Efficacy of thalidomide‐based therapy following lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma
Authors: Vishal Kukreti, Esther Masih‐Khan, Trieu Young, Chia‐Min Chu, Haiyun Jiang, Suzanne Trudel, Christine Chen, Victor Jimenez‐Zepeda, Donna E. Reece
Journal: American Journal of Hematology (2013)

Immunomodulatory drugs (IMiDs), thalidomide and its derivative lenalidomide, have emerged as an effective treatment for relapsed/refractory multiple myeloma (MM). Clinical studies have demonstrated that thalidomide and lenalidomide each have their own distinct toxicity and efficacy 1-4 despite sharing an overlapping immunomodulatory profile 5, 6. It is evident that patients previously refractory to the less potent IMiD thalidomide can still respond when treated with lenalidomide 7, 8. However, the efficacy of thalidomide in patients refractory to lenalidomide is largely unknown. Two recent studies have looked at the use of thalidomide as a possible treatment regimen post-lenalidomide. Firstly, Guglielmelli et al. 9 followed a diverse group of 20 patients with MM that relapsed while on a reduced maintenance dosage of lenalidomide and treated these patients with a thalidomide-based salvage regimen. Their results showed a 10% overall response of equal or greater than partial response (≥ PR) and median response duration of 5 months. Secondly, Madan et al. 10 reported an overall response rate of 25% in a subset of four patients with lenalidomide refractory MM subsequently treated with thalidomide. We retrospectively studied 24 patients with advanced MM with relapsed disease, refractory disease, or intolerance to full dose lenalidomide and dexamethasone that were subsequently treated with a thalidomide-based regimen. In our study, the median age of subjects at the start of thalidomide therapy was 67 years (44–83) with 67% of patients being males. Monoclonal types were IgG 54% (n = 13), IgA 33% (n = 8), and free light chains comprising 13% (n = 3). Seven patients (29%) had a prior thalidomide exposure pre-lenalidomide either as induction therapy pre-autologous stem cell transplant (ASCT), post-ASCT maintenance or treatment in a relapsed setting. Median time to re-exposure of thalidomide (post lenalidomide) from the end of initial exposure (pre-lenalidomide) for the described seven patients was 2.9 years (1.2–4.0 years). The same seven patients that received thalidomide prior to lenalidomide when compared to the remaining 17 patients exposed to thalidomide only post-lenalidomide had an expectedly reduced median treatment duration and overall response to thalidomide regimen given after lenalidomide (84 versus 103 days; 29 versus 35%). However, these values were not statistically significant. Table 1 summarizes the lenalidomide- and thalidomide-based regimen and responses for all 24 patients. Nineteen of these patients tolerated and eventually progressed on lenalidomide having median treatment duration of 11.1 months, comparable with 11.3 months reported by the MM009 trial 2. Overall, response to thalidomide-based regimen post-lenalidomide resulted in nine patients (38%) achieving a very good partial response or a partial response (VGPR + PR) and 13 patients (54%) achieving less than a partial response, stable disease or progressive disease (SD + PD). No complete responses (CR) were observed. Progression-free survival for all 24 lenalidomide-treated patients receiving thalidomide-based treatment was a median of 3.1 months (95% CI; 63–226 days) and overall survival was a median of 9.6 months (95% CI; 255–444 days). In the thalidomide containing responsive group (VGPR + PR), the median duration of thalidomide-based treatment was improved to 9.1 months (95% CI: 2.8–19.3) versus 2.4 months (95% CI: 1.4–2.9) in the non-response group (P < 0.001). In these advanced disease patients, low to medium level dosing of thalidomide (100 mg–200 mg daily) was generally well tolerated. Only one patient experienced grade 3 neuropathy and consequently discontinued thalidomide treatment. Grade 1–2 neuropathy was noted in 13 patients. No venous thromboembolisms were observed. Eight patients (72%) experienced neutropenia of which seven patients (64%) were given Granulocyte colony-stimulating factor (G-CSF) support. Six of the eight patients with neutropenia were on a cyclophosphamide containing regimen. Twelve patients treated with thalidomide in combination with cyclophosphamide showed an overall response rate of 54% and a median treatment duration of 5.3 months (1.5–18.2 months) which was significantly longer than the 2.9 months (2.0–9.1 months) median seen in patients treated with thalidomide regimens without an alkylator (P = 0.05). Synergism between alkylating agents and thalidomide with dexamethasone is reported to improve overall response rates for relapsed/refractory myeloma (56%), higher than thalidomide alone 11, 12. Our patients treated with thalidomide in combination with cyclophosphamide were not previously refractory to the alkylator and therefore it is difficult to delineate whether the activity seen in this subgroup is due to drug combination synergism or primarily due to cyclophosphamide. Further systematic studies are warranted to establish cyclophosphamide as a beneficial synergistic agent with repeat IMiDs. Analyzing 11 patients treated with thalidomide and steroids without cyclophosphamide showed a PR in two patients (18%), SD in eight patients (73%), and PD in one patient (9%). However, the two patients that responded to this thalidomide regimen were not refractory to lenalidomide and were only discontinued from lenalidomide due to toxicity reasons. Of the remaining patients in this subset, seven patients were lenalidomide refractory and showed a best response of only stable disease when subsequently treated with thalidomide and steroids. Nonetheless, two lenalidomide refractory patients showed a clinical benefit (SD) on their thalidomide with steroid regimen and remained on this treatment for more than 5 months (5.9 and 8.3 months). These same two patients had a VGPR response to lenalidomide with treatment durations of 8 and 27 months, respectively. Considering all 24 patients, the level of response to lenalidomide-based regimen was not indicative of the response to thalidomide-based treatment. No significant relationship between the two responses was observed (P value >0.99). However, duration of thalidomide-based treatment and duration of lenalidomide treatment were correlated with a Pearson correlation coefficient of 0.584 and P value of 0.003. This may be describing a general overall sensitivity to IMiDs. In summary, results from this small subset of patients treated with repeat IMiDs at our site suggests that patients able to tolerate longer lenalidomide treatment durations also tend to show more benefit when later treated with thalidomide-based regimen. These preliminary observations still need to be evaluated via a larger prospective randomized study in order to define molecular biomarkers predictive of a clinical response for patients able to benefit from multiple IMiD exposures. Vishal Kukreti1 Esther Masih-Khan1 Trieu Young1 Chia-Min Chu1 Haiyun Jiang2 Suzanne Trudel1 Christine Chen1 Victor Jimenez-Zepeda1 Donna E. Reece1 1Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada 2Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada