Conflicts of interest
The authors declare no financial support and no conflicts of interest.
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