Anti-Inflammatory, Immuno-Modulatory and Angiostatic Treatment As Third-Line Therapy for Multiple Myeloma (MM) – a Combined Treatment Setting of Lenalidomide with Pioglitazone, Dexamethasone and Low-Dose Treosulfan (phase I/II)

Therapeutic options for patients (pts) with second progression of multiple myeloma (MM) are limited, as patients have already received novel targeted therapy approaches at this stage, i. e. bortezomib and lenalidomide. Acknowledging that continuous production of pro-inflammatory cytokines contributes to resistance towards the agents, we hypothesized, that a multi-targeted approach consisting of anti-angiogenic, anti-inflammatory, immuno-modulatory and anti-tumor components given continuously may have the potential to overcome resistance mechanisms.

To clinically test this hypothesis we initiated a phase I/II trial combining daily lenalidomide (len, cohort 1: 10mg, cohort 2: 15 mg) with pioglitazone 60 mg and treosulfan 250 mg (twice daily), and dexamethasone 1 mg administered for one month (mo). Pulsed dexamethasone, 40 mg p. o. was given on day 1 to 4 and 14 to 17, then 20 mg every 14 days. In the absence of toxicity, pts were eligible to continue the same treatment regimen until progression. Key inclusion criteria were progressive/relapsing MM after at least two previous lines of therapy. Whereas the phase I of the study aimed to assess tolerance of this combination regimen, inclusion criteria in phase II also required previous treatment with len, since it aimed to test the hypothesis that this combination might overcome resistance towards len. We here report the results for phase I of the study.

Between November 2009 and February 2011 two cohorts of three patients have been included in the phase I part of the study. All six patients (4 males, 2 females) were heavily pretreated with tandem autologous transplantation using high-dose melphalan (n=5), bortezomib (n=4), thalidomide (n=1), interferon-alpha (n=2) as well as standard anti-myeloma chemotherapies (anthracycline, bendamustin, cyclophosphamide, n=6). Median number of previous lines of treatment were 3. 3 (range 3 to 5). Four pts suffered from progressive IgG MMs, 2 pts had light chain MMs. Median age was 64. 1 years (range 60 to 72 years). Noteworthy, neither the 3 pts included in cohort I receiving the combination regimen with 10mg, nor the 3 pts in cohort (15mg) experienced a dose limiting toxicity (defined as any toxicity with NCI-CTCAE grade ³ 3 during the first treatment cycle). Therefore, all pts continued treatment in the extension phase. Serious adverse reactions observed during follow-up were infections (n= 6, Grade 2 NCI-CTCAE toxicity), depressed mood (n=1, Grade 2), osteonecrosis of the jaw and tooth extraction (n=1), and thrombosis during anticoagulation (n=1, Grade 2). Assessment of response demonstrated that 4 of the 6 pts increased serum hemoglobin levels by at least 1. 0 g/dl already during the first treatment cycle. During the extension phase (median observation time 23. 3 months), two patients achieved a partial response (duration: 24 mos, >19 mos), two a very good partial response (8 mos, respectively), and one pt the first complete response ever in his disease course, lasting for 14 mos. This pt had his longest progression-free interval (31 mo) since start of therapy for stage IIIA multiple myeloma. One pt achieved stable disease during 15 mos. Thus, none of the patients had progressive disease. Due to the high tolerance and the encouraging response data, this study proceeded to phase II including patients to be treated with 15 mg lenalidomide daily. All patients were treated in an outpatient setting. Hospitalization was necessary in 3 cases.

We here provide evidence from a prospective phase I study that the combination of low-dose chemotherapy, dexamethasone and lenalidomide administered as long-term treatment on a daily basis exhibits a very favorable toxicity profile and is a feasible regimen applicable in an outpatient setting. In addition, we provide preliminary data that this combination treatment might have considerable clinical activity in heavily pretreated pts with relapsing/progressing MM.

No relevant conflicts of interest to declare.