Cardiac Safety of One Versus Four Hour Romidepsin (Istodax®) Infusion In the Setting of a Phase I/II Trial of Romidepsin, Dexamethasone and Bortezomib for Relapsed or Refractory Multiple Myeloma

Abstract 5037

Various bortezomib (Bz)-based combinations are being examined in the context of relapsed and/ or refractory Multiple Myeloma (MM). Histone Deacetylase Inhibitors (HDACIs) are a novel group of agents that effect a variety of cellular and intracellular processes by enhancing the acetylation of histone and non-histone targets. Romidepsin (Romi), a cyclic tetrapeptide, is a class 1 HDACi. Initial reports suggested that various HDACi induced QTc prolongation as a class effect, although subsequently it has been shown that careful electrolyte management prevent this from being a clinical problem.

32 patients (pts) have been enrolled in a Phase I/II Trial of Romi, Bz and dexamethasone (Dex) in relapsed or refractory MM. The maximum tolerated dose (Romi 10mg/m², Bz 1.3mg/m² and Dex 20mg) was determined in the first 6 pts with Romi given on day 1, 8 & 15, Bz on D1, 4, 8 and 11 and Dex D1, 2, 4, 5, 8, 9, 11 and 12 of a 28 day cycle (n=25). In an ongoing expanded Phase IIb cohort Romi is only given on day 1 & 8 of a 21 day cycle (n=7/15).

Romidepsin was initially given as the standard 4 hour infusion. However animal and clinical safety data support the use of 1hr Romi infusions. In the expansion cohort, the duration of Romi infusions was reduced to 1 hour from cycle 2. To monitor safety (specifically QT interval), ECGs were mandatory pre and post the 4 hour infusions in cycle one and the 1 hour infusions in cycle 2 and reviewed prior to the continuation of the 1 hour infusion from cycle 3. Prolongation of QTc was defined as an increase of 33%, or 60 msec, or QTc ³500 msec. The maintenance of serum potassium > 4.0 mmol/L and magnesium >0.85 mmol/L prior to Romi infusion was mandated. Any patients in the initial cohort remaining on study and still receiving Romi were eligible to move to 1 hour Romi infusions with ECG monitoring during the first cycle.

32 patients have received 598 Romi infusions. 525 infusions have been given over 4 hours and 73 over 1 hour. 19 pts only received 4 hour infusions and 13 pts received at least one 1 hour infusion of Romi.

The phase I/II cohort (n=25, median lines of therapy 2 (range1-3)) received 4 hour infusions, the overall response (CR+PR+MR) by modified EBMT criteria was 76% in 21 assessable patients. 2pts had CR (10%), 13 PR (62%), 1 MR (4%), 4 pts had SD, and 1PD. The Phase IIb cohort (n=7, median lines of therapy 2 (range 1–4)) received 1 hour infusions and 6 pts are currently assessable for response with 3 PR and 3 MR.

In the first 25 pts receiving the 4 hour infusions, 2 patients experienced arrhythmias during their first cycle, grade 2 atrial flutter possibly related to drug and sinus tachycardia definitely not related. 1pt developed severe ischaemic heart disease and 1pt has died, likely from a PE. Since the introduction of 1hr Romi infusions, only one patient has experienced a Grade 1 cardiac event of asymptomatic lateral T wave flattening and mild ST depression on ECG. This occurred in cycle one, with 4 hour infusions. Full cardiac assessment reveled no clinically significant abnormality. This patient went on to receive the 1 hour infusions without incident.

The implementation of the 1 hour infusions has successfully reduced the overall treatment time with Romi/ Bz/ Dex without increase in toxicity. Although numbers are small the response rates appear similar to those using the 4 hour infusions.