Background: The histone deacetylase inhibitor vorinostat was approved by the United States FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following 2 systemic therapies. Vorinostat has also demonstrated promising preclinical activity in multiple myeloma.

Patients and Methods: A Phase I trial of oral vorinostat 200, 250 or 300 mg bid for 5 days each week of a 4 week cycle or 200, 300, or 400 mg bid for 14 days/3 week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed and/or refractory multiple myeloma with adequate hematologic, hepatic, and renal function were eligible. The objectives were to determine the maximum tolerated dose (MTD) on each of the schedules and assess activity and safety.

Results: Thirteen patients (median age, 63 years; median 7 prior systemic therapies) were enrolled. The MTDs were not determined due to early termination of the study due to the decision of the sponsor. One patient (250 mg bid 5 days/week) developed dose-limiting toxicity (DLT) of grade 3 fatigue. There were no other DLTs and the maximum administered doses were 250 mg bid for 5 days each week of a 4-week cycle and 200 mg bid for 14 days/3-week cycle. Common drug-related adverse experiences included fatigue (69%), anorexia (62%), dehydration (46%), diarrhea (46%), and nausea (38%) and were mostly grade 2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease (Table 1).

Conclusions: Oral vorinostat was generally well tolerated at 250 mg bid for 5 days each week of a 4 week cycle or 200 mg bid for 14 days/3 week cycle in patients with advanced multiple myeloma. Modest activity was demonstrated in relapsed and/or refractory multiple myeloma and combination studies with other anti-myeloma agents are warranted.

Table 1. Clinical outcomes of patients per EBMT Criteria*

Allocation Number	Age	Baseline Myeloma Stage	Prior Systemic Therapies	Prior Bone Marrow Transplant	Baseline 2-microglobulin	On-study Duration (days)	Best Response
Cohort 1 (200 mg twice daily x 5 days/week)
1001	55	III	12	1	ND	41	NE
1002	47	II	3	1	2.0	254	SD
1003	64	III	4	0	2.6	62	SD
Cohort 2 (250 mg twice daily x 5 days/week)
1004	38	I	5	0	1.7	55	SD
1005	74	III	7	1	6.7	240	MR
1006	65	ND	7	2	3.3	74	NE
1007	67	ND	1	0	10.1	118	SD
1008	42	III	5	0	4.7	109	SD
1009	50	III	5	0	1.4	123	SD
Cohort 4 (200 mg twice daily x 14 days/3 weeks)
861	69	IIIa	16	1	4.6	56	SD
862	63	IIIa	20	1	3.1	25	NE
863	61	IIIa	10	1	2.7	62	SD
864	71	IIIa	16	1	11.0	155	SD