A Multi-Center Phase I/II Study of Melphalan, Prednisone, Thalidomide and Defibrotide in Avanced Multiple Myeloma Patients.

Defibrotide (DF) is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects, which has been shown to be active in various micrangiopathies, including the treatment and prophylaxis of veno-occlusive disease. While DF has minimal inhibitory effect on multiple myeloma (MM) in cell isolates, it showed single agent activity on human MM xenografts in SCID/NOD mice and markedly increased responsiveness of MM to cytotoxic agents, including melphalan, cyclophosphamide and dexamethasone in the same models. DF might thus enhance the response rate of Melphalan, Prednisone and Thalidomide, while protecting against the prothrombotic state seen with this combination in the treatment of MM. In this multicenter, open label, non-randomised phase I/II trial, dosing safety and efficacy of melphalan, prednisone, thalidomide, and DF (MPTD) were determined in pts with relapsed/refractory MM. Between March 2006 and July 2006 we enrolled 14 MM pts in first or second relapse. Primary refractory or pts receiving therapeutic anticoagulation were excluded. Oral melphalan was administered at 0.25 mg/Kg on D1–4, oral prednisone at 1.5 mg/kg on D 1–4, thalidomide was delivered at 50 mg on D1–35 on cycle 1 and at 100 mg from cycle 2 to cycle 6.

DF dose levels were:

Level + 1 DF = 17 mg/Kg i.v. or 2.4 g p.o. D1–4, followed by 1.6 g p.o. through D 35

Level + 2 DF = 34 mg/Kg i.v. or 4.8 g p.o. D 1–4, followed by 3.2 g p.o. through D 35

Level + 3 DF = 51mg/Kg i.v. or 7.2 g p.o. on D 1–4, followed by 4.8 g p.o. through D 35.

Each course was repeated every 35d for a total of 6 courses and no DVT prophylaxis was used.

Eleven pts received at least one MPTD-course and were evaluated. 9 pts were in 1^st relapse (5 after autologous transplant, 4 conventional chemotherapy), 2 pts in 2^nd relapse (autologous transplant, conventional chemotherapy, thalidomide based regimen). In the first 8 pts who received DF at Level +1 one DLT was observed: G3 ileus, which resolved. G3 or 4 hematological toxicities were reported in 7 pts (63%), which were manageable. Two pts (18%) experienced G 3 non-hematologic toxicity: 1 pt ataxia and motor neuropathy and 1 pt with G 3 ileus described above. G 1–2 non-hematological toxicities included fatigue (5 pts), neuropathy (4), infections (3), constipation (2), urinary frequency (1), hyperglycemia (1), rash (2), CVS (hypotension and bradycardia) (2) and lower limb edema (2). There were no DVTs reported, only 1 episode of G 1 bleeding and no G4 non-hematological toxicity.

M-protein reduction was evaluated according to the EBMT/IBMTR criteria, after 1 and 3 cycles of MPTD see table. After 3 cycles the overall response rate was 80%.

Initial results suggest that MPTD is an effective oral salvage therapy with manageable toxicity and no DVT seen to date in pts with relapsed, refractory MM. Accrual continues to define maximal tolerated dose. An update of these results will be presented.