Page 194 - 2021_12-Haematologica-web

Letters to the Editor
These two regimens have not been compared in ran- domized clinical trials, but few studies reported conflict- ing results.9-12 In a small non-randomized prospective study for patients older than 65 years, there was a trend for inferior PFS and OS for patients who received Mel140.9 In contrast, three recent studies reported com- parable outcomes between the two regimens. The Mayo group reported no significant differences in survival esti- mates by melphalan dose intensity in older patients, despite observing improved post-transplant response rates with Mel200.11 The study by Katragadda et al. showed comparable response and survival outcomes for Mel140 versus Mel200.10 In a recent study by the EBMT group that provides the largest analysis of outcomes between the two melphalan doses,12 Mel200 was found to be associated with better outcomes only in patients with <PR at the time of ASCT. In contrast, Mel140 was associated with a better OS in patients transplanted in >VGPR.
Our results from this large single center study further indicate that Mel140 has comparable efficacy to Mel200. Consistent with the EBMT results, we found that Mel140 can be particularly beneficial for patients who have achieved VGPR or better at ASCT. Of importance to note, the majority of patients in our study were (after matching) older (median age, 69 years) and/or with comorbidities. Hence, our findings might not be general- izable for younger fit patients. Furthermore, 46% of patients in the Mel140 group had an HCT-CI >3. Despite older age and medical comorbidities, the use of Mel140 was generally well-tolerated in this high-risk population. Mel140 was associated with less gastrointestinal toxici- ties and significantly less mucositis. Patients in the Mel140 group, despite matching, had higher rates of renal insufficiency and worse KPS, in addition to higher HCT-CI. All of these characteristics may have con- tributed to higher grades 3-4 non-hematological toxici- ties, when compared to Mel200. However, even with these adverse baseline characteristics, there was no increase in treatment-related mortality in patients who received Mel140. Besides the impact of dose intensity on the increased toxicity, the melphalan dosing in our study was fixed based on the body surface area, as opposed to pharmacokinetic-directed dosing, which could have potentially lead to inter-patient differences in their expo- sure to mephalan and hence a variability in the associated safety and efficacy profile.
Our study has the predictable limitations of a retro- spective analysis, including patient selection and missing data, such as revised ISS (R-ISS) stage and minimal resid- ual disease status, the use of which were limited during the study period. In order to overcome some of these lim- itations, we limited the study period to patients trans- planted after 2010 and used a propensity matched scor- ing model to account for most of the known risk factors that may influence the outcomes. Furthermore, the results were reproduced by a second analytic method using multivariable regression models fit on all patients and adjusting for the same variables that were used in the matched cohort.
In conclusion, in this large, single-center matched analysis of a homogeneous patient population with MM we showed that Mel140 has comparable efficacy to Mel200, particularly in older patients and those with VGPR or better at the time of transplant.
Samer A. Srour,1 Denái R. Milton,2 Qaiser Bashir,1
Yago Nieto,1 Neeraj Saini,1 May Daher,1 Jeremy Ramdial,1
Jin Im,1 Chitra Hosing,1 Ruby Delgado,1 Elisabet Manasanch,3 Hans C. Lee,3 Sheeba Thomas,3 Gregory Kaufman,3
Krina Patel,3 Uday Popat,1 Donna Weber,3 Robert Orlowski,3 Elizabeth Shpall,1 Richard E. Champlin1
and Muzaffar H. Qazilbash1
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center; 2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, and 3Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence:
SAMER A. SROUR - ssrour@mdanderson.org doi:10.3324/haematol.2021.279179
Received: May 8, 2021.
Accepted: August 3, 2021.
Pre-published: August 19, 2021.
Disclosures: no conflicts of interest to disclose.
Contributions: SAS and MQ conceived and designed the research; RD helped in data collection and monitoring; DRM performed statistical analysis; SAS, DRM and MQ interpreted data;
SAS wrote the manuscript; and SAS, DRM, QB, YN, NS, MD, JR, JI, CH, RD, EM, HCL, ST, GK, KP, UP, DW, RO, ES, REC and MHQ critically reviewed and edited the manuscript for important intellectual content.
References
1. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol. 2019;37(14):1228-1263.
2. Kumar SK, Callander NS, Hillengass J, et al. NCCN guidelines insights: multiple myeloma, version 1.2020. J Natl Compr Canc Netw. 2019; 17(10):1154-1165
3. Martino M, Olivieri A, Offidani M, et al. Addressing the questions of tomorrow: melphalan and new combinations as conditioning regimens before autologous hematopoietic progenitor cell transplantation in mul- tiple myeloma. Expert Opin Investig Drugs. 2013;22(5):619-634.
4. Bashir Q, Thall PF, Milton DR, et al. Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol. 2019;6(5):e266-e275.
5. Palumbo A, Bringhen S, Bertola A, et al. Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs. 200 mg/m2). Leukemia. 2004;18(1):133-138.
6. Palumbo A, Bringhen S, Bruno B, et al. Melphalan 200 mg/m2 versus mel- phalan 100 mg/m2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood. 2010;115(10):1873-1879.
7. Badros A, Barlogie B, Siegel E, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol. 2001;114(3):600-607.
8. Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell trans- plant in multiple myeloma patients with renal failure. Br J Haematol. 2001;114(4):822-829.
9. Garderet L, Beohou E, Caillot D, et al. Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: a prospective multicenter study. Haematologica. 2016;101(11):1390- 1397.
10. Katragadda L, McCullough LM, Dai Y, et al. Effect of melphalan 140 mg/m2 vs 200 mg/m2 on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation-a single center experience. Clin Transplant. 2016;30(8):894-900.
11. Muchtar E, Dingli D, Kumar S, et al. Autologous stem cell transplant for multiple myeloma patients 70 years or older. Bone Marrow Transplant. 2016;51(11):1449-1455.
12. Auner HW, Iacobelli S, Sbianchi G, et al. Melphalan 140 mg/m(2) or 200 mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018;103(3):514- 521.
3214
haematologica | 2021; 106(12)