Peripheral Neuropathy (PN) in Multiple Myeloma (MM) Responder Patients during Maintenance Therapy with Low-Intermittent Doses of Thalidomide (TAL).

Novel agents for MM treatment such as TAL, bortezomib and lenalidomide while offering higher rates of response and CR have lead to new side-effects, in particular peripheral neuropathy that is dose limiting in more than 40% of patients. We have investigated the toxicity and the effectivness of low doses of TAL as maintenance treatment in MM in order to minimize this harmful side-effect.

METHODS: From October 1999, 54 pts (20 males/34 females) with advanced/relapsed MM (IgG-K 28; IgG-λ 11; IgA-K 8; IgA-λ 4; λ 2; K 1) were treated with TAL at 100 mg/day; if well tolerated, the dose could be increased to a maximum of 400 mg/day. 2 pts stopped treatment and weren’t valuables for response. 11 pts (20%) progressed and 5 (9%) reached only a stable disease/minimal response. 27 pts (50%) responded to treatment with 22 (81%) PR (> 50% of reduction of MC) and 5 (9%) CR. Somnolence and stypsis were seen in all pts but were reversible and treated with symptomatic drugs. In 17 pts (11 F, 6 M, median age 70 yrs) we observed a symptomatic neuropathy and we decided to reduce dosage at 100 mg dayly only for 10 days at month as MT. All other causes of neuropathies were excluded. We prospectively performed longitudinal neurological and nerve conduction study before and during TAL treatment every 3 months. Nerve conduction studies included recording of sensory and motor nerve action potential from surale, radial, ulnar, common peroneal and tibial nerves. We considered -p SNAP and Cmap amplitude for each nerve. Electromyography examination was performed in distal muscles of the limbs including denervation potentials and pattern of activation.

RESULTS: In 2 out of 17 we found a mild distal sensory-motor neuropathy before TAL treatment. One referred paresthesia in the 8 months before the diagnosis of MM; the other one was asymptomatic and the diagnosis of neuropathy was made on the basis of clinical and electrophysiological data. The 2 pts with PN before TAL treatment showed a mild clinical and electrophysiological progression of the disease after 6 months of therapy. The first clinical symptoms were painful paresthesias and numbness in all pts. At neurological examination we found a symmetric distal polyneuropathy of sensory type with major evidence at lower limbs. Hypopallestesia and hyporeflexia at lower limbs were detected in all pts; in 3 there was areflexia of achillei reflexes. In 2 pts we found hyperesthesia a stock and gloves distribution. No pts showed motor deficits or cranial nerves impairments. In 12 out of 17 pts an axonal sensory-motor neuropathy was found; in 3 pts a pure sensitive neuropathy, more evident at lower limbs, was detected. In the subsequent 58 months follow-up evaluation, no progression of clinical and electrophysiological findings was demonstrated in the 17 pts. Two of them, however, had to discontinue TAL therapy for severe painful paresthesias. After a median of 8 months’ follow-up, 10/17 pts are alive (2–58 months) and in remission (2 CR and 8 PR); 5 pts showed a disease progression after a median therapy of 5 months (2–23 months) and two pts, who had achieved a PR, had to stop therapy because of severe neurotoxicity after 8 months of treatment (5–12 months).

CONCLUSIONS: The incidence of TAL neuropathy is high and problematic, but the lower cumulative doses of this schedule appear to be less toxic and manageble also mainteining a high rate of response (58%).