Isatuximab Plus Pomalidomide and Dexamethasone Association for Patients With AL Amyloidosis Not in VGPR or Better After Any Previous Therapy

This phase 2 study ain to evaluate the efficacy of Isatuximab plus Pomalidomide and Dexamethasone (IPd), in patients with AL amyloidosis not in VGPR or better after any previous therapy. It will enrolled 46 patients (34 in France and 12 in Australia) through 15 sites (11 in France and 4 in Australia).

Systemic AL amyloidosis is a rare disease caused by the deposition of misfolded monoclonal immunoglobulin free light chains (FLC) in various tissues and organs. It is usually associated with a clonal plasma cell dyscrasia with a low tumor burden. Treatment of AL amyloidosis relies mainly on chemotherapy aimed at suppressing the underlying plasma cell clone secreting monoclonal FLC. The organ responses and the survival are greatly influenced by the degree of hematological response evaluated by the decrease in serum FLC that has been the principal endpoint in recent trials in AL amyloidosis. The goal of treatment is to reach at least a very good partial response (VGPR) defined as a difference between the involved FLC and the normal one below 40 mg/L. Over the last 5 years, monoclonal antibodies (mAb) as daratumumab and Isatuximab (anti CD38 mAb) has emerged as a breakthrough targeted therapies for patients with multiple myeloma (MM). CD38, is a type II transmembrane glycoprotein that functions both as a signal-transducing receptor and a multifunctional ectoenzyme. The expression of CD38 is increased in MM and AL amyloidosis plasma cells. Daratumumab (DARA) is an IgG 1k human mAb that received initial approval as monotherapy in patients with heavily pretreated RRMM and who were refractory to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiD®). DARA has since been approved in combination with Lenalidomide/Dexamethasone1,2 and Bortezomib/Dexamethasone3,4 for the treatment of frontline and relapsed/refractory (RR) MM patients. IFM and other groups previously demonstrated that DARA in monotherapy is safe and effective in relapsed AL amyloidosis patients5. Our prospective phase II study showed that about 70 to 80% of patients have a response but only around 50% reached a VGPR. DARA activity could be increased with IMiD® as treating plasma cells with IMiD®, such as pomalidomide or lenalidomide, has been shown to increase the expression of CD38 levels on the surface of these cells. In AL amyloidosis, the Italian and the British groups demonstrated that pomalidomide is very effective and better tolerated than lenalidomide especially in patients with renal insufficiency6,7. The dose of pomalidomide (4 mg) was like the dose used in MM. Combining an anti CD38 mAb to pomalidomide could therefore be an attractive regimen for relapsed AL amyloidosis patients. Isatuximab (ISA) is another IgG1 κ mAb that binds selectively to a unique epitope on the human CD38 receptor and has anti plasma cells activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of Isatuximab with Pomalidomide and low-dose Dexamethasone. The addition of Isatuximab to Pomalidomide-Dexamethasone was used in a large phase III study in RRMM8. Safety profile was also favorable, and these results granted an approval of the combination of ISA plus Pomalidomide (4 mg) and Dexamethasone in these patients.