Results of a Phase II Study of Propylene Glycol (PG)-Free, Captisol-Enabled Melphalan Conditioning for Autologous Hematopoietic Stem Cell Transplantation (AHCT) in Patients with Multiple Myeloma (MM)

Melphalan 200 mg/m² IV is the most common conditioning regimen for AHCT in MM.  Conventional melphalan formulations (eg, Alkeran) have marginal solubility, limited chemical stability and require PG as a co-solvent, which is associated with renal dysfunction and arrhythmias.  Captisol-enabled Melphalan HCL (CE-Melphalan) is a PG-free formulation of melphalan that incorporates Captisol, a modified cyclodextrin that improves  its solubility, stability and bioavailability. In a previous Phase 2 study, CE-Melphalan was shown to be bioequivalent to Alkeran.

Methods: This Phase II, open-label study enrolled  61 pts with MM who received 200 mg/m² of CE-Melphalan (100 mg/m²/day x 2) followed by AHCT. Most subjects were male (57%) with a median age of 62.0 years (range 32-73), including 56 (92%) subjects who received upfront AHCT and 5 (8%) after relapse (Table 1). Median lines of prior therapy was 3 (range 2-16). High risk cytogenetics in 6 (10%) pts.  Disease status at Pre-treatment included CR in 3 subjects, VGPR in 27 and PR in 20 subjects.

Results: All subjects achieved myeloablation followed by successful engraftment. Median time to neutrophil engraftment was 12 days post-AHCT (range: 10-12); time to platelet engraftment was 13 days (range 10-28). There was no mortality by Day 100, and as expected the most common Grade 3 and 4 toxicities were hematologic. Non-hematologic toxicities are summarized in Table 2. Severe mucositis was reported in few patients (Grade 3/4; 10%).  At Day 100 post-AHCT, all patients (100%) had a response with 82% of subjects achieving a >= VGPR response including sCR in 13%, CR in 8% and VGPR in 61%.

Conclusions: CE-Melphalan led to successful myeloablation and subsequent engraftment in MM patients with no mortality or unexpected transplant-related toxicity over conventional melphalan. The incidence of Grade 3-4 mucositis was low. Overall, 100% of subjects responded to high dose CE-Melphalan, and in the subgroup of high risk patients (n=6, 10%), an encouraging 67% VGPR or better responses were achieved.

Table 1.  Patient Characteristics

	Total (N =61)
Median Age (range) in yrs	62 (32 -73)
Age ≥ 65 yrs	30%
Male Gender	57%
Race   White   Black/African American   Other	80% 18% 2%
ECOG Status   0   1   2	59% 38% 3%
Disease Status Pre-treatment   sCR   CR   VGPR   PR	0% 5% 44% 32%
Disease Status at Day 100 post-AHCT   sCR   CR   VGPR   PR	13% 8% 61% 18%

Table 2. Grade 3/4 Non-hematologic Toxicities

Preferred Term	All Grades % (N=61)	Grade 3/4 % (N=61)
Diarrhea	93	3
Nausea	90	2
Fatigue	77	2
Hypokalemia	74	28
Vomiting	64	0
Hypophosphatemia	49	48
Decreased Appetite	49	0
Pyrexia	48	3
Constipation	48	0
Febrile Neutropenia	41	28
Mucosal Inflammation	38	10
Dizziness	38	0
Stomatitis	28	5
Abdominal Pain	28	0
Dysgeusia	28	0
Dyspepsia	26	0