High dose therapy and autologous stem cell transplantation continues to be an important component of the treatment approaches for multiple myeloma in transplant eligible patients.1
In fact, myeloma remains the most common indication for autologous stem cell transplantation in North America according to data reported to the CIBMTR. The wider adoption of this modality has resulted from randomized trials demonstrating a survival benefit for this approach compared to conventional non-transplant approaches. However, results of the initial trials also suggested that the improved outcome with SCT may be a reflection of the depth of response and an overall survival improvement was not consistently seen in all trials.15–17
The results of the S9321 trial suggested that the survival advantage might not persist once the complete response rates of conventional therapy improved.16
Introduction of newer, more effective therapies such as IMiDs and the proteasome inhibitor bortezomib has led to high response rates and deeper responses and has raised questions regarding the continued role of SCT in this disease. As a result of the high response rates seen at the end of the induction therapy, and low toxicity profile of current regimens, patients are increasingly opting to delay SCT and continue with initial therapy.8, 12
This raises important questions as to the efficacy of SCT when given in the context of disease refractory to the novel therapies and whether such a delay may compromise the eventual benefit a patient may obtain with this procedure.
In this study, we were able to show that the paradigm of comparable survival with early or delayed-SCT holds true in the context of newer therapies as it did with the alkylator based regimens of the past. The results are true irrespective of the specific IMiD used, whether thalidomide or lenalidomide, further confirming that the equivalence of SCT used in an early or deferred fashion is therapy independent. One might argue that there were more patients being treated with thalidomide in the early transplant group, but the comparisons hold true irrespective of the initial drug used. The differences in proportion of patients on the two drugs in the two groups likely reflects the better tolerability of lenalidomide and the increasing comfort on the part of physicians to defer transplant with the availability of more long term data with lenalidomide. The results serve to further underscore that SCT should be considered as a therapeutic regimen, like any other drug regimen, and not necessarily as platform to base other therapies on. This concept is further supported by the comparable time to progression after “first line therapy”; whether it was induction therapy followed by an early SCT or continued primary therapy with the intent to delayed-SCT. This is not surprising given the comparable response rates and depth of response seen with early SCT versus continued primary therapy from phase 2 trials and subgroup analysis of phase 3 trials. So it is reasonable to assume that short induction therapy followed by an SCT and continued induction therapy till progression represent two comparable “regimens” in terms of the duration of disease control; and two non cross resistant approaches that can be used in either order. We only included patients receiving IMiD based induction therapy in this study, since we had very few patients being initiated on bortezomib based regimens, given the predominantly referral nature of our patient population and the preference for oral regimens. It is likely that the results will hold true for patients treated with other effective agents as well. An important finding from the current study is the 4 year overall survival of over 80% in a group of transplant eligible patients, treated with lenalidomide and dexamethasone as primary therapy with the intent of transplant either early or deferred. This is comparable to results seen with multidrug combination therapies, highlighting the need to study sequential approaches using currently available drugs versus combination approaches in prospective studies, simultaneously examining the impact on quality of life.
Another important finding from this study is the comparable time to progression after early or delayed-SCT. This is in stark contrast to the results from the previous randomized trials that examined early versus delayed-SCT. In the MAG90 trial, a delayed-SCT was associated with a shorter TTP after SCT even though the overall survival was comparable with the two approaches.6
The type of therapy used as primary therapy in patients deciding on a delayed-SCT likely explains this. Unlike the earlier trials where patients were alkylator refractory or previously responsive to alkylating agents, patients going to a delayed-SCT in this study were all alkylator naïve at the time of SCT. In this aspect they were similar to their counterparts who elected to go for an early SCT. However, there was a trend to shorter overall survival following SCT in the delayed-SCT group. This is explained by the fact that this group of patients have “used up” one of the available treatment option since they went to transplant having relapsed following continued therapy with an IMiD and hence less likely to obtain a durable response to the treatment again.
The aspect of an early transplant approach that had traditionally tilted the decision in favor of an early transplant has been the reduced time without symptoms and side effects of therapy seen in phase 3 trials.6
However, this paradigm has changed with the newer agents, which are much better tolerated and can often be continued for prolonged duration with minimal toxicity and impact on quality of life. Hence it is not surprising that there is increased acceptance of the delayed-SCT approach. The current study, being retrospective in nature, does not allow up to compare the quality of life parameters with the two approaches. This will have to explored in the context of prospective trials comparing an early-SCT to delayed-SCT. The decision to go ahead with an early SCT or to defer transplant till relapse can be based on several factors including response to induction therapy, toxicity from treatment, physician bias, and patient perception among others. In the current study, the proportion of patients with deep responses was higher among those deciding to defer the SCT, a finding that would have undoubtedly influenced the decision. However, a recent study of patients undergoing SCT showed inferior survival for patients who obtained less than a PR to initial therapy with an IMiD unlike what had been seen in the pre-IMiD era.18
This does not necessarily contradict the current findings since over a third of patients with less than a PR opted for delayed-SCT and alternative therapies. Retrospective nature of the current study precludes an accurate determination of the reasons for early vs. delayed decision. Also, this study addresses the use of SCT primarily as the second line of therapy, as was the common practice in this patient group, and the results cannot be necessarily extrapolated to patients receiving an SCT after failing multiple lines of therapy with different newer drugs.
It is important however, to underscore that fact that nearly all patients underwent an early stem cell collection even when a delayed-SCT was planned. While slightly delayed compared to the early SCT group, the median time to collection of stem cells among the delayed-SCT group was 6.8 months representing 6–7 cycles of therapy. This is very important, as several studies have shown increased risk for collection failure in patients receiving initial therapy with lenalidomide while the impact of thalidomide and bortezomib appear to be less profound.19–22
The duration of therapy appear to be a strong predictor along with age of the risk of failure of stem cell collection.19
Had the approach been one of deferred stem cell collection at the time of stem cell transplant, the results may have been different as a higher proportion of patients would have failed to collect and hence unable to proceed to SCT.
Finally, the 4-year survival of over 80% among patients receiving lenalidomide and dexamethasone as initial therapy highlights the impact of newer therapies on patient outcome in myeloma. This is comparable to the results seen in the sub-analyses from the E4A03 clinical trial focusing on patients undergoing a stem cell transplant after lenalidomide and dexamethasone induction therapy. 23
Moreover, in this group of transplant eligible patients receiving lenalidomide and dexamethasone as initial therapy, the timing of transplant does not appear to alter the overall survival outcome.
In conclusion, this study conveys three important messages. It confirms the role of SCT as an effective treatment strategy for patients with myeloma with comparable survival outcomes when applied early in the course of disease or in a deferred manner following failure of continued initial therapy. It highlights the retained efficacy of high dose melphalan in alkylator naïve patients, demonstrating non-cross resistant mechanisms for disease control for these two approaches. Third, it demonstrates excellent long-term outcome for patients receiving initial therapy with lenalidomide and dexamethasone with overall survival of over 80% at 4 years. Thus patients have the option of delaying SCT and continuing with initial therapy if that is their preference. However, it is important to collect stem cells early on, given the reports of difficult stem cell collection in patients receiving prolonged treatment with lenalidomide. Whether such an approach will result in comparable quality of life metrics need to be studied prospectively.