More Is Not Better
Claudia Andreu-Vieyra, Ph.D and James Berenson, M.D.
Multiple myeloma (MM) is the most common primary malignancy of the bone marrow.1, The 5-year survival rate for MM patients has increased from 25% in 1975 to almost 40% due to newer and more effective drugs, such as the immunomodulatory agents (IMiDs) thalidomide and lenalidomide and the proteasome inhibitors (PIs) bortezomib and carfilzomib.2,3 The number of treatment options is rapidly expanding, due to not only the availability of new combinations involving already approved drugs, but also the development of new investigational products available to patients through clinical trials.
The goal of therapy for the MM patient should be to provide maximum survival time with minimal impact on their quality of life (QOL) from both the effects of the disease and the treatment, and patients must be given the opportunity to take advantage of the plethora of choices that are presently available and will become available during their disease course. This does not necessarily mean that administering the regimen associated with the highest proportion of complete responses (CRs) is best for the patient in the long-run. In fact, there is little difference in tumor burden between patients showing stable disease and CRs. Until recently, high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) was associated with the highest CR rates for MM patients and this procedure has been the standard frontline treatment for younger MM patients with normal renal function.4,5 Three main arguments have been used in support of ASCT: 1) high CR rates; 2) prolonged progression-free survival (PFS) and in some trials overall survival (OS) advantage; and 3) the lack of a need for additional therapies following ASCT.
First, the higher CR rates resulting from ASCT compared to conventional therapy have been consistently associated with both a delay in time to progression and prolongation of PFS. It is important to recognize that CR is based on the absence of measurable paraprotein but, unfortunately, this does not translate to the absence of tumor cells in the vast majority of MM patients. Thus, patients in CR may show progressive disease at a time when their paraprotein remains immeasurable whereas patients in less than a CR will have a marker that can be measured as they progress. Thus, it is obvious that patients in CR will show a longer PFS than patients who do not obtain a CR and continue to have a measurable protein marker.
Most importantly, the advantage of ASCT in terms of OS has proven to be inconsistently demonstrated in the randomized trials despite the consistent PFS advantage even in randomized trials completed prior to the advent of many new more effective therapies.6– ,9 Furthermore, trials comparing early ASCT vs. this procedure at the time of disease progression have shown no differences in OS.10 Notably, the recent introduction of PIs and IMiDs into induction regimens administered prior to ASCT has greatly improved response rates especially CRs even prior to these patients undergoing the HDT procedure. But even a scenario in which patients underwent induction treatment with IMiDs, followed by early (within 12 months of diagnosis) or late ASCT (more than 12 months of diagnosis) has failed to demonstrate significant changes in either PFS or OS in a recently published retrospective study.11 More recently, a phase 3 trial of 402 MM patients ages 65 and younger, evaluated PFS and OS for the combination of melphalan, prednisone, and lenalidomide (MPR) compared to high-dose melphalan followed by ASCT (MEL200-ASCT). After a median follow-up time of 45 months, the results showed that MEL200-ASCT significantly prolonged PFS compared to MPR; however, OS was similar between both arms.12 Interestingly, a previous study comparing MPR to MP showed no OS advantage among MM patients who were not transplant candidates suggesting that the ASCT procedure provided no OS advantage even compared to conventional chemotherapy. An ongoing phase 3 trial (NCT01208662) is currently evaluating whether HDT is still necessary for the management of MM in younger patients (< 65 years) in the era of new anti-MM drugs. This study is exploring the lenalidomide-bortezomib-dexamethasone combination with or without ASCT, followed by maintenance therapy with lenalidomide.
Regarding the need for additional therapies after ASCT (or lack thereof), both consolidation (short-term) and maintenance (long-term) therapies following ASCT have been used to improve outcomes for MM patients for the past several years. Before novel agents became available, the consolidation treatment consisted of a second, tandem ASCT.13,4 More recently, bortezomib, thalidomide, dexamethasone, and lenalidomide either as single agents or in combination therapy have been evaluated.13 Bortezomib, thalidomide and lenalidomide have also been evaluated for maintenance therapy.14 For instance, in the randomized MPR vs. MEL200 study, a second randomization showed that the addition of lenalidomide as maintenance therapy reduced the risk of progression, irrespective of the previous treatment.12 Another study evaluated time to progression and OS in 460 patients (≤71 years old), who received lenalidomide as maintenance therapy or placebo 100 days after MEL200-ASCT. After a median follow‑up of 35 months, the results from this trial demonstrated that patients receiving lenalidomide had a significantly longer time to progression and improved OS,15 making the argument that MM patients could have a treatment-free interval following ASCT likely obsolete.
In the past, HDT and newer induction regimens followed by ASCT were far superior in achieving CR than any other treatment regimen for MM patients; however, times have changed, and, recently, the combination of carfilzomib, lenalidomide and dexamethasone without ASCT for previously untreated MM patients demonstrated the highest CR rates and superior PFS.16 The studies mentioned above clearly show that there are no recent trials demonstrating an OS advantage associated with ASCT, and this recent three-drug combination trial suggests that newer drug combinations may offer superior outcomes without HDT.
As more treatment options become available, it is important to consider that the toxicity associated with HDT, especially when combined with aggressive multi-drug induction regimens, may compromise the ability of MM patients to receive the ever evolving panoply of new therapeutic options that are continually becoming available to them. Using these multi-drug combinations in induction therapy also may come at an additional cost, since being exposed to these newer anti-myeloma agents may compromise the patient’s eligibility for investigational treatments that may be of significant benefit to the patient.
MM patients are living much longer; and, therefore, finding the treatment that best fits their overall needs in the long and not the short run, as well as optimizing their QOL during their disease course is becoming increasingly important. In this case, “more” is not necessarily better, and transplants are all about “more.” Unfortunately, they are not “more specific” and they are not “better” at targeting the myeloma tumor cells. Thus, this type of therapy is fraught with off-target negative effects on other organs, which need to be kept at their optimum as patients face a future of many different treatment regimens given that the disease remains, for the most part, incurable today. As the medical community moves towards personalized medicine in other oncology areas, it is time to focus and develop anti-MM therapies that are tailored to the patient’s disease, age, co-morbidities, and life and work styles. Ultimately, therapies that only impact the myeloma tumor cells need to be made available. Advances in biology have led to the recent identification of targets on myeloma cells that can be exploited to allow the specific delivery of toxic therapy that only eliminates the tumor cell population. These approaches are now showing high efficacy in the laboratory not only in vitro but curing mice harboring human myeloma without any off-target negative effects. These therapies will hopefully be available for clinical testing in the near future and provide MM patients with treatments that will finally eliminate the cancer cells permanently without compromising their other organs. Most importantly, this new chapter in the era of targeted therapies will allow patients to lead lives that are not limited by the untoward effects of their anti-MM treatments.
References
1. Smith ML, Newland AC. Mini-review QJM Treatment of myeloma. 2000:11–14.
2. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111(5):2521–6. doi:10.1182/blood-2007-08-104984.
3. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20. doi:10.1182/blood-2007-10-116129.
4. Cavo M, Brioli A, Tacchetti P, Zannetti BA, Mancuso K, Zamagni E. Role of consolidation therapy in transplant eligible multiple myeloma patients. Semin Oncol. 2013;40(5):610–7. doi:10.1053/j.seminoncol.2013.07.001.
5. Moreau P, Avet-Loiseau H, Harousseau J-L, Attal M. Current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies. J Clin Oncol. 2011;29(14):1898–906. doi:10.1200/JCO.2010.32.5878.
6. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996;335(2):91–7. doi:10.1056/NEJM199607113350204.
7. 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(19):1875–83. doi:10.1056/NEJMoa022340.
8. Bladé J, Rosiñol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106(12):3755–9. doi:10.1182/blood-2005-03-1301.
9. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006;24(6):929–36. doi:10.1200/JCO.2005.04.5807.
10. Fermand JP, 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(9):3131–6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9787148. Accessed March 18, 2014.
11. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118(6):1585–92. doi:10.1002/cncr.26422.
12. Boccadoro M, Cavallo F, Gay FM, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients. ASCO Meet Abstr . 2013;31 (15_suppl ):8509. Available at: https://meeting.ascopubs.org/cgi/content/abstract/31/15_suppl/8509.
13. Moreau P. VI. Autologous stem cell transplantation and maintenance therapy. Hematol Oncol. 2013;31 Suppl 1:42–6. doi:10.1002/hon.2066.
14. Leleu X, Attal M, Arnulf B, et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02. Blood. 2013;121(11):1968–75. doi:10.1182/blood-2012-09-452375.
15. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770–81. doi:10.1056/NEJMoa1114083.
16. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801–9. doi:10.1182/blood-2012-04-422683.