Bortezomib in Patients with Relapsed-Refractory Multiple Myeloma (MM). Clinical Observations.
Authors: Kyrtsonis Marie-Christine , Sachanas Sotirios , Vassilakopoulos Theodoros P. , Kafassi Nikoletta , Tzenou Tatiana , Papadogiannis Argyro , Kalpadakis Christina , Antoniadis Antonios G. , Dimopoulou Maria N. , Angelopoulou Maria K. , Siakantaris Marina P. , Dimitriadou Evangelia M. , Kokoris Styliani I. , Plata Eleni , Tsaftaridis Panagiotis , Panayiotidis Panayiotis , Pangalis Gerassimos A. 
Published: October 2019

Abstract
Bortezomib is a reversible proteasome inhibitor that was recently approved for the treatment of relapsed-refractory MM. However, dosage, schedule, management of adverse events and duration of response are still under investigation. We present our experience with bortezomib. 27 relapsed-refractory MM patients were studied. They were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 every three weeks for eight cycles and dexamethazone was planned to be added at 20 mg every other day of bortezomib (2,5,9,12) if no signs of response were observed after the 1st cycle. There were 20 males and 7 females (median age 71y old). Immunoglobulin type was IgG in 16, IgA in 7, BJ in 3 and IgD in 1. All patients had received at least 2 previous treatment lines (median 4, thalidomide in 52%). At treatment initiation, 59% of patients were Durie-Salmon stage III and 63% ISS stage 3. B2Microglobulin was increased in 81%, CRP in 33%, LDH in 22%, creatinin in 7%, plasma cell bone marrow infiltration> 60% in 100%, hemoglobin< 10g/L in 59%, platelet count>100x109/L in 92% and no patient had peripheral neuropathy> grade 1. Free light chains ratio (FLCR, FREELITETM) was determined in 16 patients at baseline (increased in all) and during treatment. With the treatment scheme described above, 55% of patients received additional dexamethasone. Two in resistant relapse died during the 2nd course. Treatment was stopped or reduced in the majority of patients because of severe neuropathy after 4–6 cycles and discontinued in 3 patients because of no response (4 patients completed 3 courses, 17 completed 11, 1 completed 5, 3 terminated 6). Hematology toxicity, fatigue, gastrointestinal toxicity and fever were mild and manageable. Severe side effects were neuropathy in 63% (sensory, instability, burning pains- median time of onset 85 days after bortezomib initiation and median duration 2 months) hypotension in 7% and hypoglycemia in 3%. 21/25 (84%) patients responded (2 complete remission [CR], 4 near CR, 10 partial response, 5 minimal response. Median time to response was 42 days but with median follow-up of 6 months 6/21 (28%) patients have relapsed and 3/25 (12%) died. Relapse was aggressive (onset with acute renal failure in 3, spine plasmacytoma in 1, automatic bone fracture in 1). B2M, CRP and stage were not predictors of response or early relapse but of 8/16 with FLCR>200 at baseline, 4 were resistant and 4 relapsed. In 2 of the 4 resistant patients FLCR decreased after the 1st course and increased after the 2nd; in the same way in responders with an early relapse, FLCR started to increase during the last cycles of bortezomib. It is possible that some patients develop quickly resistance to the drug. In conclusion, Bortezomib, in combination with low-dose dexamethasone produce rapid responses but neuropathy represent a frequent and severe side effect and the duration of response is short. An adequate or palliative treatment for neuropathy is needed as well as a maintenance schedule overcoming resistance. FLCR seems to predict response and early relapse.