Lenalidomide Therapy Is Associated with Improvement of Peripheral Neuropathy in Patient with Relapsed/Refractory Multiple Myeloma: Preliminary Results From a Single-Centre Prospective Non Interventional Study.
Authors: Zambello Renato , Berno Tamara , Candiotto Laura , Torre Chiara Dalla , Campagnolo Marta , Lucchetta Marta , Trentin Livio , Briani Chiara , Semenzato Gianpietro 
Published: October 2019

Abstract
Abstract 4949
In recent years, proteasome inhibitors and immunomodulatory drugs (IMIDs) have provided invaluable advantage in the therapy of multiple myeloma (MM) in terms of disease free survival and often overall survival. However the benefits have sometimes been blunted by the occurrence of adverse effects which strongly impact quality of life. Among them, peripheral neuropathy (PN) represents one of the most disabling and often dose-limiting side effect. Lenalidomide, a second generation IMID and a structural analogue of thalidomide, has been claimed to have low toxicity on peripheral nervous system. In a single-centre prospective study we evaluated the natural history of chemotherapy-induced PN in consecutive patients previously treated with bortezomib and/or thalidomide, who shifted to lenalidomide for relapsed or refractory MM. The aim was to evaluate the clinical course of PN during lenalidomide therapy.

Patients and methods
34 consecutive patients previously treated with bortezomib and/or thalidomide were treated with lenalidomide (25 mg daily for 21 day cycle) alone or associated with low dose dexametasone for relapsed/refractory MM. Patients previously treated with bortezomib and/or thalidomide, who developed a chemotherapy-induced PN and whose MM was still in remission, were used as control. Neurological evaluation was planned at baseline, after 6 and 12 months from the beginning of lenalidomide therapy. Patients were assessed with the Total Neuropathy Score clinical version (TNSc), which has been previously validated against the most common neurotoxicity scales used by oncologists (NCI-CTC 2.0, ECOG); pain was assessed with the visual analogue score (VAS). The Eastern Cooperative Oncology Group (ECOG) performance status was also assessed. Nerve conduction studies were performed at the beginning of the treatment and regularly during follow up. Lack of chemotherapy-induced PN at baseline was not an exclusion criteria, as well as progression of myeloma during lenalidomide treatment.

Results
Of the 34 patient in lenalidomide therapy, sixteen (mean age 66 yrs ± 8) were available for evaluation with at least six months follow up. Fourteen patients presented chemotherapy-induced PN at baseline, confirmed also by neurophysiological studies. Two patients had no PN at baseline (TNSc: 0) despite previous exposure to bortezomib in one case, and bortezomib and thalidomide in the other case. The majority of evaluable patients (75%) had a TNSc >2 at baseline (median = 6.7, SD ±3.6, range 3-15). Two patients had a baseline TNSc ' 2 (median 1,5). After 6 months of follow up, hematological response was documented in 14 patients (4 patients were in VGPR, 10 in PR) whereas 2 patients were in progression after initial response. Neurological evaluation after 6 months revealed improvement or stability of symptoms and neurological scale in 12 out of 14 patients (TNSc 5.5, SD ±3.9 at baseline vs 3.8, SD ±2.2 post 6 months therapy, respectively). The improvement of symptoms was generally more evident in those patients with the highest baseline TNSc. One patient with bortezomib and thalidomide-induced PN, while presenting a subjective and neurophysiologic improvement, had a worse TNSc score due only to a worse vibration sensibility score alone. However, this patient was also on antituberculosis treatment with isoniazid, which is known to be neurotoxic. Two patients without PN at baseline, still remained with score 0 at 6 months follow up. As expected, clinical improvement not always correlated with electrophysiological improvement. In two cases evaluation at one year was possible, and data showed a continuous improvement of PN.

Conclusions
Using validated clinical and instrumental tools, the preliminary results of our prospective study suggest that during lenalidomide therapy PN improves, regardless of myeloma response. Updated results of the study will be presented at the meeting. The results of the on-going follow up study on a wider population of patients will help confirm these data and define appropriate timing for the detection of electrophysiological improvement.

Disclosures
No relevant conflicts of interest to declare.