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JOURNAL ONKOLOGIE – STUDIE
ELIAS

Expression-linked and R-ISS-adapted Stratification for First Line Therapy in Multiple Myeloma Patients

Rekrutierend

NCT-Nummer:
NCT05665140

Studienbeginn:
Februar 2023

Letztes Update:
28.11.2023

Wirkstoff:
Isatuximab, Lenalidomide, Bortezomib, Dexamethasone

Indikation (Clinical Trials):
Multiple Myeloma, Neoplasms, Plasma Cell

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
University Hopsital Schleswig Holstein Campus Lübeck

Collaborator:
-

Studienleiter

Cyrus Khandanpour, Prof. Dr.
Principal Investigator
University Hospital Schleswig-Holstein, Campus Lübeck

Kontakt

Cyrus Khandanpour, Prof. Dr.
Kontakt:
Phone: +49 451 500
Phone (ext.): 75621
E-Mail: Cyrus.Khandanpour@uksh.de» Kontaktdaten anzeigen

Studienlocations
(3 von 6)

Universitätsklinikum Hamburg Eppendorf (UKE)
20246 Hamburg
(Hamburg)
GermanyRekrutierend» Google-Maps
Darmkrebszentrum am Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160
23562 Lübeck
DeutschlandRekrutierend» Google-Maps
Kinderonkologisches Zentrum am Universitätsklinikum Münster
Albert-Schweitzer-Campus 1
48149 Münster
DeutschlandRekrutierend» Google-Maps
Onkologisches Zentrum Universitätsklinikum Würzburg
Josef-Schneider-Straße 6
97080 Würzburg
DeutschlandNoch nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

Multiple myeloma is a malignant disease of the BM characterized by clonal expansion of plasma

cells. Current guidelines recommend that newly diagnosed transplant-eligible patients with

multiple myeloma (NDMMTE) shall undergo several cycles of induction, followed by one or two

cycles high-dose melphalan followed by autologous stem cell transfusion (ASCT). With the

introduction of new drugs, the prognosis of multiple myeloma patients has considerably

improved over time. Currently, induction therapy schemes usually consist of an

immunomodulator (thalidomide or lenalidomide), a CD38 targeting antibody, a proteasome

inhibitor, and dexamethasone. The induction therapy is then followed by stem cell

mobilization and subsequently one or two cycles of high-dose melphalan-chemotherapy based on

the initial cytogenetic findings of the malignant plasma cells and the initial stage of the

disease. Current guidelines recommend two cycles of high-dose melphalan therapy followed by

autologous stem cell transplantation in case of the following initial findings: presence of

cytogenetic: (4;14), (14;16), (14;20) translocations or deletion 17p (del 17p), determined by

fluorescence in situ hybridization (FISH). In addition, initial stage of R-ISS stage III

leads also to the recommendation of two rounds of high-dose melphalan. Furthermore, if the

patient does not achieve partial response as described by International Myeloma Working Group

(IMWG) recommendations after the first cycles of high-dose melphalan, a second cycle of

high-dose melphalan therapy should be administered. Later, patients treated outside clinical

trials receive either 2-3 cycles of consolidation therapy and finally take lenalidomide

(usually 10 or 15 mg on a daily basis) or proceed directly to a lenalidomide based

maintenance therapy till progression or intolerable toxicity. Essentially, all NDMMTE

patients undergo at least one cycle of high-dose chemotherapy, which is associated with high

morbidity including acute toxicities like cytopenia, infection, and long-term effects such as

myelodysplastic disease (MDS) and secondary malignancies and rarely death.

Based on preliminary data and published reports, exposure to high-doses of the genotoxic

agent melphalan might render the residual malignant myeloma cells into more aggressive

clones, accelerating relapse by potentially altering stroma. Finally, exposure to melphalan

is well known to increase the possibility of secondary malignant disease development. In MM

patients, high-dose melphalan therapy improves OS and PFS if patients from all risk groups

are taken in consideration. Yet, it remains to be answered, whether also low risk patients

have an additional benefit from high-dose melphalan therapy or whether for these patients, a

less toxic regime would be similarly sufficient with regard to PFS and OS. The challenging

question will be whether the effect of melphalan on initial disease control might be outpaced

by the negative effects as described above. Hence, the sponsor will explore whether treatment

with high-dose melphalan might represent an overtreatment for certain subpopulation myeloma

patients. These patients might be adequately treated without need of high-dose melphalan as

part of the first line treatment. We, therefore, propose to use a personalized approach to

evaluate whether patients with a low-risk profile (R-ISS stage I, characterized by low tumor

burden and absence of adverse cytogenetic findings or elevated LDH) and with a gene

expression profile indicating a standard risk of relapse (please see below) might be

sufficiently treated with an intensified induction course without subsequent upfront

high-dose melphalan chemotherapy.

Personalized therapy can be achieved by considering gene expression analysis of the malignant

BM cells together with the diagnostic work-up. We have a standardized CE-certified gene

expression array, the MMprofilerTM, allowing accurate prediction of high-risk disease based

on the SKY92 risk signature, calculating a risk score based on the expression of 92 genes

from the malignant plasma cells. Its prognostic superiority has been analyzed in multiple

retrospective analyses, totaling over 3,000 MM patients. This enables us to better define the

aggressiveness of the disease and NDMMTE patient's 'individual' risk for disease progression

within this research initiative and to define appropriate clinical strategies.

As an ultimate goal of this study, the sponsor aims to combine the outcome of gene expression

array with the revised international staging system (R-ISS) to achieve a more personalized

treatment. For patients with R-ISS stage I and the absence of high-risk disease as determined

by the SKY92 signature (GEP-SR), the sponsor proposes a therapeutic approach without a

requirement for high-dose chemotherapy as part of first-line therapy. This study would

provide personalized treatment for myeloma patients, which could dramatically reduce

toxicity, cost of therapy and lower the probability to develop a malignant clone (by about

25%) in all NDMMTE, and simultaneously improving the outcome of overall survival (OS) and

progression-free survival (PFS).

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. newly diagnosed, untreated, symptomatic, documented myeloma (according to the revised

Hypercalcaemia, renal dysfunction, anaemia and bone lesions (CRAB) criteria 2014, see

Appendix 1) with clonal bone marrow (BM) plasma cells ≥10% or biopsy-proven osseous or

extramedullary plasmacytoma and any one or more of the following myeloma defining

events: I. Hypercalcemia: serum calcium >0,25 mmol/L (>1 mg/dl) higher than the upper

limit of normal or >2,75 mmol/L (>11 mg/dL) II. Renal insufficiency: serum creatinine

> 177 μmol/l (>2 mg/dl) III. Anemia: hemoglobin value of >20 g/l below the lower limit

of normal or a hemoglobin value lower than 10g/dl.

IV. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-

CT (positron emission tomography) V. Clonal BM plasma cell percentage ≥60% VI.

Involved: uninvolved serum free light chain ratio ≥100 VII. >1 focal lesion on MRI

examination

2. Presence of measurable disease:

I. Serum M-protein ≥ 0.5 g/dL or urine M-protein ≥ 200 mg/24 hours. II. Involved FLC

(free light chain) level ≥ 10 mg/dl, provided sFLC (free light chain) ratio is

abnormal.

3. R-ISS stage I33 (see appendix 2)

4. Standard gene expression pattern of isolated plasma cell based on SKY92 GEP assay

5. Must be ≥ 18 and ≤70 years at the time of signing the informed consent form.

6. Must be able to adhere to the study visit schedule and other protocol requirements in

the investigator's opinion.

7. WHO (see Appendix 3) performance status 0-2 (WHO=2 is allowed only if caused by MM and

not by co-morbid conditions).

8. Ability to understand and willingness to sign written informed consent. Signed

informed consent must be obtained before any study specific procedure.

9. Suitable for high-dose melphalan and stem cell retransfusion.

10. Subjects must have adequate vascular access for leukapheresis

.

11. Male or Female

Male participants:

A male participant must agree to use contraception during the intervention period and for

at least 5 months after the last dose of isatuximab treatment and refrain from donating

sperm during this period.

Female participants:

A female participant is eligible to participate if she is not pregnant, not breastfeeding,

and at least one of the following conditions applies:

i) Not a Female of childbearing potential (FCBP), OR ii) A FCBP who must have a negative

serum or urine pregnancy test with a sensitivity of at least 25 milliliter units (mIU)/mL

within 28 days prior to and again within 24 hours prior to starting study medication and

before each cycle of study treatment as well as day 21 of induction and experimental arm

consolidation as well as every 28 days during all other cycles. If heavy menstruation

appears or a menstruation is delayed, additional tests have to be performed. Participants

must either commit to continue abstinence from heterosexual intercourse or apply a highly

effective method of birth control during the intervention period and for at least 5 months

after the last dose of isatuximab treatment Of note: contraception duration should take

also into consideration any backbone therapy

All females:

Must understand the damages and hazards lenalidomide can cause to an unborn fetus and the

necessary precautions associated with the use of lenalidomide.

Females of childbearing potential (FCBPs) must understand the need for effective

contraception, without interruption. This should be 28 days before starting lenalidomide,

isatuximab, throughout the entire duration of study and at least 5 months after the last

dose of lenalidomide or isatuximab.

All female and male patients with fertile partners must adhere to the following

recommendations:

I. If the female patients are permanently sterile or post-menopausal, they are considered

to have no childbearing potential. Permanent sterilization methods include hysterectomy,

bilateral salpingectomy. The postmenopausal state is defined as the absence of menstruation

within 12 months without alternative medical reasons.

II. Female patients with fertility (and male patients with fertile partners) must agree to

use an effective method of contraception (pearl index <1) throughout the study period and

for 12 months thereafter.

III. According to the "Recommendations Related to Contraception and Pregnancy Tests in

Clinical Trials" (Clinical Trial Facilitation Group, 2014-09-15), birth control methods

considered to be very effective include:

- Combined (including estrogen and progesterone) hormonal contraception related to

ovulation suppression*:

- oral

- In the vagina

- Transdermal *Due to the increased risk of venous thromboembolism in subjects with

multiple myeloma taking lenalidomide and dexamethasone, the use of combined oral

contraceptive pills are not recommended and the method should be changed

- Progesterone-only hormone contraception associated with inhibition of ovulation*:

- oral

- Injectable

- Implantable

- Intrauterine device (IUD)

- Intrauterine Hormone-releasing System (IUS)

- Vasectomized partner (with confirmed surgical success)

- Sexual abstinence (when consistent with the subject's usual lifestyle) IV.

Investigational medicial product (IMP) may interact with hormonal contraceptives and

may reduce the effectiveness of contraceptive methods V. Women using hormonal

contraceptives should add a barrier method as a second form of contraception, because

it is currently unknown whether lenalidomide, isatuximab, bortezomib or dexamethasone

may reduce the effectiveness of hormonal contraceptives.

VI. Breast-feeding lenalidomide and its metabolites are excreted in human milk. It is

unknown whether isatuximab is secreted in milk. A risk to the newborns/infants cannot be

excluded. Breast-feeding should be discontinued during treatment with lenalidomide and

isatuximab VII. Must adhere to regular pregnancy tests (at least every 21 days during

induction and consolidation (experimental arm) and 28 days during maintenance and other

therapy cycles, in case of irregular menstruation at least every two weeks, if heavy

menstruation appears or menstruation is delayed, additional tests have to be performed).

VIII. Notify investigator if method of contraception is changed. IX. Notify investigator

immediately in case of pregnancy

Male subjects must agree:

I. to use a condom during sexual contact with a pregnant female or a FCBP while taking

lenalidomide or isatuximab, during any dose interruptions and for 5 months after the last

dose of lenalidomide or isatuximab, II. Not donate semen or sperm while receiving

lenalidomide, during dose interruptions and for at least 5 months after the last dose of

lenalidomide and/or isatuximab.

III. Receive counseling about pregnancy precautions and the potential risks of fetal

exposure to lenalidomide at a minimum of every 28 days l) All subjects must: I. Agree to

abstain from donating blood while taking lenalidomide, during dose interruptions and for at

least 5 months after the last dose of lenalidomide and/or Isatuximab.

II. Agree never to give lenalidomide to another person. III. Agree to return all unused

lenalidomide capsules to the investigator (with exception of prescribed lenalidomide

capsules) IV. Be aware that no more than a 28-day lenalidomide supply may be dispensed with

each cycle of lenalidomide during induction and consolidation therapy and be prescribed

during maintenance therapy.

Exclusion Criteria:

1. Direct Coombs test positive hemolytic anemia.

2. Involvement of the central nervous system (CNS).

3. History or presence of clinically relevant CNS pathology such as clinically relevant

epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS

bleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease,

organic brain syndrome, or psychosis.

4. Subject with active or history of plasma cell leukemia, Waldenström's

macroglobulinemia, POEMS syndrome or clinically significant amyloidosis.

5. Patients having nonsecretory MM.

6. Systemic AL amyloidosis (with exception of AL amyloidosis of BM).

7. Previous chemotherapy or radiotherapy during the past 5 years except local

radiotherapy in case of local myeloma progression or benign diseases, such as

nonmalignant thyroid diseases. (Note: patients may have received a cumulative dose of

up to 320 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy

due to smouldering myeloma or a single dose of bortezomib may be acceptable. In this

case the coordinating investigator or his deputy has to be consulted prior to

inclusion.

8. Patients with any of the following laboratory abnormalities:

I. Absolute neutrophil count (ANC) < 1,000/μL. II. Platelet count < 50,000/µL

(Platelet transfusions are not permitted to improve platelet count one week prior to

study inclusion.) III. Serum Creatinine Clearance (CrCl) < 30 mL/min/1,73m2. IV. Serum

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit

of normal (ULN) (unless due to liver infiltration by myeloma cells), serum total

bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert's syndrome.

V. International ratio (INR) or partial thromboplastin time (PTT) > 1.5 × ULN, or

history of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoing treatment

with chronic, therapeutic dosing of anticoagulants (e.g. warfarin, low molecular

weight heparin, or Factor Xa inhibitors).

9. Echocardiogram (ECHO) with left ventricular ejection fraction < 45%.

10. An inadequate pulmonary function defined as oxygen saturation (Sa02) < 92 % on room

air

11. Known to be HIV+ or to have hepatitis A, B, or C active infection.

Uncontrolled or active hepatitis B virus (HBV) infection: Patients with positive HBsAg

and/or HBV DNA

Of note:

Patient can be eligible if anti-HBc immunoglobulin G (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 before initiation of

IMP, the anti-HBV therapy and monitoring should continue throughout the study

treatment period.

Patients with negative HBsAg and positive HBV DNA observed during screening period

will be evaluated by a specialist for start of anti-viral treatment: study treatment

could be proposed if HBV DNA becomes negative and all the other study criteria are

still 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 positive

HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout

the treatment period until seroconversion.

Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for

HCV are eligible.

12. Subjects with prior history of malignancies, other than MM, unless the subject has

been free of the disease for ≥ 5 years.

13. Subjects with severe polyneuropathy with accompanying pain

14. Hypersensitivity or allergy against any of the study drugs.

15. Contraindications against any of the study drugs as outlined in the Investigator

brochure or equivalent.

16. Prisoners or subjects who are legally institutionalized, or those unwilling or unable

to comply with scheduled visits, drug administration plan, laboratory tests, other

study procedures, and study restrictions.

17. Participation in another interventional clinical trial during this trial or within 4

weeks before entry into this trial. There may be exceptions at the discretion of the

(coordinating) investigator.

18. Active systemic infection and severe infections requiring treatment with a parenteral

administration of antibiotics.

19. Any clinically significant, uncontrolled medical conditions that, in the

Investigator's opinion, would expose the patient to excessive risk or may interfere

with compliance or interpretation of the study results.

20. Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized

starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine

hydrochloride, poloxamer 188, sucrose or any of the other components of study

intervention that are not amenable to premedication with steroids and H2 blockers or

would prohibit further treatment with these agents.

-

Studien-Rationale

Primary outcome:

1. Rate of minimal residual negativity combined with complete remission rate according to IMWG and EuroFlow criteria (Time Frame - Week 40 after start of induction therapy (18 weeks after randomization).):
Minimal Residual Disease (MRD) (less than 1 malignant plasma cell per 1 Mio bone marrow cells based on EuroFLow criteria) and complete remission rate (no paraprotein detectable, Immunfixation negative urine and serum) according to international myeloma working group (IMWG) criteria after high dose chemotherapy or 6 courses of IVRD (Isatuximab, Bortezomib, lenalidomide, Dexamethasone) (week 40)



Secondary outcome:

1. PFS (Time Frame - from inclusion till end of overall study):
to compare the two arms regarding Progression free survival (PFS) [ Time Frame: time from study inclusion to progression or death whichever comes first] from start of therapy till maximum of 5 years after start of trial

2. OS (Time Frame - From start to end of overall study):
to compare the two arms regarding Overall survival [ Time Frame: time from study inclusion) to death up to a maximum of 5 years

3. Toxicity (Time Frame - From start to end of overall study):
Toxicity during induction and maintenance with respect to adverse events of National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade >3 up to 5 years after start of treament

4. Response criteria (Time Frame - week 20, week 40, year 1, year 2):
Response according to IMWG criteria at week 20, 40, 1 year and 2 years after start of trial

5. Response criteria MRD (Time Frame - week 20, week 40, year 1, year 2):
Rate of MRD negativity (less than 10-5) at week 20, 40, 1 year and 2 years after start of trial

6. Quality of life (EORTC-5 questionnaire) (Time Frame - week 20, 40, year 1, year 2):
Quality of Life Assessment [based on EORTC-5 questionnaire) Time Frame: assessed at baseline, at week 20, 40, 1 year ) and 2 years after start of trial

Studien-Arme

  • Active Comparator: Arm A (Control)
    Three cycles of induction (isatuximab, bortezomib, lenalidomide, dexamethasone, I-VRD), followed by standard of care therapy (e.g. stem cell mobilization, and apheresis with a subsequent high-dose melphalan and autologous stem cell transfusion). Both groups will receive subsequently an isatuximab- and lenalidomide-based maintenance therapy.
  • Experimental: Arm B (Experimental)
    Three cycles of induction (I-VRD), stem cell mobilization, and apheresis followed by three cycles of consolidation (I-VRD). Both groups will receive subsequently an isatuximab- and lenalidomide-based maintenance therapy.

Geprüfte Regime

  • Isatuximab (Sarclisa®):
    i.v. Induction Phase (Arm A and B): Induction Cycle 1 10 mg/kg D 1, 8, 15, 22, 29. Induction Cycle 2-3 10 mg/kg D 1, 15, 29 Consolidation Phase (Arm B): Consolidation Cycle 1-3 10 mg/kg D 1, 15, 29 Maintenance Phase (Arm A and B): Maintenance Cycle 1 and subsequent cycles 10 mg/kg D 1, 15, 29
  • Lenalidomide (Lenalidomid®):
    hard capsule for oral use. Induction Phase (Arm A and B): Induction Cycle 1-3 25 mg D1-14, 20-35. Consolidation Phase (Arm B): Consolidation Cycle 1-3 25 mg D1-14, 20-35. Maintenance Phase (Arm A and B): Maintenance Cycle 1-2 10 mg D1-28. Maintenance Cycle 3 and subsequent cycles 15 mg D1-28 if tolerable
  • Bortezomib (Velcade®):
    s.c. injection. Induction Phase (Arm A and B): Induction Cycle 1-3 1,3 mg/m² D1, 4, 8, 11, 22, 25, 29, 32. Consolidation Phase (Arm B): Consolidation Cycle 1-3 1,3 mg/m² D1, 4, 8, 11, 22, 25, 29, 32
  • Dexamethasone:
    orally and i.v. Induction Phase (Arm A and B): Induction Cycle 1 20 mg p.o. D 1-2, 4-5, 8-9, 11-12, 15; 22-23, 25-26, 29-30, 32-33; 20 mg i.v. D1, 8, 15, 22 and 29. Induction Cycles 2 and 3 20 mg p.o. D 1-2, 4-5, 8-9, 11-12, 15; 22-23, 25-26, 29-30, 32-33; 20 mg i.v. D1, 15 and 29. Consolidation Phase (Arm B): Consolidation Cycle 1-3 20 mg p.o. on D 1-2, 4-5, 8-9, 11-12, 15; 22-23, 25-26, 29-30, 32-33; 20 mg i.v. on D1, 15 and 29
  • autologous stem cell transplant:
    autologous stem cell transplant

Quelle: ClinicalTrials.gov


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