Page 191 - 2021_12-Haematologica-web

Letters to the Editor
Melphalan dose intensity for autologous stem cell transplantation in multiple myeloma
High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) remains the standard of care upfront treatment for transplant-eligible multiple myelo- ma (MM) patients.1,2 High-dose melphalan 200 mg/m2 (Mel200) is the standard preparative regimen for MM.1 Over the past two decades, several prospective clinical trials compared Mel200 to more intense preparative reg- imens in an attempt to improve efficacy.3 Generally, none of these regimens showed an overall survival (OS) advan- tage over Mel200. However, some reported superior pro- gression-free survival (PFS),4 albeit with higher rates of regimen-related toxicity. Furthermore, older and frail patients are not candidates for more intense regimens.
Reduced-dose melphalan is frequently used as an alter- native for older patients and those considered unfit for Mel200 because of frailty or medical comorbidities. Melphalan 100 mg/m2 (Mel100) was shown to be less effective compared to Mel200, albeit better tolerated.5,6 An intermediate dose of melphalan 140 mg/m2 (Mel140) has been widely used in older patients and those with significant comorbidities. Several groups reported feasi- bility of Mel140, particularly for older patients and those with renal impairment,7,8 however with conflicting out- comes when compared to Mel200.9-11 A recent report by the European Society for Blood and Marrow Transplantation (EBMT) showed similar outcomes between Mel140 and Mel200, except for a subset of patients with suboptimal responses to pretransplant induction therapy.12 In this study, we compared the safe- ty and efficacy of Mel140 versus Mel200 in a recent cohort of MM patients who received an ASCT at our institution.
We included all consecutive adult patients, who were 18 years or older, with newly diagnosed MM who under- went upfront ASCT consolidation and received single agent HDC of Mel140 or Mel200. Primary endpoints
were PFS and OS, computed from date of transplant. Secondary endpoints included cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and toxici- ties. OS and PFS estimates for each melphalan group were obtained from Cox regression models, adjusting for the selected variables. We identified 911 eligible patients between January 2010 and December 2015, with a medi- an age of 62 (range, 31-82) years. Ninety-seven (11%) received Mel140 and 814 (89%) received Mel200. Patient and disease characteristics are summarized in Table 1. Patients in the Mel140 group had significantly higher rates of hematopoietic cell transplantation-specific comorbidity index (HCT-CI) >3 and were significantly older. Furthermore, a higher proportion of patients in the Mel140 group had Karnofsky performance status (KPS) <90, International Staging System (ISS) stages II-III, renal impairment, and less frequently had received triplet induction therapy (Table 1). In order to correct for poten- tial bias for the impact of disease status at transplant (i.e., partial response [PR] or worse and very good partial response [VGPR] or better), we performed 1:3 (Mel140 vs. Mel200) propensity score matching within disease status using the variables listed in Table 2. Matching was done separately for patients with ≤PR and those with ≥VGPR at ASCT. After matching, only HCT-CI scores for patients with ≥VGPR 1st transplant remained significantly different between the two melphalan groups (Table 2). The median age of the matched patients was 69 (range, 43-81)years.
With a median follow-up of 54.6 (range, 0.3-112.2) months of all study patients, the median PFS and OS were 39.6 (95% confidence interval [CI]: 36.7-43.8) and 92.0 (95% CI: 85.0-101.1) months, respectively. At the time of transplant, 52% had ≥VGPR in the Mel140 group compared to 50% in the Mel200 group (P=0.75). At 3 months after transplant, the response rates were similar between the two melphalan groups (P=0.23). The com- plete response (CR)/stringent CR (sCR), VGPR, and PR rates were 26%, 49%, and 20%, respectively, in the Mel140 group, compared to 29%, 46%, and 22%,
AB
Figure 1. Kaplan-Meier survival curves of multiple myeloma patients treated with either Mel140 (dashed lines) or Mel200 (solid lines) conditioning prior to autologous stem cell transplantation. (A) Progression-free survival; (B) overall survival. Mel140: intermediate dose of melphalan 140 mg/m2; Mel200: high dose of melphalan 200 mg/m2.
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