New therapeutic options for the treatment of multiple myeloma are capable of achieving sustained and deep remissions, calling into question the role of upfront stem cell transplantation. ASH Clinical News has invited Shaji Kumar, MD, and Ola Landgren, MD, to debate the question: “What is the optimal timing for hematopoietic cell transplantation in patients with multiple myeloma – early or delayed?” Dr. Kumar will be arguing on the “early” side, and Dr. Landgren will be arguing on the “delayed” side.
Disclaimer: The following positions were assigned to the participants and do not necessarily reflect ASH opinions, the participants’ opinions, or what they do in daily practice.
Shaji Kumar, MD: For more than two decades, autologous hematopoietic cell transplantation (AHCT) has been used for the treatment of myeloma, based on studies that demonstrated that the combination of high-dose chemotherapy and AHCT enhanced response rates and improved survival – particularly in younger patients with the disease – compared with conventional therapy alone.1
Over the past 10 to 15 years, new agents in new therapeutic classes have become available and have been shown to improve patient outcomes; yet, randomized trials have consistently demonstrated that patients do benefit from receiving AHCT.2 I think the majority of hematologists would agree that AHCT is capable of producing durable disease control and improving the survival outcomes in multiple myeloma. Treatment with novel drug combination can demonstrate comparable levels of response, but complements the role of transplant.
Ola Landgren, MD: Yes, one can’t argue that certain patients benefit from AHCT, but does it benefit every single patient? Every patient is unique and the myeloma disease biology varies across patients. Beyond these facts, the myeloma treatment landscape and our possibilities to assess treatment response have changed dramatically the past few years.
As you mentioned, Dr. Kumar, there has been an influx of new drugs as alternatives to transplantation. Since 2012, when the U.S. Food and Drug Administration approved carfilzomib, there have been five new agents approved either as monotherapy or as part of a multiple-drug regimen for the treatment of multiple myeloma. Three of these agents (elotuzumab, ixazomib, and daratumumab) were approved in the month of November 2015 alone.
The pipeline we have ahead of us also promises more options in the near future. With all of these new configurations of drugs, the response to treatment and the duration of the response continues to grow, raising the question of whether the addition of high-dose melphalan will remain the standard of care for every patient. In simple language: Does high-dose melphalan followed by AHCT add progression-free and overall survival in patients who already have obtained a deep response following modern combination therapy? This question becomes increasingly more important as the proportion of newly diagnosed multiple myeloma patients who obtain MRD 10-6 negativity after modern effective combination therapy already is reaching 50 to 60 percent.3
Dr. Kumar: The initial randomized trials looking at this clinical question found that AHCT was effective consolidation therapy after the initial treatment of myeloma, but these trials were conducted when available therapies (such as doxorubicin, cyclophosphamide, vincristine, and melphalan) were simply not as effective,1,4 and three to four cycles of treatment failed to produce deep responses in the vast majority of patients. If no further measures were taken, these patients would inevitably relapse.
In these trials, AHCT served as consolidation therapy and allowed patients to achieve much deeper responses, which then translated into a longer relapse-free survival and overall survival than what was achieved in non-transplant cohorts. Even with new, more effective therapies for the initial treatment of myeloma, recent clinical trials have shown a benefit with transplantation, in terms of progression-free survival. The question we now have to answer is whether transplant should be performed early or late, after the initial treatment has stopped working.
We will have to wait for future clinical trials to inform us about the advantages and disadvantages of early versus delayed transplant, as well as which subgroups of patients would benefit most from transplant – either early or delayed.
The way I look at the question about the optimal timing of transplant is to consider AHCT like any other drug that’s out there. Just because it has been around for a while does not mean that it is any less effective – particularly for a patient who would rather receive one transplant versus multiple rounds of chemotherapy.
Dr. Landgren: I agree, but I would stress that the map of myeloma treatment is being redrawn, and it has to include these new drugs. There are many questions lacking answers; at the same time, though, almost 25,000 people are being diagnosed with multiple myeloma every year in the United States. They do not have time to wait for new trials to be developed – they need therapy now.
The IFM/DFCI trial you referred to demonstrated similar overall survival rates between upfront and delayed AHCT, and improved progression-free survival in the upfront transplant group. In my opinion, though, the most important part of the results from this study were presented separately at the 2015 ASH Annual Meeting.
In a sub-analysis of the IFM/DFCI data presented by Herve Avet-Loiseau, MD, PhD, immediate AHCT increased three-year progression-free survival compared with delayed AHCT, as well as overall survival and complete response rates.5 This difference in progression-free survival was driven by the proportion of “good” responders in the two treatment arms.
Indeed, he showed that there were more complete responders in the transplant arm, and that several patients achieved a complete response in the non-transplant arm. Importantly, when progression-free survival was assessed among patients who were MRD-negative, the results were similar, independent of treatment arm.
Mortality rates were low, but we still need to see how transplant will affect quality of life in longer-term follow-up.
Dr. Kumar: Nearly 20 years ago, researchers attempted to answer this question in a trial designed to assess the optimal timing of high-dose therapy and AHCT, comparing the combination of upfront AHCT and high-dose therapy with conventional-dose treatment followed by AHCT as rescue treatment.6 Rates of overall survival were similar, irrespective of the timing of transplant. However, event-free survival was longer in the early-transplant group. Most importantly, the quality of life was much better among patients who received AHCT early, with a longer average time without symptoms, treatment, and treatment toxicity.
So, even though the length of overall survival was similar, performing AHCT early clearly led to a better experience for the patient and was associated with a shorter period of chemotherapy. In my opinion, the potential benefit of performing a transplant early on in the treatment course is the ability to have less intensive chemotherapy and a better quality of life. With the newer drugs, this overall paradigm has not changed.
And again, though newer therapies are leading to higher response rates for the vast majority of patients, recent studies have continued to show that patients being treated with newer agents do benefit from early AHCT followed by some type of maintenance therapy. The results of the IFM/DFCI 2009 trial, which were presented at the 2015 ASH Annual Meeting, have provided us with some answers to this clinical question.2 The IFM group conducted a randomized trial comparing outcomes for patients treated with conventional therapy (8 cycles of lenalidomide, bortezomib, and dexamethasone [RVD]) with or without AHCT (3 induction cycles of RVD, followed by stem cell collection and AHCT conditioned with melphalan 200 mg/m2, followed by 2 cycles of RVD as consolidation) in 700 patients with previously untreated myeloma. Patients in the RVD arm were to receive delayed transplant at the time of relapse.
Immediate AHCT increased three-year progression-free survival compared with delayed AHCT, as well as overall survival and complete response rates. Mortality rates were low, but we still need to see how transplantation will affect quality of life in longer-term follow-up.
Dr. Landgren: The results of the small sub-analysis presented by Dr. Avet-Loiseau – though not definitive – raise a key question: What role does high-dose melphalan followed by AHCT have in a newly diagnosed multiple myeloma patient who has obtained MRD-negative status after combination therapy?
In the absence of a formal study, I think a reasonable statement to tell patients is: “We have no strong data either way. Based on our current knowledge, it seems very reasonable to collect stem cells and to go right to maintenance therapy without high-dose melphalan followed by AHCT.” In this setting, I would monitor MRD status longitudinally. Extrapolating into the future, if formal results from clinical trials continue to confirm and expand on these observations, I envision that myeloma treatment for newly diagnosed patients will become response-driven.
In countries with access to modern, powerful therapies, I conjecture that the role of high-dose melphalan followed by AHCT most likely will change. Instead of being offered upfront to every myeloma patient who can tolerate it, transplantation may move to a treatment given to myeloma patients who do not obtain a deep response after modern combination therapy or those who relapse. For these settings, transplant should be considered in the context of all available treatment options, and not as the default, “go-to” option.
Dr. Kumar: That’s true. One of the things myeloma specialists have come to realize over the past few years is that myeloma is heterogeneous. To some extent, we understand what happens based on genetic abnormalities or other risk-stratification categories, and we know that high-risk patients tend to have early death and relapse very soon after initial treatment.
Therefore, it is particularly important for us to identify the most aggressive therapies possible that still keep patients safe.
So, again, for patients with high-risk myeloma, it is crucial that we get them to an MRD-negative state by using all of our available options for treating this disease. Maybe some of the newer drugs are powerful enough to get patients to that state, but, if not, transplantation is a viable option that has a proven ability to get patients to that point.
Dr. Landgren: I agree with you that myeloma is highly heterogeneous. However, I think that many of the risk markers we rely on to stratify patients are superficial. Instead, these prognostic factors and risk-management strategies seem to assign risk in an arbitrary fashion – simply classifying a patient as either “negative” or “positive.”
As clinical researchers, we know that there are many more details beyond single arbitrary markers, such as t(4;14) or del17p.
Also, with many of the new drugs I referred to, the concept of “high” and “low” risk are not necessarily separate entities. And, after more therapies are developed and our treatment options and understanding of the disease improve, what used to be called “high risk” may actually be considered “standard risk” over time. My experience with newer drugs is that some of these so-called high-risk patients do extremely well with them; so, I don’t think that transplantation is necessary simply because these patients have genetic markers that are considered high-risk.
I would argue that myeloma doctors should stop looking at all available options for treating the disease upfront. We should instead focus more on how the disease behaves in each patient to help guide treatment decisions. The goal of myeloma treatment should be achieving a deep response, or MRD to levels of 10-5 or 10-6, with chemotherapy in a defined, shorter time period. Then, if at that point the patient reaches MRD negativity on highly sensitive assays, perhaps that patient could be spared from the transplant – independent of whatever markers show up.
- Attal M, Harousseau J, Stoppa A, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-7.
- Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Abstract #391. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.
- Korde N, Roschewski M, Zingone A, et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015;1:746-54.
- Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-83.
- Avet-Loiseau H, Corre J, Lauwers-Cances V, et al. Evaluation of minimal residual disease (MRD) by next generation sequencing (NGS) is highly predictive of progression free survival in the IFM/DFCI 2009 trial. Abstract #191. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.
- Fermand J, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92:3131-6.
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