Parameswaran N. Hari, MD, MRCP
Luciano J. Costa, MD, PhD
Over the past 20 years, the Intergroupe Francophone du Myelome (IFM) and Dr. Michel Attal have pioneered the use of autologous hematopoietic cell transplantation (AHCT) for multiple myeloma in a series of randomized studies. Notable studies include comparisons of planned upfront AHCT vs nontransplant chemotherapy in the 1990s (the IFM 90 trial), single AHCT vs tandem AHCT, and the use of lenalidomide (Revlimid) maintenance after AHCT vs placebo. In fact, the IFM 90 trial established the current standard of care for transplant-eligible patients with multiple myeloma, which remains to this day an initial period of disease-controlling “induction” therapy followed by planned upfront AHCT.
In the 20 years since IFM 90, several classes of new drugs have been approved—the immunomodulatory drugs (thalidomide [Thalomid], lenalidomide, pomalidomide [Pomalyst]); the proteasome inhibitors (bortezomib [Velcade], carfilzomib [Kyprolis], ixazomib [Ninlaro]); the antibodies (daratumumab [Darzalex], elotuzumab [Empliciti]); and the histone deacetylase inhibitor panobinostat (Farydak). The use of some of these “novel” agents in combination has undoubtedly made initial therapy for multiple myeloma much more effective, with excellent response rates.
Rightly so, the established standard of care of upfront planned AHCT has recently again become the subject of clinical trials, with comparisons of it against newer induction approaches, such as the bortezomib, lenalidomide, dexamethasone combination (RVD) tested in the IFM 2009 study recently reported by Attal et al in The New England Journal of Medicine.1 The study is reviewed in this issue of The ASCO Post.
Current Role of Upfront AHCT
The IFM 2009 trial1 is now the fourth trial in the novel agent era to compare planned upfront AHCT with a strategy of collecting hematopoietic cells early but delaying AHCT until after relapse; and it is the only one of the four trials to compare upfront AHCT with the RVD combination.2-4 Like the other three studies, IFM 2009 demonstrated the clear superiority of upfront AHCT as measured by the primary endpoint of progression-free survival. Notably, although two of the four prior studies have also shown the superiority of upfront AHCT in terms of overall survival,2,3 survival was near identical between the two arms in IFM 2009 at 44 months of follow-up. This led the authors to conclude that in the context of RVD induction therapy and lenalidomide maintenance, an approach of delaying AHCT to the time of first relapse was associated with inferior progression-free survival but equivalent overall survival compared with the standard of upfront AHCT.
We see no reason to overturn the existing standard of upfront transplantation in medically fit myeloma patients, even if they receive novel combination induction.— Parameswaran N. Hari, MD, MRCP, and Luciano J. Costa, MD, PhD
While applauding the authors for yet another landmark IFM study, we must caution the readers not to read too much into the lack of overall survival benefit. Specifically, this study (and the other three previously noted) has proven that the established standard of upfront AHCT cannot be abandoned, even in the era of novel agent induction. To place this study in clinical context, we need to examine the various outcomes of IFM 2009, analyze the reasons behind the lack of overall survival benefit for AHCT, and thereafter answer the question whether this study provides strong enough therapeutic evidence to make upfront AHCT optional or clinically equivalent to delayed AHCT.
Among the outcomes examined, response rates, depth of response, and achievement of minimal residual disease negativity were all superior for the upfront transplant arm in addition to the progression-free survival benefit. The only outcome that was similar between the arms was overall survival, but the study was not powered to detect an effect on overall survival; and thankfully within the short follow-up interval, only a small proportion of patients died (over 80% of patients are still alive in both arms).
AHCT was performed as salvage therapy in 79% of patients experiencing disease progression on the nontransplant arm. Thus, although a higher proportion of transplant-related adverse events were reported for the upfront AHCT arm, the study did not account for/report on similar transplant-related issues in the delayed AHCT arm. We agree with the authors that progression-free survival was rightly the primary endpoint—and perhaps the most meaningful feasible endpoint in a study such as this, which appraises the efficacy of an early therapeutic intervention in myeloma. Recent long-term analyses of the Cancer and Leukemia Group B (CALGB) 100104 study5 have shown that for upfront transplant recipients receiving lenalidomide maintenance, median survival is now close to a decade.
Additionally, with the multiplicity of effective therapies available at relapse (including delayed transplant), any overall survival effect of the first intervention is blunted by the efficacy and availability of subsequent therapy. Finally, in myeloma therapeutics, we have now come to an era where multiple recent therapies were published, and approved for treatment of relapse after randomized trials demonstrated progression-free survival superiority, without demonstrating an overall survival difference.6-11
Key Clinical Questions
Here is the key clinical question for the practitioner: Do the IFM 2009 results give us enough confidence to change the established clinical standard of care of upfront AHCT in transplant-eligible patients? The upfront AHCT arm was the “winner” based on the predetermined primary endpoint of progression-free survival, which essentially measured the duration of disease control achieved with first-line therapy. Additionally, this approach led to more patients achieving deeper remissions, including minimal residual disease–negative status, an endpoint that is consistently associated with superior survival in multiple studies including this one.12,13 We therefore see no reason to overturn the existing standard of upfront transplantation in medically fit myeloma patients, even if they receive novel combination induction.
What should we make of the lack of overall survival benefit? We should celebrate the fact that with a follow-up close to 4 years, this most definitive of endpoints was not reached for the vast majority of patients. Physicians treating myeloma have accepted and regulatory agencies have approved numerous combination therapies for relapse based purely on progression-free survival benefit without an overall survival benefit,6-11 for reasons previously mentioned.
For IFM 2009, the study design accepted the practical futility of powering for overall survival benefit in a first-line treatment study. It is therefore disingenuous to argue that delaying AHCT in eligible patients is an equivalent strategy based on these results. Even if we exclude the benefits of AHCT documented in numerous other studies,14 practical concerns should guide us to recommend upfront AHCT in all eligible patients in the modern era.
Premature to Abandon Upfront AHCT
As discussed in The ASCO Post on May 10, 2017, a recent updated analysis of the two major upfront AHCT followed by lenalidomide maintenance studies (CALGB 100104 and IFM 2005-02) has shown an unprecedented median overall survival of 111 and 106 months , respectively (For more details on this analysis, visit http://www.ascopost.com/issues/may-10-2017/lenalidomide-as-maintenance-therapy-in-multiple-myeloma-after-autologous-stem-cell-transplantation/.) This 10-year overall survival of almost 50% is a dramatic improvement from the historic results with AHCT, which were more on the order of 15% to 30% at 10 years, as summarized by van Rhee et al in 2014.14 It is therefore troubling to abandon a time-tested strategy in myeloma on the basis of studies with shorter follow-up. Next, the utilization of AHCT remains worryingly low in the United States, especially among disadvantaged minorities,15 and we believe sending the message that upfront AHCT is optional is premature, if not misleading.
High-dose melphalan treatment with autologous hematopoietic progenitor cell support is performed in many centers as an outpatient procedure, with < 1% mortality, and leads to a long progression-free period, which translates into excellent quality of life (which was not reported for IFM 2009). Remarkably, with the escalation of cost of new myeloma agents, transplantation is now a “value proposition,” with an incremental cost-effectiveness ratio estimated at $72, 852 per life-year gained,16 under the $100,000 generally considered acceptable for society and much lower than the incremental cost-effectiveness ratio associated with newer drugs.
Minimal Residual Disease Status
Dr. Attal and colleagues should be commended for generating prospective data on the importance of minimal residual disease with sensitivity to detect 1 myeloma cell in 104. Patients who became minimal residual disease–negative had longer survival, confirming that depth of initial remission is important in myeloma patients. As noted earlier, a higher proportion of patients receiving upfront AHCT reached a minimal residual disease–negative state (79% vs 65%), providing an excellent biologic basis for the extended progression-free survival (and perhaps survival with longer term follow-up?).
The supplemental data published with the manuscript also clearly indicate progression-free survival was improved with upfront AHCT, even within the minimal residual disease–negative cohort. This finding raises the possibility that (1) not all methods to reach 10-4 minimal residual disease are equal, and (2) that more sensitive minimal residual disease techniques are needed, such as next-generation flow cytometry and next-generation sequencing, which can detect 1% to 10% of the minimal residual disease burden detectable by the assay in the IFM 2009 trial.12,13,17
Although upfront autologous transplantation is effective at prolonging remissions and achieving deeper remissions, in the short term, it is inconvenient, uncomfortable, and poses risks of gastrointestinal symptoms, hospitalization, infection, alopecia, and the need for temporary intravascular catheter and in the long term an increased risk of second malignancies. A strategy of delayed transplantation, however, does not abrogate any of the acknowledged logistic and toxicity problems.
What the IFM 2009 study does prove is that AHCT is still the best approach to reach deep and durable remissions in patients with multiple myeloma, and it is best employed upfront if a long first remission is desired. It is also important to emphasize that no modern trial, including IFM 2009, has compared a strategy of AHCT with no transplantation in myeloma. Patients were still required to perform hematopoietic progenitor cell collection upfront after brief induction therapy, and those randomized to delayed transplantation were to pursue transplant at the time of first disease progression. It is therefore crucial that physicians caring for myeloma patients refer them for consultation with a transplant center soon after diagnosis, even if a delayed transplant strategy is chosen for logistic reasons.
In the future, combination therapies that lead to better disease eradication upfront will hopefully eliminate the need for transplantation and/or maintenance. This may be even at hand with second-generation proteasome inhibitors and immunotherapeutic interventions, including monoclonal antibodies and/or checkpoint inhibitors. Testing this approach would require an induction regimen more active than RVD (since most RVD-treated patients still relapse), a more sensitive minimal residual disease technique (since minimal residual disease–negative patients in IFM 2009 still relapsed), and a randomized noninferiority study design in which minimal residual disease–negative patients are randomly assigned to transplantation vs no transplantation. Until such a trial shows benefit, upfront AHCT still needs to be standard of care for suitable patients regardless of minimal residual disease status after induction. ■
Dr. Hari is the Armand J. Quick/William F. Stapp Professor of Hematology at the Medical College of Wisconsin and Director of the Adult Blood and Marrow Transplant Program at Froedtert Hospital in Milwaukee, and Dr.Costa is Associate Professor in the Department of Medicine at the University of Alabama at Birmingham.
DISCLOSURE: Dr. Hari has received research funding from Amgen, Takeda, and Celgene and honoraria from Amgen, Sanofi, Celgene, and Takeda. Dr. Costa has received research funding from Amgen, Janssen, AbbVie, and Celgene, as well as honoraria from Amgen and Sanofi.
3. Gay F, Oliva S, Petrucci MT, et al: Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: A randomised, multicentre, phase 3 trial. Lancet Oncol 16:1617-1629, 2015.
4. Cavo M, Beksac M, Dimopoulos MA, et al: Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: An intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM Trial). 2016 ASH Annual Meeting. Abstract 673.
5. Holstein SA, Owzar K, Richardson PG, et al: Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide vs. placebo maintenance therapy after single autologous stem cell transplant for multiple myeloma. 2015 ASCO Annual Meeting. Abstract 8523.
6. San-Miguel JF, Hungria VT, Yoon SS, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: A multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195-1206, 2014.
13. Flores-Montero J, Sanoja-Flores L, Paiva B, et al: Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. March 10, 2017 (early release online).
16. Shah GL, Winn AN, Lin PJ, et al: Cost-effectiveness of autologous hematopoietic stem cell transplantation for elderly patients with multiple myeloma using the Surveillance, Epidemiology, and End Results-Medicare database. Biol Blood Marrow Transplant 21:1823-1829, 2015.
17. Munshi NC, Avet-Loiseau H, Rawstron AC, et al: Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: A meta-analysis. JAMA Oncol 3:28-35, 2017.