Abstract

Background

Melphalan at a dose of 200 mg/m2 IV (MEL 200) is considered the standard preparative regimen for autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma. However, reduced doses of melphalan such as140 mg/m2 (MEL 140) are often used in older patients or patients with renal dysfunction.

Methods

The purpose of this retrospective analysis was to determine if there was a difference in toxicity, treatment-related mortality (TRM), response rate, progression- free survival (PFS) or overall survival (OS) in patients that received 140 mg/m2 of melphalan (MEL 140) compared to those receiving MEL 200 for auto-HCT. From June 1, 1996 through December 31, 2012, 63 patients received MEL 140. We compared their outcomes with 252 patients that received MEL 200.

Results

Patient characteristics and outcomes are shown in the attached Table. Patients in the MEL 140 group were older, had a higher β2 microglobulin (β2M) level both at diagnosis and auto-HCT, and had a higher serum creatinine (Cr) at auto-HCT (Table). A higher proportion of patients in MEL 140 were older than 65 with serum Cr > 2 mg/dL. There was no significant difference in disease status or high-risk cytogenetics between the 2 groups (Table). NCI CTCv3 > III non-hematologic toxicity was not significantly different between MEL 140 and MEL 200. Transplant-related mortality (TRM) at 100 days and at 1 year was 0% and 0.4% in MEL 140 and 200 (p=1.0), respectively. Complete remission (CR) rates in MEL 140 and MEL 200 were 16% and 29%, respectively (p=0.03). There was no significant difference in (CR) + very good partial remission (VGPR), or overall response (CR + VGPR + PR) between MEL 140 and MEL 200. Median follow up in surviving patients in MEL 140 and 200 was 7.6 and 25 months, respectively. Fifteen (24%) and 64 (25%) patients died in MEL 140 and MEL 200 groups, respectively, with >90% of deaths due to recurrent disease. Median PFS was 26.4 and 30.6 months in MEL 140 and MEL 200 groups, respectively (p=0.46). Median OS was 38.4 and 93.0 months in MEL 140 and MEL 200 groups, respectively (p=0.02). However, there was no significant difference in PFS or OS in patients older than 65 or with serum Cr > 2 mg/d between MEL 140 and MEL 200.

Conclusion

The dose of melphalan can be safely reduced to 140 mg/m2 in patients >65 or with renal insufficiency without adversely impacting the overall response rate or PFS.

MEL 140 (N=63)MEL 200 (N=252)p value
Age at auto-HCT (median) 71 (47-82) 63 (36-76) 0.0001 
Patients > 65 at auto-HCT 43 (68%) 77 (31%) 0.0001 
ISS Stage
I
II/III
Unknown 
11 (17%)
34 (54%)
18 (29%) 
80 (32%)
114 (45%)
58 (23%) 
0.02
0.25
0.41 
Serum Cr mg/dl at auto-HCT (median) 1.3 1.045 0.05 
Serum creatinine
>/= 2 mg/dl 
15 (24%) 32 (13%) 0.04 
Serum b2M mg/dl (median) at Dx 5.5 3.7 0.0002 
Serum b2M at auto-HCT (median) 4.0 2.5 <0.0001 
High-Risk cytogenetics 9 (14%) 31 (12%) 0.67 
Interval Dx to auto-HCT (months) 8.8 7.5 0.05 
Disease Status at auto-HCT
 • First Remission/Prim.
 • Ref.Relapsed 
48
15 
205
47 
0.37
0.37 
Post auto-HCT Response
CR
CR + VGPR
CR + VGPR + PR 
10 (16%)
35 (56%)
56 (89%) 
73 (29%)
154 (61%)
231 (92%) 
0.03
0.47
0.46 
Maintenance 22 (35%) 76 (30%) 0.54 
Median F/U (months) 7.6 25 <0.0001 
>/= Grade III AE 31 (49%) 101 (40%) 0.20 
100-day TRM 1 (0.4%) 1.00 
1-year TRM 1 (0.4%) 1.00 
Median PFS (months) 26.4 30.6 0.46 
Median OS (months) 38.4 93.0 0.02 
Median OS >65 only (months) 38.6 62.2 0.10 
Median PFS >65 only (months) 26.0 24.4 0.99 
Median OS Cr >/= 2 mg/dl (months) 32.1 69.3 0.50 
Median PFS Cr >/= 2 mg/dl (months) 24.5 31.3 0.87 
MEL 140 (N=63)MEL 200 (N=252)p value
Age at auto-HCT (median) 71 (47-82) 63 (36-76) 0.0001 
Patients > 65 at auto-HCT 43 (68%) 77 (31%) 0.0001 
ISS Stage
I
II/III
Unknown 
11 (17%)
34 (54%)
18 (29%) 
80 (32%)
114 (45%)
58 (23%) 
0.02
0.25
0.41 
Serum Cr mg/dl at auto-HCT (median) 1.3 1.045 0.05 
Serum creatinine
>/= 2 mg/dl 
15 (24%) 32 (13%) 0.04 
Serum b2M mg/dl (median) at Dx 5.5 3.7 0.0002 
Serum b2M at auto-HCT (median) 4.0 2.5 <0.0001 
High-Risk cytogenetics 9 (14%) 31 (12%) 0.67 
Interval Dx to auto-HCT (months) 8.8 7.5 0.05 
Disease Status at auto-HCT
 • First Remission/Prim.
 • Ref.Relapsed 
48
15 
205
47 
0.37
0.37 
Post auto-HCT Response
CR
CR + VGPR
CR + VGPR + PR 
10 (16%)
35 (56%)
56 (89%) 
73 (29%)
154 (61%)
231 (92%) 
0.03
0.47
0.46 
Maintenance 22 (35%) 76 (30%) 0.54 
Median F/U (months) 7.6 25 <0.0001 
>/= Grade III AE 31 (49%) 101 (40%) 0.20 
100-day TRM 1 (0.4%) 1.00 
1-year TRM 1 (0.4%) 1.00 
Median PFS (months) 26.4 30.6 0.46 
Median OS (months) 38.4 93.0 0.02 
Median OS >65 only (months) 38.6 62.2 0.10 
Median PFS >65 only (months) 26.0 24.4 0.99 
Median OS Cr >/= 2 mg/dl (months) 32.1 69.3 0.50 
Median PFS Cr >/= 2 mg/dl (months) 24.5 31.3 0.87 

Dx= diagnosis, TP= transplant, Prim.Ref.= primary refractory, AE= adverse effects, Cr= creatinine, b2M = beta 2 microglobulin

Disclosures:

Qazilbash:Otsuka Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Author notes

*

Asterisk with author names denotes non-ASH members.