This study enrolled 22 heavily pretreated patients with relapsed and refractory MM who had received a median of five prior lines of therapy. All patients had been exposed to prior bortezomib and lenalidomide, with 18% and 27% refractory to these prior agents, respectively. Responses (MR or better) were observed in 14% of patients and 50% of patients achieved stable disease, suggesting that the tanespimycin and bortezomib combination had antitumour activity in this patient population, consistent with prior studies.
While all enrolled patients had prior MM therapy that included bortezomib and lenalidomide, five participants (23%) did not receive melphalan, a long-accepted first-line treatment typically given in combination with prednisone. Reasons for this departure from standard practice are speculative, but may have been due to preference for SCT as initial therapy or based on recent studies supporting bortezomib and lenalidomide as primary therapy for patients with relapsed or refractory MM, the type of patient population enrolled in our study (Fonseca & Rajkumar, 2008
; Richardson et al, 2009b
The AE profile for tanespimycin + bortezomib was also consistent with that observed previously (Richardson et al, 2009a
), with fatigue, nausea and diarrhoea as the most commonly reported treatment-emergent AEs. Overall, tanespimycin + bortezomib was generally well tolerated with manageable toxicity and the majority of AEs were mild to moderate.
The liver toxicity observed with tanespimycin treatment is noteworthy, but appears to be manageable and reversible. Liver toxicity resolved within 1–2 weeks and some patients were then successfully rechallenged with tanespimycin. Results of this study were similar to two earlier Phase 1 studies of tanespimycin in which severe LFT abnormalities were rare (Modi et al, 2007
; Richardson et al, 2009a
Thrombocytopenia was observed at all dose levels, with platelet decreases on day 11 of each cycle, consistent with the pattern observed with bortezomib monotherapy (Lonial et al, 2008
). Characterization of bortezomib-associated thrombocytopenia in previous trials, specifically the Study of Uncontrolled Multiple Myeloma managed with proteasome Inhibition Therapy (SUMMIT) (Richardson et al, 2003
) and the Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST) (Jagannath et al, 2004
), revealed the toxicity to be transient, cyclical, and predictable with platelet counts decreasing during treatment with bortezomib and then rapidly recovering during the 10-d rest period at the end of each cycle (Richardson et al, 2003
). This pattern was attributed to a reversible effect on megakaryocytes, possibly due to transient inhibition of platelet budding (Lonial et al, 2005
Bortezomib-induced, cyclical neutropenia with a decrease on day 11 has also been reported (Lonial et al, 2008
). In the APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial, ≥ grade 3 neutropenia was more common with bortezomib (14%) than with dexamethasone (1%) (Lonial et al, 2008
). However, in the present study of tanespimycin + bortezomib, only a few patients had decreases in ANC on day 11 during the first two cycles. This is consistent with the low incidence of grade ≥3 neutropenia AEs in this study (3%) and with similar observations from an earlier study (Richardson et al, 2009a
). The numbers of patients are nonetheless small and this potential protective effect needs further clinical evaluation in large trials.
In the 12 months preceding study entry, most patients (17/22%) had a history of peripheral neuropathy suggesting that peripheral neuropathy is common in heavily pretreated patients with MM. Peripheral neuropathy is the most common DLT reported with bortezomib treatment. In fact, when bortezomib was used as part of a combination approach first-line treatment in MM, drug administration was discontinued because of peripheral neurotoxicity in 4% of the patients, with an overall incidence of peripheral neuropathy of 30% including 6% grade 3 in one study (Harousseau et al, 2006
), while 31% of the patients had grade 2 or higher (16% grade 3) peripheral neuropathy reported in another study (Jagannath et al, 2005
). The incidence, severity and clinical features of bortezomib-induced peripheral neuropathy were confirmed in other studies of patients with haematological malignancies, as well as MM, but it appears especially important in MM (Orlowski et al, 2005
; Fisher et al, 2006
In the present study, two patients with a history of painful peripheral neuropathy developed grade 2 peripheral neuropathy while on study. One patient randomized to the 340 mg/m2
dose group developed grade 3 peripheral neuropathy; however, this patient had discontinued tanespimycin and, interestingly, was on bortezomib alone during the 7 days prior to the onset of significant peripheral neuropathy. Despite the high incidence of peripheral neuropathy prior to study entry, no other patients discontinued due to peripheral neuropathy. These observations are consistent with the lack of grade ≥ 3 peripheral neuropathy observed in a previous study of tanespimycin + bortezomib in 72 heavily pretreated patients, which was then corroborated in a preclinical rodent model of peripheral neuropathy demonstrating that tanespimycin was neuroprotective against bortezomib-induced peripheral neuropathy (Zhong et al, 2008
; Richardson et al, 2009a
Although not well understood, the mechanisms underlying this neuroprotective response appear to be multifactorial, encompassing a range of cellular chaperone functions from the prevention of protein aggregation to interfering with various cell death cascades (Yenari, 2002
). In the nervous system, HSP70 overexpression in cultured hippocampal and peripheral neurons and glia protects against insults such as heat shock and metabolic stress (Yenari, 2002
). HSP70 overexpression in various non-neuronal cell lines also protects against oxidative injury, apoptotic stimuli and ischaemia, as well as neurodegenerative disease, epilepsy and trauma (Yenari, 2002
The induction of HSP70 in peripheral blood mononuclear cells (PBMCs) has been found to represent a classic stress response to heat (Banerji et al, 2005
; Goetz et al, 2005
; Grem et al, 2005
; Modi et al, 2007
; Ramanathan et al, 2007
; Solit et al, 2007
). In one study, HSP70 induction occurred 6 h after a dose of ≤80 mg/m2
of tanespimycin per week (Banerji et al, 2005
). At the highest dose levels, 320 and 450 mg/m2
per week, HSP70 induction in PBMCs persisted for 48 and 96 h, respectively. In two earlier tanespimycin studies in patients with relapsed and refractory MM, PBMCs were obtained on day 1 and day 11 in cycle 1 before infusion and 4 h after infusion of tanespimycin. Induction of HSP70 was observed in lysates from PBMCs following a single dose of tanespimycin on day 1 as well as before the fourth dose on day 11, suggesting that the heat stress response is sustained over a 3- to 4-d dosing interval (Richardson et al, 2005
). In the present study, plasma HSP70 levels increased on day 11 at the 340 mg/m2
dose () suggesting that biologically active plasma concentrations of tanespimycin were achieved and tanespimycin effectively inhibited its target, HSP90.
Fig 1 HSP70 Relative to Cycle 1 Day 1 Hour 0 mean + standard error. HSP70 expression, a measure of HSP90 inhibition, was assessed on days 1 and 11 at h 0 and h 4. From day 1 h 0 to day 11 h 0, HSP70 levels increased 3·1-, 4·6- and 26·5-fold (more ...)
Proteasome inhibition was also observed in this study indicating that tanespimycin does not interfere with the effects of bortezomib on its target. Evidence of antimyeloma activity of tanespimycin + bortezomib in this study included observed responses of an MR, PR, and very good PR (VGPR) in the 340 and 175 mg/m2 dose groups with no responses seen in the 50 mg/m2 group. Most notably, the patient with a PR in the 340 mg/m2 dose group had progressed on the last prior regimen of bortezomib + vorinostat.
In an earlier phase 1/2 study of tanespimycin + bortezomib, the ORR was 64% in bortezomib-naive patients who had ≤3 prior regimens. The median duration of response was 12 months (n
= 18), including three bortezomib-refractory patients each with durable PRs through months 12, 22 and 27, respectively. Of these three bortezomib-refractory patients with long-term responses, two patients had progressed while being treated with prior bortezomib (bortezomib/dexamethasone and bortezomib/thalidomide/dexamethasone). Median progression-free survival for bortezomib-naive, pretreated and refractory patients was 7·2, 3·7 and 1·6 months respectively (Richardson et al, 2009a
). Patients received a tanespimycin dosage of 100–340 mg/m2
In our study, tanespimycin was given at a broader dosage range (50–340 mg/m2), with the 50 mg/m2 dose administered to more than a quarter (n = 6) of the patients. The 50% total response rate to bortezomib-tanespimycin was an encouraging result in patients that had relapsed or were refractory after at least three prior bortezomib and lenalidomide treatment regimens. The relatively small patient population was a limitation of the study. However, our study was perhaps a more rigorous evaluation of the therapy in that all patients had measurable MM as determined by M protein values, all were relapsed and refractory cases involving at least three prior treatment regimens, and 27% (6/22) received a low (50 mg/m2) tanespimycin dose that detracted from overall response rates. The favourable outcomes of this study in relapsed and refractory patients together with results of the earlier, larger Phase 1/2 study supports continued evaluation of patients with MM given bortezomib at 1·3 mg/m2 in combination with tanespimycin at 340 mg/m2.