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

Inclusion Criteria:

1. Age ≥ 18
2. Histologic diagnosis of AL amyloidosis;
3. Patients should have received at least one line with an alkylating agent and/or a PI,and Dexamethasone and not be in VGPR (or better) at the time of inclusion (patientswho did not reach VGPR before, or patients in VGPR or better before but with ahematological relapse at the time of inclusion can be included);
4. Measurable hematologic disease: difference between involved and uninvolved FLC > 50mg/L with an abnormal k/l ratio;
5. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervoussystem) (See Appendix 1);
6. Wash-out period of at least 4 weeks from previous antitumor therapy or anyinvestigational treatment or 5 half-lives from previous antibodies, whichever islonger.
7. Adequate bone marrow function prior to 1st drug intake (C1D1), without transfusion orgrowth factor support within 5 days prior to 1st drug intake, defined as:

• Absolute neutrophils count ≥ 1000/mm3,
• Platelets ≥ 75000/mm3,
• Hemoglobin ≥ 8.0 g/dL,

8. Adequate organ function defined as:

• Serum ASAT or ALAT ≤ 3.0 X Upper Limit of the normal range (ULN),
• Serum total bilirubin level < 1.5 x ULN, unless for subjects with Gilbert'ssyndrome where the direct bilirubin should then be ≤ 2.0 x ULN.

9. ECOG status ≤ 2
10. Male participants must agree to use contraception during the intervention period andfor at least 5 months after the last dose of IsaPd and refrain from donating spermduring this period.

• Female participants are eligible to participate if they are not pregnant, notbreastfeeding, and at least one of the following conditions applies: Not a Femaleof childbearing potential (FCBP), OR a FCBP who must have a negative serum orurine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 daysprior to and again within 24 hours prior to starting study medication and beforeeach cycle of study treatment and must either commit to continue abstinence fromheterosexual intercourse or apply a highly effective method of birth control 4weeks before initiation of treatment, during the intervention period and for atleast 5 months after IsaPd treatment,
• Female patients who are postmenopausal for at least 1 year before the screeningvisit, or are surgically sterile, or if they are of childbearing potential, agreeto practice effective methods of contraception from the time of signing theinformed consent through 30 days after the last dose of study drug, or agree tocompletely abstain from intercourse (serum pregnancy test must be performed forall women of childbearing potential at the beginning of each cycle during thestudy. In addition, a pregnancy test may be done at any time during the study atthe discretion of the investigator if a subject misses a period or has unusualmenstrual bleeding);

11. Voluntary written consent must be given before performance of any study-relatedprocedure not part of standard medical care with the understanding that consent may bewithdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

1. Presence of non-AL amyloidosis
2. AL amyloidosis with isolated soft tissue involvement
3. Bone marrow plasma cells >30% and clinically symptomatic multiple myeloma with lyticbone lesions
4. NT-proBNP > 8500 ng/L and hs-troponin I > 100 ng/L or hs-troponin T > 50 ng/L (cardiacstage IIIb patients)
5. Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatmentsustained ventricular tachycardia, aborted ventricular fibrillation, atrioventricularnodal or sinoatrial nodal dysfunction with no pacemaker
6. Chronic atrial fibrillation with uncontrolled heart rate
7. Significant cardiac dysfunction; myocardial infarction within 12 months; unstablepoorly controlled angina pectoris
8. Uncorrected valvular disease unrelated to AL amyloid cardiomyopathy
9. QT interval as corrected by Fridericia's formula >550 msec without pacemaker,
10. Undergoing dialysis
11. Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) fromany prior therapy >G1 (NCI-CTCAE v5.0)
12. Supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic hypotension,defined as a decrease in systolic blood pressure upon standing of <80 mmHg despitemedical management (i.e. midodrine, fludrocortisones) in the absence of volumedepletion
13. Previous anti-CD38 therapy or Pomalidomide therapy (if refractory to Pomalidomide)
14. Hypersensitivity to IMiD® defined as any hypersensitivity reaction leading to stopIMiD® within the 2 first cycles or toxicity, which does meet intolerance definition
15. Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinizedstarch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), argininehydrochloride, polysorbate 80, poloxamer 188, sucrose or any of the other componentsof study treatment that are not amenable to premedication with steroids and H2blockers or would prohibit further treatment with these agents
16. History of malignancy (other than AL amyloidosis) within 3 years before the date ofinclusion (exceptions are squamous and basal cell carcinomas of the skin, carcinoma insitu of the cervix or breast, or other non-invasive lesion that in the opinion of theinvestigator, with concurrence with the sponsor's medical monitor, is considered curedwith minimal risk of recurrence within 3 years)
17. Any clinically significant, uncontrolled medical conditions that, in theInvestigator's opinion, would expose the patient to excessive risk or may interferewith compliance or interpretation of the study results
18. Active systemic infection and severe infections requiring treatment with a parenteraladministration of antibiotics
19. Received any investigational drug within 14 days or 5 half-lives of theinvestigational drug prior to initiation of study intervention, whichever is longer.In case of very aggressive disease (i.e acute leukemia) delay could be shortened afteragreement between sponsor and investigator, in absence of residual toxicities fromprevious therapy
20. Known positive for HIV or active hepatitis A, B or C:

• Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA Of note: Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs)but HBsAg and HBV DNA are negative.
• If anti-HBV therapy in relation with prior infection was started beforeinitiation of IMP, the anti-HBV therapy and monitoring should continue throughoutthe study treatment period. Patients with negative HBsAg and positive HBV DNA observed during screening periodwill be evaluated by a specialist for start of anti-viral treatment: study treatmentcould be proposed if HBV DNA becomes negative and all the other study criteria arestill met.
• Active HCV infection: positive HCV RNA and negative anti-HCV. Of note: Patients with antiviral therapy for HCV started before initiation of IMP and positiveHCV antibodies are eligible. The antiviral therapy for HCV should continue throughoutthe treatment period until seroconversion. Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy forHCV are eligible

21. Pregnant or breast-feeding females