Neoplasms

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Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasm, Residual

Neoplasms by Histologic Type

Hemostatic Disorders

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Antineoplastic Agents

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Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Melphalan

Lenalidomide

Dexamethasone acetate

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Arm A: consolidation with 6 additional cycles of Isa-KRD (cycles 7 to 12) 6 cycles of Isatuximab Carfilzomib Lenalidomide Dexamethasone (Isa-KRD) (28-day cycle):

* Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 12)
* Carfilzomib: 56 mg/m2 I.V on days 1, 8 and 15 (cycles 7 to 12)
* Lenalidomide: 25 mg per day orally from days 1 to 21
* Dexamethasone: 40 mg orally on day 1, 8, 15, 22

Arm B: consolidation with ASCT followed by 2 cycles of Isa-KRD (cycles 7 and 8) Melphalan 200 mg/m2 followed by autologous stem cell transplantation (please refer to section 6.3.2) 2 cycles of Isatuximab Carfilzomib Lenalidomide Dexamethasone (Isa-KRD) (28-day cycle):

* Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 8)
* Carfilzomib: 56 mg/m2 I.V on days on days 1, 8 and 15 (cycles 7 to 8)
* Lenalidomide: 25 mg per day orally from days 1 to 21
* Dexamethasone: 40 mg orally on days 1, 8, 15, 22

Arm C: ASCT followed by 2 cycles of Isa-KRD (cycles 7 and 8) Melphalan 200 mg/m2 followed by autologous stem cell transplantation. 2 cycles of Isatuximab Carfilzomib Lenalidomide Dexamethasone (Isa-KRD) (28-day cycle):

* Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 8)
* Carfilzomib: 56 mg/m2 I.V on days on days 1, 8 and 15 (cycle 7 to 8)
* Lenalidomide: 25 mg per day orally from day 1 to day 21
* Dexamethasone: 40 mg orally on days 1, 8, 15, 22

tandem ASCT Melphalan 200 mg/m2 followed by autologous stem cell transplantation.

treatment with Isa-KRD during induction and consolidation , with revlimid or Iberdomide +isatuximab during maintenance phase

Isatuximab

ASCT for ams B, C and D during consolidation

ASCT

Philippe Moreau, Professor

IFM 2020-02 will enroll patients eligible for ASCT less than 66 years. All patients will receive induction based on 6 cycles (28-day) of KRD-Isatuximab (Isa-KRD), in order to achieve deep responses and high MRD negativity rates. Patients will be classified at diagnosis according to cytogenetics (standard vs high-risk cytogenetics defined by the LP score including 17p deletion, t(4;14), del(1p32), gain 1q, trisomy 21 and trisomy 5).

According to international guidelines, outside clinical trials, frontline autologous stem cell transplantation (ASCT) is the standard of care for fit patients less than 71 years of age, who are newly diagnosed with multiple myeloma.

Triplet combinations are now the backbone of induction therapy prior to ASCT. KRD (Carfilzomib, Lenalidomide, Dexamethasone) is potentially the more active regimen.

Quadruplet combinations are under evaluation. The prospective phase 3 CASSIOPEIA trial conducted by the IFM and HOVON cooperative groups investigated the outcome of transplant-eligible patients treated with VTD (Bortezomib, Thalidomide, Dexamethasone) +/- Daratumumab administered both before (induction, 4 cycles) and after (consolidation, 2 cycles) single ASCT prepared by Melphalan 200 mg/m2.5 The addition of Daratumumab to VTD during induction induced significantly higher response rates, but also higher minimal residual disease (MRD) - negativity rates. The high response rates achieved after induction (MRD negativity rates at 10-5 by 8-color flow cytometry 35% (188/543) in the VTD-Dara arm vs 23% (125/542) after 4 cycles of VTD in the intent-to-treat population), but also after consolidation and before maintenance (MRD negativity rates at 10-5 by 8-color flow cytometry 63% in the VTD-Dara arm vs 43% in the VTD in the intent-to-treat population), translated into a significant improvement in progression-free-survival (PFS) in the Daratumumab arm of the study: 18-month PFS 93% vs 85% before maintenance, HR 0.47 (0.33-0.67), p \< 0.0001. Cassiopeia is the first study showing a correlation between MRD negativity after induction (before ASCT) and PFS benefit, in the setting of quadruplet combination induction. Based on these results, VTD + daratumumab was recently approved by the FDA and EMA.

KRD has also been combined with Daratumumab in several phase 2 trials. Early results indicate that this quadruplet combination might potentially be the most effective regimen prior to ASCT in terms of response and MRD-negativity rates. Carfilzomib was administered intravenously weekly, on days 1, 8 and 15 of 28 day-cycles at the dose of 56 mg/m². Based on 70 patients, the MRD-negativity rate after four cycles of KRD-Daratumumab was 39% at a detection level of 10-5 by next generation sequencing (NGS). The weekly KRD-Daratumumab regimen was associated with low toxicity, and stem cell harvest was adequate. The rate of MRD negativity in 42 patients further improved after single ASCT, to 67% and 43% at a detection level of 10-5 and of 10-6 by NGS, respectively. Due to the short 7.9 months median follow-up time at the time of presentation, no PFS data were presented. At ASCO 2020, Weisel et al reported the results of induction based on 6 cycles of KRD plus Isatuximab, in patients with high-risk cytogenetics.8 In this interim analysis on the first 46 patients eligible for ASCT with high-risk disease, the overall response rate was 100%, including 60% MRD negativity at 10-5 by NGS after induction and before ASCT. No death on study was reported. No data are yet available regarding MRD negativity rates after ASCT or PFS. At ASH 2019, Landgren et al. reported the results of eight weekly KRD-Daratumumab cycles without ASCT in a small phase 2 study on 41 patients after a short median follow-up time of 8.6 months.

On the same intent-to-treat basis, MRD-negativity rate at a detection level of 10-5 by NGS was 61% and 65% in patients after six and eight cycles, respectively, including a very good partial response (VGPR) rate or better of 85% after 8 cycles and an overall response rate (ORR) of 100%. No death on study was seen. At the time of the report, no patient with MRD-negative disease had progressed. Despite the short follow-up time, based on the high rate of MRD-negativity and the 0% relapse rate achieved so far with this quadruplet combination, the authors of this small phase 2 series now propose to systematically delay ASCT in patients with standard-risk disease. This provocative recommendation requires validation in a phase 3 randomized trial comparing frontline versus delayed ASCT in patients with MRD-negative disease after induction.

Patients MRD positive after quadruplet induction are at higher risk of disease progression. For patients with high-risk (HR) disease, tandem ASCT has been proposed in order to improve PFS and overall survival (OS). In an integrated analysis of four phase III studies independently conducted by HOVON/GMMG, IFM, PETHEMA/GEM and GIMEMA European cooperative groups, in the era of Bortezomib-based induction regimens, double ASCT significantly improved PFS and OS in HR patients.

In the EMN02/HO95 study, in centers with a policy of double ASCT, patients were assigned to receive VMP (Bortezomib, Melphalan, Prednisone), single ASCT (ASCT-1) or two planned ASCTs (ASCT-2) to prospectively compare ASCT-1 with ASCT-2. Patients who received ASCT-2 had a prolonged PFS compared to those who received ASCT-1. Importantly, ASCT-2 overcame the adverse prognosis conferred by high-risk cytogenetics. In the same study, OS from the first randomization was significantly prolonged with ASCT-2 as compared with ASCT-1, a benefit also seen in subgroups of patients with adverse prognosis, including those with R-ISS stage II+III and high-risk cytogenetics. To date, no prospective trial has compared single vs tandem ASCT in HR patients in the era of quadruplet induction combinations.

After ASCT, a systematic maintenance is recommended by International Guidelines. Lenalidomide is approved in this setting, and proposed until progression. Other agents or combinations are under evaluation for maintenance, such as Ixazomib, Elotuzumab, Daratumumab or Isatuximab. Iberdomide is a next generation cereblon targeting agent, with antitumor and immunostimulatory activities in Lenalidomide- and Pomalidomide-resistant multiple myeloma. This oral agent, which could be the ideal agent for maintenance therapy, is currently tested after ASCT. Phase 2 and 3 randomized studies are currently investigating the combination of Lenalidomide with anti-CD38 monoclonal antibodies as maintenance therapy after autologous stem cell transplant. We assume that a fixed duration of maintenance using Iberdomide and Isatuximab will induce a high-rate of sustained MRD negativity.

All patients will receive ISa-KRD treatment for induction. Depending on MRD status, patients will be randomized :

MRD Standard-risk post induction MRD \<10-5,(1:1 Randomization):

Arm A: 6 additional cycles of Isa-KRD Arm B: ASCT followed by 2 cycles of Isa-KRD MRD High-risk (post induction MRD \>10-5) (1:1 Randomization) Arm C: ASCT followed by 2 cycles of Isa-KRD Arm D: tandem ASCT

Maintenance:

In arms A/B, patients will receive commercial Lenalidomide, for 3 years. In arms C/D, patients will receive Iberdomide and Isatuximab for 3 years. Treatment allocation A/B to patients: randomization stratified per center according to LP score.

Treatment allocation C/D to patients: randomization stratified per center according to LP score.

For each randomization, primary analysis will evaluate MRD (NGS, 10-6 threshold) after all subjects have completed the post-consolidation response evaluation or have been discontinued from study treatment by this timepoint

MInimal Residual Disease Adapted Strategy

MInimal Residual Disease Adapted Strategy: Frontline Therapy for Patients Eligible for Autologous Stem Cell Transplantation Less Than 66 Years; a Prospective Study

For both parts of the trial (A vs B and C vs D), the primary comparison of the 2 strategies will be made with respect to negative MRD rate (10-6 NGS) before maintenance using the chi square test in the ITT population.

The observed MRD negative rate will be provided along with its 2-sided 95% Confidence interval (CI). Treatment effect will be described by an Odds Ratio, along with its 2-sided 95% confidence interval, by fitting a logistic regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison). In case of missing MRD, data will be imputed as positive in all arms.

Sensitivity analyses will be performed using best-worst and worst-best case to check for robustness of the results.

Sustained MRD rate at after consolidation phase ( 6 months) than year 1, 2, 3 post consolidation phase will be analyzed similarly to the primary endpoint

For Overall Survival (OS), the distribution of OS since randomization will be estimated using Kaplan Meier method. The comparison of the 2 arms will be made by log-rank test. Treatment effect will be described by Hazard Ratio and its 2-sided 95% confidence intervals will be estimated using a Cox regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison).

Progression Free Survival, defined as time from randomization to either progression or death will be analyzed similarly to OS

rate of adverse events that occured during treatment period

Amgen

Sanofi

Bristol-Myers Squibb

Intergroupe Francophone du Myelome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Cytarabine

Daunorubicin

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

If WBC ≥ 30 G/L, chemotherapy the induction cycle :

* Daunorubicin 60 mg/m²/day IV on D1, D2, and D3
* Cytarabine 200 mg/m²/day D1 to D7
* OMEGAVEN® 2 ml/kg D1 to D9,

If WBC ≤ 30 G/L, OMEGAVEN during 48 hours

Induction cycle :

OMEGAVEN® 2 ml/kg D-2 to D7 Daunorubicin 60 mg/m²/day IV on D1, D2, and D3

- Cytarabine 200 mg/m²/day IV D1 to D7

bone marrow aspirate at D15: If BM blasts are \> 5% or if second induction course :

* Daunorubicin 35 mg/m²/day IV D17 and D18
* OMEGAVEN® 2 ml/kg
* Cytarabine 1000 mg/m²/12h IV on D17, D18, and D19

For all patients: G-CSF 5 µg/kg/day subcutaneously from D21 to hematopoietic recovery (PMN \> 1 G/L or \> 0.5 G/L during 3 days).

Consolidation will be administered at investigator's discretion

OMEGAVEN

Emmanuel GYAN, MD

Pilot study of the efficacy and tolerance of the adjunction of a Fish oil emulsion to daunorubicin and cytarabine chemotherapy for the treatment of Acute MYeloblastic Leukemia of Younger patients (under 61 years) with high-risk cytogenetics.

Adjunction of a Fish oil emulsion OMEGAVEN to daunorubicin and cytarabine chemotherapy for the treatment of Acute MYeloblastic Leukemia of Younger patients.

Pilot Study Efficacy and Tolerance Fish Oil Emulsion Daunorubicin and Cytarabine Treatment of AML Younger Patients

Pilot Study of the Efficacy and Tolerance of the Adjunction of a Fish Oil Emulsion to Daunorubicin and Cytarabine Chemotherapy for the Treatment of Acute MYeloblastic Leukemia of Younger Patients With High-risk Cytogenetics

Number of patients incomplete response rate after the adjunction of a Fish oil emulsion to daunorubicin and cytarabine chemotherapy for the induction of untreated AML

Number of patients with side effects during and after the admistration of a Fish oil emulsion with daunorubicin and cytarabine chemotherapy for the induction of untreated AML

Daily quantification of peripheral blasts by flow cytometry during the adjunction of a Fish oil emulsion to daunorubicin and cytarabine chemotherapy

Measure of plasma concentration of daunorubicin and cytarabine administered together with a fish oil emulsion

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
MInimal Residual Disease Adapted Strategy	NCT04934475	Multiple Myelom...	Isatuximab ASCT	18 Years - 66 Years	Intergroupe Francophone du Myelome
MInimal Residual Disease Adapted Strategy	NCT04934475	Multiple Myelom...	Isatuximab ASCT	18 Years - 66 Years	Intergroupe Francophone du Myelome
Pilot Study Efficacy and Tolerance Fish Oil Emulsion Daunorubicin and Cytarabine Treatment of AML Younger Patients	NCT01999413	Acute Myeloid L...	OMEGAVEN Daunorubicin Cytarabine	18 Years - 61 Years	French Innovative Leukemia Organisation
MInimal Residual Disease Adapted Strategy	NCT04934475	Multiple Myelom...	Isatuximab ASCT	18 Years - 66 Years	Intergroupe Francophone du Myelome
Pilot Study Efficacy and Tolerance Fish Oil Emulsion Daunorubicin and Cytarabine Treatment of AML Younger Patients	NCT01999413	Acute Myeloid L...	OMEGAVEN Daunorubicin Cytarabine	18 Years - 61 Years	French Innovative Leukemia Organisation

Spots Global Cancer Trial Database for younger patients