Melphalan 140 mg/m2 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

Abstract

Melphalan at a dose of 200 mg/m2 is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m2 and melphalan 140 mg/m2 are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m2 (n=245) and melphalan 200 mg/m2 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m2 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m2versus melphalan 140 mg/m2: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m2 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m2 and melphalan 140 mg/m2 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m2 or melphalan 140 mg/m2 for key transplant outcomes (NCT01362972).

Copyright© 2018 Ferrata Storti Foundation.

Figures

Figure 1.

Overall survival after autologous stem cell transplantation for patients who received conditioning with melphalan 140 mg/m2 (Mel140) or 200 mg/m2 (Mel200). (A) Kaplan-Meier curves. (B) Multivariate analyses. The overall hazard ratio and corresponding P value (bottom line) refers to the comparison between Mel140 and Mel200 performed in a Cox model without interactions; the other hazard ratios and P values refer to interaction terms between melphalan dose and the indicated factors. All comparisons are adjusted for: age at transplant, renal function, prior proteasome inhibitor treatment, gender, status of disease, and Karnofsky score. CR/VGPR: complete response/very good partial response; PR: partial response.

Figure 2.

Progression-free survival after autologous stem cell transplantation for patients who received conditioning with melphalan 140 mg/m2 (Mel140) or 200 mg/m2 (Mel200). (A) Kaplan-Meier curves. (B) Multivariate analyses. The overall hazard ratio and corresponding P value (bottom line) refers to the comparison between Mel140 and Mel200 performed in a Cox model without interactions; the other hazard ratios and P values refer to interaction terms between melphalan dose and the indicated factors. All comparisons are adjusted for: age at transplant, renal function, prior proteasome inhibitor treatment, gender, status of disease, and Karnofsky score. CR/VGPR: complete response/very good partial response; PR: partial response.

Figure 3.

Cumulative incidence of relapse after autologous stem cell transplantation for patients who received conditioning with melphalan 140 mg/m2 (Mel140) or 200 mg/m2 (Mel200). (A) Kaplan-Meier curves. (B) Multivariate analyses. The overall hazard ratio and corresponding P-value (bottom line) refers to the comparison between Mel140 and Mel200 performed in a Cox model without interactions; the other hazard ratios and P values refer to interaction terms between melphalan dose and the indicated factors. All comparisons are adjusted for: age at transplant, renal function, prior proteasome inhibitor treatment, gender, status of disease, and Karnofsky score. CR/VGPR: complete response/very good partial response; PR: partial response.

Figure 4.

Survival and relapse risk by cytogenetic risk. (A) Overall survival, (B) progression-free survival and (C) relapse risk estimates and confidence intervals at 2 years after ASCT are shown for patients with high-risk or standard-risk chromosomal abnormalities.