A Prospective Pilot Study of Ixazomib, Lenalidomide, and Dexamethasone for Patients with Newly Diagnosed or Relapsed/Refractory POEMS Syndrome

Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We conducted a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF 2x normal, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp 1, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant; Gp 2, 13 cycles for patients (pts) who had relapsed or refractory disease. Primary endpoint was VEGF complete response (CR=normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response (50% reduction in sum of SUVmax from baseline), clinical responses including neurologic response were also studied. Neurologic assessments were done using the modified neurological impairment score (mNiS+7_POEMS), the overall neuropathy limitation scale, and the polyneuropathy disability score. To date, 13 pts enrolled since 10/31/2016-4 to Gp 1 and 9 to Gp 2. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 07/15/2019. Results: Median age was 55; 73% were male. Of the evaluable patients, three were newly diagnosed (Gp 1), and 8 had relapsed or refractory disease (Gp 2). 72% met primary endpoint of VEGF CR (Table). At 3 months, the following improvements were seen: VEGF, 10/11; hematologic, 1/3; PET 1/3; neurologic impairment score, 3/11. By 12-months according to the modified nerve impairment scale, 3/6 had achieved objective improvement and 2/6 stable disease. With a median follow-up of 16 months, 2 patients have died of progressive disease and another patient progressed on therapy (Gp 2) with an extravascular leak progression. 27% of patients had grade 3+hematologic AE; 81% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection, diarrhea, and hypotension in 2 each; atrial fibrillation, edema, dyspnea, and thromboembolism in 1 each. 5 pts had non-objective worsening of their neuropathy.

Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Longer follow-up will be important to determine durability of this approach and for neurologic assessment given the slow rate of remyelination.

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