Anti-EGFR Antibody Cetuximab in Refractory or Relapsed Multiple Myeloma: Preliminary Results and Evaluation of Response Prediction in a Phase II Clinical Trial

INTRODUCTION: Cetuximab (Erbitux©) is an anti-epidermal growth factor receptor (EGFR) antibody approved for the treatment of colorectal cancer and head and neck cancer. EGFR is also expressed on multiple myeloma (MM) plasma and bone marrow stromal cells (BMSC). Recently, the inhibition of EGFR by small molecule inhibitors has been shown to induce apoptosis in primary myeloma cells revealing a synergistic effect with dexamethasone. Therefore, the anti-EGFR antibody cetuximab might be of clinical benefit in the treatment of MM, especially in combination with dexamethasone. Here we show preliminary data of the first clinical trial with an anti-EGFR antibody in MM and discuss possible response predictors.

METHODS: Cetuximab in a loading dose of 400 mg/m² followed by 250 mg/m² once weekly was administered to patients with refractory or relapsed MM who had previously received at least one line of prior treatment and were not eligible to undergo autologous stem cell transplantation. Responses were assessed according to the EBMT criteria. Dexamethasone 20 mg on day 1–3 of each cycle was added starting week 5 in case of tumor progression or week 9 if no partial response (PR) or complete response (CR) was achieved with cetuximab alone. Planned treatment duration was 16 weeks (primary endpoint). Patients achieving a response or stable disease after 16 weeks of treatment could continue study medication for up to 24 further weeks. In addition, patients who had responded could start treatment according to study protocol for a second time. To assess possible predictive markers for a response to cetuximab we collected patient plasma cells to perform toxicity assays and we analyzed BMSCs of patients for IL-6 secretion after treatment with cetuximab in vitro.

RESULTS: Thirteen patients have been enrolled so far. Seven patients were treated for a minimum of 16 weeks and 5 of those patients received cetuximab for at least 28 weeks. One patient still continues cetuximab treatment as single agent for more than one year. Thrombocytopenia and hyponatremia were the most common CTC grade 3 or 4 side effects with grade 3 thrombocytopenia in one patient, grade 4 thrombocytopenia in 2 patients and grade 3 hyponatremia in 3 patients. Acneiform rash CTC grade 1 occurred in all patients and 1 patient suffered from acneiform rash CTC grade 2. Two serious adverse events (SAEs) with a possible relationship to the study medication were observed: Fever and shivering requiring hospitalization in 1 patient and dyspnea in 1 patient who suffered from chronic obstructive pulmonary disease, this patient was excluded from the study after the first application of cetuximab. Three SAEs with causal relationship not likely to study drug administration were noted: Septic shock resulting in death in 1 patient, fever due to infection requiring hospitalization in 1 patient and transient atrial fibrillation in 1 patient. After 16 weeks (primary endpoint) cetuximab in combination with dexamethasone induced 3 responses (2 minimal responses (MR) and 1 partial response (PR)) and led to stable disease (SD) in 3 patients, cetuximab as single agent led to SD in 1 patient. Five of the 13 patients included did not receive the planned 16 weeks of treatment due to progressive disease (PD). Six patients were treated more than 16 weeks: 1 patient still receives cetuximab as single agent and is SD since a year and 5 patients continued treatment with cetuximab and dexamethasone in combination. There was 1 PD after 21 weeks and 2 SDs and 2 MRs after 28 weeks in this cohort. In viability assays with patient plasma cells we could demonstrate that cetuximab is cytotoxic in some of the patient samples. Furthermore, cetuximab suppressed the production of growth stimulating IL-6 in BMSCs of the patient who still receives cetuximab and remains SD. To assess whether cytotoxicity of cetuximab in patient plasma cells in vitro or cetuximab-induced inhibition of IL-6 secretion might predict response to treatment, more samples will be evaluated.

CONCLUSIONS: Cetuximab is safe and effective in MM patients. Because of its favourable side effect profile it should be evaluated in clinical trials in combination with other compounds. Analyzing the effects of cetuximab on patient plasma and BMSCs might become useful for response prediction of cetuximab in MM patients in the future.