Compassionate Use of Combined Anti-Inflammatory and Angiostatic Treatment as Third-Line Therapy in Eight Patients with Multiple Myeloma – a Combined Treatment Setting of Lenalidomide with Pioglitazone, Dexamethasone and Low-Dose Treosulfan.

Therapeutic options for patients with refractory and multifold pretreated multiple myeloma (MM) are limited, as patients have already received the novel targeted therapy approaches at this stage. Continuous production and release of pro-inflammatory cytokines may account for its resistance towards cytotoxic agents. Therefore, a multi-targeted approach consisting of anti-angiogenic, anti-inflammatory and anti-tumor components was implemented for response induction prior to and after allogeneic transplantation.

Within a compassionate-use program eight patients suffering from refractory or relapsed osteolytic multiple myeloma (MM) or plasma cell leukemia (PCL) and proven progression of serum paraprotein levels were treated in third-line continuously with daily lenalidomide 10 mg, pioglitazone 60 mg, treosulfan 250 mg once daily, and dexamethasone 1 mg.

Here we report results of eight patients (48 to 63 years old) treated for refractory (n= 7) or relapsed (n= 1) multiple myeloma (n= 7) or PCL (n= 1). Prior therapy consisted of double autologous transplantation with high-dose treosulfan/melphalan conditioning, lenalidomide and/or bortezomib. One patient suffered from progressive disease following allogeneic stem cell transplantation (allo-SCT). No side effects > WHO 2 occurred on treatment. In one patient, bortezomib-induced motoric polyneuropathia partially resolved on study medication. Biomodulatory therapy induced clinically meaningful and very rapid responses, stable disease, n= 2, partial remission (PR), n= 3, and very good PR (VPR, n= 3). Therapy-induced PR and VPR facilitated allo-SCT in 2 refractory patients. A third patient with refractory disease after allo-SCT received donor lymphocytes. Two patients with allo-SCT survived in VPR for 10+ and 3+ months, respectively. One patient remained in ongoing VPR since 9 months after donor lymphocyte infusion. Patients not proceeding to allo-SCT had SD for 3 (PLC) and 4 months, VPR and PR for 3+, 4+ and 5+ months.

Together, biomodulatory therapy has remarkable clinical activity in pretreated and refractory patients with MM. The eight cases show comparatively high efficacy at low toxicity rates of a biomodulatory acting therapy approach: Although the substances have limited or no efficacy at the respective dose levels, and were already administered previously at higher dose-levels (i.e. treosulfan and/or lenalidomide), the combined treatment setting is promising since it targets the myeloma cells itself as well as the surrounding stroma. Therefore, this treatment schedule deserves further investigation and discharges now in a novel multi-center phase II trial for third-line therapy in multiple myeloma.

No relevant conflicts of interest to declare.