Cytoprotective Palifermin Allowed Melphalan Dose Escalation to 280mg/² for Multiple Myeloma Patients with Normal Renal Function Receiving Autologous Stem Cell Transplantation (ASCT) - Final Results of a Phase 1 Trial

Melphalan (M) 200 mg/m² is a standard conditioning regimen for myeloma patients (pts) with normal renal function (NRF) undergoing ASCT. M exhibits a steep, log-linear dose effect with a potential for dose escalation (DE) to overcome M resistance. However, severe oral mucositis (OM) at M ≥ 200 mg/m² precludes DE due to significant morbidity. Palifermin (P) as a cytoprotective agent has demonstrated efficacy in reducing intensity and duration of OM in pts receiving intensive chemo-radiotherapy. We designed a phase I study to determine the MTD of M in pts with NRF when used with P.

We enrolled 19 pts from 07/2007 to 09/2009. Data is reported on 18 evaluable pts as 1 pt was removed due to the inability to receive all 6 doses of P. DE was done (3 pt cohorts) in 20 mg/m² increments, depending on the dose limiting toxicities (DLT). Level (L) 1 began at M 200 mg/m² with P 60 mcg/kg/d, given as I.V. bolus on Day -5, -4, -3 and Day +1, +2 and +3 (PBSCs infused on Day 0). M was given on D-2 up to and including 280 mg/m² (n = 6). If no symptomatic grade ≥ 3 DLTs were noted by day +30, an additional cohort of 3 pts were entered at the next dose level. Dose escalations were to stop if ≥ 2 DLTs occurred at M dose; with that dose declared as the MTD. Grade 3/ 4 diarrhea and ≥ grade 3 cardiac toxicity was considered DLT; grade 3/4 hematological toxicity was acceptable. The grade of OM was assessed daily according to the WHO oral-toxicity scale (grade 0–4). Key Eligibility Criteria: age 18–74 years, stage 2/3, ECOG performance status < 2, CrCl > 60, total bilirubin ≤ 1.5 × IULN, ALT/AST ≤ 3 × IULN, eligible for ASCT per institutional criteria and at least 2.0 × 10⁶ CD34+ cells/kg cryopreserved for ASCT. Calculation of M dose: M dose was calculated using the actual body weight except when the actual body weight was > 40% above the ideal body weight; in that case, adjusted body weight was used.

Med age 48.5 y (33-65). Med # of prior Rx: 2 (1-5). Median CD34 cells dose 4.77 × 10(6) [2.18-11.36]; median day of neutrophil recovery +10 (10-13) and median day of platelet engraftment 19.5 (0 to 29). The overall incidence of OM ≥ grade 3 was 44% (8/18) with a median duration of OM 10 days (4 -20 d). Only 1 pt in L 1 group developed grade 4 OM. Two out of 6 pts given M 280 mg/m² did not develop any OM. Atrial fibrillation occurred in 1/6 pts treated with M 280 mg/m². The most common adverse events included rash (18 events, no grade 3), elevation of amylase (10, 4 grade 3-asymptomatic) and lipase (5, 2 grade 3 -asymptomatic) and edema (11, no grade 3). 11 pts (61%) required IV opioid analgesics; none needed TPN/NG feeding. All 18 pts were evaluable for response at D+100 and there were no treatment-related deaths. Median duration of follow up is 17.5 months (5.6-36.5). At D+100, all 18 patients were progression free. At D+365, 13 pts are free of progression, 2 have PD, and 2 have expired while 1 pt has not reached D+ 365 yet. First expired pt on L5 relapsed at 5 months post ASCT and no further details are available on two other expired patient.

Palifermin permits dose escalation of M up to 280 mg/m² with acceptable toxicity. A phase 2 trial is planned to better delineate the anti-myeloma efficacy of this regimen.

Abidi: Millennium: Speakers Bureau. Off Label Use: Bortezomib is currently not approved for maintenance therapy after Autologous stem cells transplant. Lum: Transtarget Inc: Equity Ownership.