Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study

doi:10.1016/S1470-2045(11)70028-6

The Lancet Oncology

Volume 12, Issue 3, March 2011, Pages 263-272

https://doi.org/10.1016/S1470-2045(11)70028-6 Get rights and content

Summary

Background

Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma.

Methods

We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0–2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1·3 or 1·6 mg/m² once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262.

Findings

20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1·6 mg/m² bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21–47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less).

Interpretation

mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids.

Funding

Millennium Inc, Pfizer Inc, Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society.

Introduction

Multiple myeloma is the second most prevalent haematological malignancy and is incurable—median survival is 45 months for newly diagnosed patients and 31 months for patients with relapsed myeloma, even when treated with new drugs.1, 2 Despite advances in our understanding of the molecular pathogenesis of multiple myeloma and promising new treatments, almost all patients who survive their original presentation and initial treatment eventually relapse.¹ Responses to bortezomib and lenalidomide used alone to treat relapsed and refractory multiple myeloma are in the range of 20–30%.¹ Therefore, there is an urgent need to identify mechanisms of resistance to these drugs and develop combinations to overcome resistance.

Tumorigenesis results from synergistic interactions of complex signal-transduction processes, including multiple oncoproteins and tumour suppressors such as RAS, MYC, AKT, P53, and PTEN.3, 4, 5 Overexpression of AKT plays an important part in the initiation and progression of malignancies, specifically, the phosphatidylinositol-3 kinase (PI3K) pathway is important in enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis.6, 7, 8, 9, 10 Several studies have shown that this pathway is activated in multiple myeloma, either because of mutations in the tumour clone or because of extrinsic stimulation through interleukin 6 or insulin-like growth factor 1 and adhesion to cells of the bone-marrow microenvironment. AKT regulates many signalling pathways that regulate cell cycle, proliferation, and resistance to apoptosis such as BAD, caspases, IKK, GSK3, Forkhead-related transcription factor 1, eNOS, and mTOR.¹¹ Targeted inhibitors of the PI3K/AKT/mTOR pathway have shown substantial preclinical activity.11, 12, 13, 14, 15, 16, 17, 18, 19 We postulate that the PI3K/AKT/mTOR pathway synergises with bortezomib in multiple myeloma. Temsirolimus is a sirolimus analogue approved by the US Food and Drug Administration for use in renal-cell carcinoma and mantle-cell lymphoma.20, 21 Bortezomib is a proteasome inhibitor that has shown substantial activity in the treatment of multiple myeloma, alone and in combination. Previous studies of mTOR inhibitors such as temsirolimus used alone in patients with multiple myeloma have shown slight activity.²² We therefore tested our hypothesis in a phase 1/2 clinical trial in patients with relapsed or relapsed and refractory multiple myeloma.

Our objectives for our phase 1 study were to assess safety and establish the maximum tolerated dose (MTD) of the combination of temsirolimus (Pfizer, New York, NY, USA) and bortezomib (Millennium/Takeda, Cambridge, MA, USA). Our phase 2 objectives were to assess the overall response rate at the MTD. Furthermore, we aimed to do a subgroup analysis to assess the response rate in patients who were refractory to bortezomib. In our phase 2 study we also aimed to assess the activity of these two drugs without the use of steroids in the regimen for multiple myeloma, as a steroid-sparing option, as well as to assess the role and toxic effects of weekly bortezomib at a higher dose than usually given of 1·6 mg/m² in patients with multiple myeloma.

Section snippets

Participants

Between June, 2007, and December, 2009, we enrolled patients into our open-label, dose-escalation study at three centres in the USA (Dana-Farber Cancer Institute, Boston, MA; Washington University, St Louis, MO; and the University of Michigan, Ann Arbor, MI). We enrolled patients into our phase 1 trial at the Dana-Farber Cancer Institute from June 12, 2007, to July 11, 2008. We enrolled patients for our phase 2 trial from the Dana-Farber Cancer Institute, Washington University, and the

Results

We enrolled 20 patients into our phase 1 study and 43 patients into our phase 2 study. Of these 63 patients, 22 had relapsed multiple myeloma, three had refractory multiple myeloma to all previous treatment, and 38 had relapsed and refractory multiple myeloma after initially responding to treatment. Table 1 lists the baseline characteristics of the patients. The median number of previous treatments in the phase 1 study was five (range 1–11) and in phase 2 was four (1–14). Previous treatments

Discussion

Our findings indicate that mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids.

Adverse events in our study were generally manageable. Adverse events accord with those reported with temsirolimus and bortezomib alone, including thrombocytopenia.20, 21 Adequate platelet supportive care with transfusions and frequent platelet-count monitoring is therefore needed for

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Fast track — ArticlesWeekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Participants

Results

Discussion

Blood

Cancer Cell

Cancer Treat Rev

Ann Oncol

Blood

Blood

J Biol Chem

Blood

Blood

Blood

Blood

Blood

Trends Biochem Sci

Multiple myeloma

N Engl J Med

PTEN loss promotes rasHa-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via PTEN-associated pathways

Cancer Res

Why is PTEN an important tumor suppressor?

J Cell Biochem

Fast track — Articles
Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study