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Patient eligible to enter the study will receive 9 to 12 cycles (according to response) of intravenous Isatuximab (10 mg/kg) and oral Pomalidomide 4 mg from day 1 to day 21 and Dexamethasone 10-20 mg weekly on days 1, 8, 15 and 22.

Each cycle will be of 28 days duration. During cycle 1, Isatuximab will be administered weekly on days 1, 8, 15, and 22 then days 1 and 15 in subsequent cycles from cycle 2 to 9 or 12.

For each individual patient, the treatment period will be 12 months, unless CR at the completion of 9 cycles, disease progression or unacceptable toxicity occurs. The duration of follow-up for overall survival will be 1 year after the last patient enters overall survival follow-up.

Patient will receive the association of Isatuximab, Pomalidomide and Dexamethasone during 9 or 12 cycles.

Isatuximab

Cécile DEAL

Léa TABONE

Pierre MOREL, Dr.

Mamoun Dib, Dr

Dr. Macro

Cécile LEYRONNAS, Dr.

Salomon MANIER, Dr.

Pr. Jaccard

Dr. Karlin

Dr. Vincent

Caroline JACQUET, Dr.

Cyrille Touzeau, Dr

Laurent FRENZEL, Dr.

Stéphanie Harel, Dr

Franck Bridoux, Pr

Olivier Decaux, Pr

Antoine Huart, Dr

Arnaud JACCARD, Pr

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.

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

A Phase 2, Open Label, Multicenter, Single-stage Study 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

To assess Minimal Residual Disease (MRD) by NGS in bone marrow and blood at the completion of 6 cycles of therapy or at 1 year from start of therapy for patients in CR/modified CR\* or low dFLC or normal iFLC (iFLC\< 10 mg/L) and by Mass Spectrometry in the blood.

\*: If iFLC \<ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR).

To assess hematologic response (VGPR or better i.e. dFLC \< 40 mg/L, CR including modified CR\*, low-dFLC response (dFLC \< 10 mg/L), iFLC \< 10 mg/l) achieved after 6 cycles of Isa-Pd.

\*: If iFLC \<ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR).

To assess in all patients according to their disease history Overall Hematologic Response Rate (VGPR, CR, modified CR\*, Low-dFLC response (dFLC \< 10 mg/L), iFLC \< 10 mg/l and PR) at the completion of the 1st, 2nd, 4th, 6th, 9th and 12th cycles.

\*: If iFLC \<ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR).

Time from the inclusion to either progressive disease or death

To evaluate the relapse-free survival (RFS)

To evaluate the Organ response rate at 1 year

To evaluate the time to and the duration of haematologic and organ responses

Rate of adverse events that occured during treatment period

To assess the impact of t(11.14) determined by Fluorescence In Situ Hybridation (FISH) at inclusion on treatment response.

To assess the concentration of NT-proBNP level and evaluate the impact of the NT-proBNP level on the strain change.

To assess albumin level to proteinuria/eGFR.

patient reported outcome to assess health status in patients. The EQ-5D (European Quality of Life 3 dimensions) measures a wide range of health conditions and treatments; it is composed of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a visual analogue scale that records the patient's self-rated overall health state.

Respondents rate each of these 5 dimensions from "no problem", "some problem" or "extreme problem".

The EQ-VAS records the respondents' self-related health on a vertical, visual analogue scale. The range for EQ-VAS is from 0 (the worst health you can imagine) to 100 (=the best healt you can imagine).

Spots Global Cancer Trial Database for not in first line of treatment