Is transplant advisable for all eligible patients with multiple myeloma in first remission?
We have not yet moved away from bone marrow transplant for these patients, and I believe the best outcomes remain with an early transplant.
Transplant has been the standard of care for many years for eligible patients with multiple myeloma based on deep responses and improved PFS and OS compared with a nontransplant strategy. Ever since the data came out that demonstrated early transplant is associated with those benefits, there have been studies that have asked whether there is a better way. But, each of those studies has come up with the same three answers.
First, early transplant is associated with improvement in deep responses. Second, early transplant is associated with improvement in PFS. Third, compared with a strategy of delayed transplant — where about 80% of patients end up getting the transplant — there is no difference in OS.
Every time our treatments improve — such as with the development of lenalidomide (Revlimid, Bristol Myers Squibb), daratumumab (Darzalex, Janssen Oncology) or carfilzomib (Kyprolis, Amgen) — the question of whether we still need transplants reemerges. And every time that question is asked, results show there is still better PFS with an early transplant compared with a delayed transplant.
Patients must be followed for several years to see a PFS advantage; that advantage won’t appear in the early data, but you have to let the data mature. PFS data also help when having conversations with patients. These data suggest 30% of patients will be alive and in remission 10 years after their transplant if the maintenance strategy is used. There is no other data set with other options that shows a 30% 10-year PFS rate. So, it’s not only the immediate effects that are important, it’s the tail of that curve.
Transplant is a very intense and difficult procedure, and PFS is always longest when transplant is used after first remission. The people who say it is no longer a standard of care only look at OS. I don’t have an emotional need to give a transplant early. I am solely using the available data to drive the decision.
Patients believe that PFS is still an important endpoint, and as long as PFS is superior with this approach, I think it will remain the standard of care. The data are not there to change practice yet. The concept is there, but the data are not yet.
Attal M, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611750.
Joseph NS, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.02515.
Jonathan L. Kaufman, MD, is associate professor and associate vice-chair in the department of hematology and medical oncology and director of the division of hematology at Emory University School of Medicine. He also serves as medical director and section chief of ambulatory infusion centers at Winship Cancer Institute of Emory University. He can be reached at email@example.com.
This has been the subject of intense debate and is understandably controversial. High-dose melphalan with autologous stem cell transplant (HDM-ASCT) has been the standard of care for newly diagnosed multiple myeloma (MM) since the mid-1990s, when the initial randomized studies were published that demonstrated an OS advantage with this approach vs. standard-dose cytotoxic agents. During this era, we essentially had conventional chemotherapy and high-dose corticosteroids to treat MM, and neither worked or were well-tolerated.
The novel-agent era officially started in the U.S. in 2003 with the approval of bortezomib (Velcade, Millennium/Takeda) followed shortly thereafter by lenalidomide and then thalidomide. Early on, these agents were mostly given in combination with cytotoxic chemotherapy or with dexamethasone alone. About a decade ago, we entered what I call the “combined novel-agent era,” which is defined by highly potent triplet combinations such as RVd (lenalidomide, bortezomib and dexamethasone) and KRd (carfilzomib, lenalidomide and dexamethasone). We may now be entering the era of quad-induction therapy, with a backbone of an immunomodulatory drug, proteasome inhibitor and dexamethasone plus daratumumab or isatuximab-irfc (Sarclisa, Sanofi Genzyme). If you poll a room of MM specialists, you might get a split opinion on what should now be considered the standard of care in this regard.
The IFM 2009 and DETERMINATION trials were designed to evaluate the benefit of early vs. delayed consolidation with HDM-ASCT in the combined novel-agent era. These studies were identical in design except that the IFM 2009 trial used only 1 year of maintenance with lenalidomide, whereas its use continued until disease progression or intolerance in DETERMINATION. Four years ago, we saw a 14-month PFS benefit in IFM 2009 among patients who received the addition of early transplant to RVd (50 months vs. 36 months; HR = 0.65; 95% CI, 0.53-0.8); however, there was no OS benefit (HR = 1.16; 95% CI, 0.8-1.68). In an updated analysis presented at ASH in December, with a median follow-up of almost 8 years, PFS is now only 12 months longer in the early transplant arm, which is essentially offset by a second PFS that is 11 months longer in the RVd-only arm, and critically there is still no difference in OS (HR = 1.03; 95% CI, 0.8-1.32).
Moreover, an important correlative study conducted by Mehmet K. Samur, PhD, and colleagues in our group, also presented at ASH, showed that the mutational burden in the MM cells of patients on this prospective randomized trial was significantly higher at the time of relapse in HDM-exposed patients vs. those treated with RVd only, with the mutation accumulation rate being approximately fourfold higher. Although we do not yet know what the implications of this significant difference are in terms of genomic instability of the disease and long-term outcome, we need to consider the possibility that we may be making MM more difficult to treat over the long run with early HDM exposure, at least in some patients, and this may explain in part the absence of OS benefit in IFM 2009.
Likewise, although the incidence of therapy-related myeloid neoplasms is relatively low in IFM 2009 and DETERMINATION, these late sequelae remain a source of concern, as patients are now living much longer with MM than ever before, and there are recent data to suggest that HDM-ASCT may increase the risk for secondary MDS/AML substantially over time.
I also find the data that we do not yet have as interesting as the data that we do. By this, I mean that DETERMINATION, which began enrolling patients over a decade ago, has yet to meet its primary endpoint of PFS difference with median follow-up now exceeding 5 years and with two-thirds of planned events having already occurred. So, it may be that long-term maintenance diminishes the magnitude of the PFS advantage of early transplant to a point of questionable clinical significance.
Further complicating treatment decisions are the emerging data on MRD. We know that both achievement and sustainability of MRD negativity are associated with better long-term outcomes, and that more patients became MRD negative with early HDM-ASCT than without on IFM 2009. However, in this study as well as multiple others, we have also seen patients achieving negativity for the first time while on maintenance therapy and, in the case of quad-induction, a majority of patients can now achieve this endpoint even without HDM-ASCT. So for me, it is still difficult to use the MRD status of a patient at a specific timepoint as a guide for recommending early transplant. This may change as we begin to get data from MRD-driven clinical trials that have recently launched.
In conclusion, I believe that there are patients with MM who probably do still benefit from early HDM-ASCT, but the problem is that we don’t have a great handle on who they are. Until we do, it’s going to be hard to tell an individual patient with certainty whether we are doing the right thing either way. There are certainly still known advantages and valid reasons to go with early transplant (eg, in high-risk disease), but also reasons to reconsider, especially for standard-risk patients (eg, early and late toxicities and impact on quality of life).
In my opinion, it’s important to have a frank discussion with patients about both the knowns and the unknowns in terms of the benefit and risk of early HDM-ASCT, and to make an individualized decision that takes into account multiple factors and, above all, the goals and preference of the well-informed patient.
Attal M, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611750.
Jakubowiak AJ, et al. Blood. 2012;doi:10.1182/blood-2012-04-422683.
Landgren O, et al. Abstract 862. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; San Diego.
Radiovoyevitch T, et al. Leuk Res. 2018;doi:10.1016/j.leukres.2018.07.016.
Richardson PG, et al. Blood. 2010;doi:10.1182/blood-2010-02-268862.
The following were presented at ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020:
Perrot A, et al. Abstract 143.
Sumar MK, et al Abstract 61.
Clifton C. Mo, MD, is director of autologous stem cell transplantation for multiple myeloma at Dana-Farber Cancer Institute. He can be reached at firstname.lastname@example.org.