A Study of Subcutaneous Daratumumab Versus Active Monitoring in Participants With High-Risk Smoldering Multiple Myeloma

Phase 3

Active, not recruiting

• Conditions: Smoldering Multiple Myeloma

• Registration Number: NCT03301220
• Lead Sponsor: Janssen Research & Development, LLC

Brief Summary

The primary objective of this study is to determine whether treatment with daratumumab administered subcutaneously (SC) prolongs progression-free survival (PFS) compared with active monitoring in participants with high-risk smoldering multiple myeloma (SMM).

Detailed Description

This study consists of 3 phases: Screening Phase (up to 35 days), an Active Monitoring Phase or a Treatment Phase of 39 cycles or 36 months (whichever occurs first), and a Follow-up Phase which will continue until death, lost to follow-up, consent withdrawal, or study end (approximately 8 years after the first participant is randomized), whichever occurs first. Active monitoring cycles and treatment cycles are 4 weeks in length. For all participants, disease evaluations will be performed every 12 weeks until confirmed progressive disease (PD). After PD, survival is to be followed at least every 6 months, until the end of the study. Participants will undergo tumor assessments, pharmacokinetics, biomarkers and safety evaluations (adverse events, laboratory tests, vital sign measurements, physical examinations, Eastern Cooperative Oncology Group \[ECOG\] performance status) over the time.

Study Timeline

• Study First Submitted: 2017-09-29
• Study First Submitted QC: 2017-09-29
• Study First Posted: 2017-10-04
• Study Start: 2017-11-07
• Primary Completion: 2024-05-01
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-09
• Last Update Posted: 2025-01-10
• Study Completion: 2025-12-16

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 390

Inclusion Criteria

• Diagnosis of high risk smoldering multiple myeloma (SMM) (per International Myeloma Working Group [IMWG] criteria) for less than or equal to (<=) 5 years with measurable disease at the time of randomization, defined as serum M protein greater than or equal to (>=) 10 gram per liter (g/L) or urine M protein >= 200 milligram per 24 hours (mg/24 hours) or involved serum free light chain (FLC) >=100 milligram per liter (mg/L) and abnormal serum FLC ratio
• Clonal bone marrow plasma cells (BMPCs) >= 10 percentage (%); and at least 1 of the following risk factors; Serum M protein >= 30 g/L, immunoglobulin (Ig)A SMM, immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes (only IgA, IgM, and IgG should be considered in determination for immunoparesis; IgD and IgE are not considered in this assessment), serum involved: uninvolved FLC ratio >= 8 and less than (<) 100, or clonal BMPCs greater than (>) 50% to <60% with measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use highly effective method of contraception
• A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to randomization
• During the study and for 3 months after receiving the last dose of daratumumab, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction

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Exclusion Criteria

• Multiple myeloma (MM), requiring treatment, defined by any of the following:

  1. Bone lesions (1 or more osteolytic lesions on low-dose whole body computed tomography [LDCT], positron-emission tomography with computed tomography [PET-CT] or CT). Participants who have benign/post-traumatic bone lesions visible on screening images as well as previous imaging, may be considered for inclusion. Details (diagnosis, location, duration) on benign/post-traumatic pre-existing bone lesions that can be seen on the screening images (example [eg.], old fractures) and were also present on previous imaging are to be reported in the case report form (CRF)
  2. Hypercalcemia (serum calcium greater than [>]0.25 millimoles per liter [mmol/L] [>1 milligram per deciliter {mg/dL}] higher than upper limit of normal [ULN] or >2.75 mmol/L [>11 mg/dL]). Participants who have clinically stable hypercalcemia attributable to a disease other than multiple myeloma (eg, hyperparathyroidism) may be considered for inclusion after a case by case review by the medical monitor
  3. Renal insufficiency, preferably determined by creatinine clearance less than (<)40 milliliter per minute (mL/min) measured or estimated using the Modification of Diet in Renal Disease (MDRD), or serum creatinine >177 micromole per liter (μmol/L). Participants who have clinically stable renal insufficiency attributable to a disease other than multiple myeloma (eg, glomerulonephritis) may be considered for inclusion after a case by case review by the medical monitor
  4. Anemia, defined as hemoglobin <10 gram per deciliter (g/dL) or >2 g/dL below lower limit of normal or both; transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted. Participants who have clinically stable anemia attributable to a disease other than multiple myeloma (eg, thalassemia, vitamin B12 deficiency, iron deficiency) may be considered for inclusion after a case by case review by the medical monitor
  5. Clonal BMPC percentage >=60%
  6. Serum FLC ratio (involved:uninvolved) >=100 (the involved FLC must be >=100 mg/L)
  7. More than 1 focal lesion >=5 millimeter (mm) in diameter by magnetic resonance imaging (MRI)

• Primary systemic amyloid light-chain (AL) (immunoglobulin light chain) amyloidosis

• Exposure to any of the following:

  1. Prior exposure to daratumumab or prior exposure to other anti-Cluster of Differentiation 38 (anti-CD38) therapies
  2. Prior exposure to approved or investigational treatments for SMM or MM (including but not limited to conventional chemotherapies, immunomodulatory agent [IMiDs], or proteasome inhibitor [PIs]). Stable standard dosing of bisphosphonate and denosumab as indicated for osteoporosis is acceptable
  3. Exposure to investigational drug (including investigational vaccines) or invasive investigational medical device for any indication within 4 weeks or 5 half-lives, whichever is longer, before Cycle 1, Day 1
  4. Ongoing treatment with corticosteroids with a dose >10 milligram (mg) prednisone or equivalent per day at the time of randomization; or >280 mg cumulative prednisone dose or equivalent for any 4-week period in the year prior to randomization
  5. Ongoing treatment with other monoclonal antibodies (eg, infliximab, rituximab), immunomodulators (eg, abatacept, methotrexate, azathioprine, cyclosporine) or other treatments that are likely to interfere with the study procedures or results

• Received treatment (chemotherapy, surgery, et cetera [etc]) for a malignancy (other than SMM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion), which is considered cured with minimal risk of recurrence within 3 years

• Medical or psychiatric condition or disease (for example, active systemic disease [including presence of auto-antibodies], uncontrolled diabetes) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study

• Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies, hyaluronidase, or other human proteins, or their excipients, or known sensitivity to mammalian-derived products (including dairy allergy)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	From the date of randomization to active multiple myeloma (MM) or the date of death, whichever occurs first (up to approximately 8 years)	PFS is time from randomization to active MM according to International Myeloma Working Group (IMWG) criteria or death. Per IMWG criteria, active MM (SLiM-CRAB) is defined as: greater than or equal to (\>=)60 percent (%) bone marrow plasma cells (BMPCs), free light chain (FLC) involved/uninvolved ratio \>=100, greater than (\>)1 focal bone lesions on magnetic resonance imaging (MRI), calcium elevation, renal insufficiency by creatinine clearance, anemia, or bone disease due to lytic bone lesions.

Secondary Outcome Measures

Name	Time	Method
Time to Biochemical or Diagnostic (SLiM-CRAB) Progression	Up to biochemical or diagnostic progression (up to approximately 8 years)	Time to biochemical or diagnostic progression is defined as the earlier of time to biochemical progression or diagnostic (SLiM-CRAB) progression. SLiM-CRAB is defined as \>=60% bone marrow plasma cells, free light chain involved/uninvolved ratio \>=100, \>1 focal bone lesions on magnetic resonance imaging (MRI), calcium elevation, renal insufficiency by creatinine clearance, anemia, or bone disease due to lytic bone lesions.
Overall Response Rate (ORR)	Up to approximately 8 years	ORR is defined as percentage of participants with partial response (PR) or better (very good partial response \[VGPR\], complete response \[CR\], and stringent complete response \[sCR\]) as defined by IMWG criteria. PR: \>=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>=90% or to less than (\<)200 mg/24 hours; if serum and urine M-protein are not measurable, \>=50% decrease in difference between involved and uninvolved free light chain (FLC) levels; if serum and urine M-protein and serum free light assay is not measurable, a \>=50% reduction in BMPC, with baseline BMPC percentage \>=30%. VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. CR: negative immunofixation on serum and urine, and \<5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4- color flow cytometry.
Complete Response (CR) Rate	Up to approximately 8 years	CR rate was defined as the percentage of participants with a CR (or better \[sCR\]) as defined by the IMWG response criteria. IMWG criteria for CR: negative immunofixation on serum and urine, and \<5% PCs in bone marrow. IMWG criteria for sCR: CR as defined above, plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Time to First-Line Treatment for Multiple Myeloma (MM)	Post-progressive disease (PD) follow-up, every 6 months until end of study (up to approximately 8 years)	Time to first-line treatment for MM was defined as the time from the date of randomization to the date of the first-line treatment given for MM (post disease progression).
Progression-Free Survival on First-Line Treatment for MM (PFS2)	Post-PD follow-up, every 6 months until end of study (up to approximately 8 years)	PFS2 is time from date of randomization to date of documented PD on first line treatment given for MM or death, whichever comes first. IMWG criteria for PD: \>=25% from lowest response level in serum M-component (the absolute increase must be \>=0.5 gram per deciliter \[g/dL\]) and/or in urine M-component (the absolute increase must be \>=200 mg/24 hour); only in participants without measurable serum and urine M-protein levels: increase of \>=25% in the difference between involved and uninvolved free light chain levels and the absolute increase must be \>10 mg/dL. BMPC%: the absolute % must be \>=10%; definite increase in size of existing bone lesions or soft tissue plasmacytomas; definite development of new bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.65 millimoles per liter \[mmol/L\]) that can be attributed solely to PC proliferative disorder.
Overall Survival (OS)	Throughout study, and at least every 3 months until PD; post-PD, every 6 months until end of study (up to approximately 8 years)	OS was defined as the time from the date of randomization to the date of the participant's death.
Percentage of Participants who Progress to MM With Adverse Prognostic Features	At screening and PD (up to approximately 8 years)	Adverse prognostic features includes International Staging System Stage III (based on beta2 \[β2\]-microglobulin \>=5.5 milligram per liter \[mg/L\] \[median survival 29 months\]) and adverse cytogenetic characteristics.
Serum Daratumumab Pharmacokinetic (PK) Concentration	Cycles 1 and 3: Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; end of the treatment (EOT: 28 days after the last daratumumab dose); and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks)	PK concentration of Daratumumab will be measured.
Maximum Observed Concentration (Cmax) of Daratumumab	Cycles 1 and 3: Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; end of the treatment (EOT: 28 days after the last daratumumab dose); and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks)	The Cmax is the maximum observed plasma concentration of Daratumumab.
Minimum Observed Concentration (Cmin) of Daratumumab	Cycles 1 and 3: Day 1 predose, and Day 4 postdose; Cycles 5, 7, 12, and 24: Day 1 predose; end of the treatment (EOT: 28 days after the last daratumumab dose); and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks)	The Cmin is the minimum observed plasma concentration of Daratumumab.
Number of Participants With Anti-daratumumab Antibodies	Cycles 1,3,5,7,12, and 24: Predose on Day 1; end of treatment (28 days after the last daratumumab dose), and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks)	Participant's serum samples will be collected and screened for antibodies binding to daratumumab using validated immunoassay methods for evaluation of potential immunogenicity.
Number of Participants With Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies	Cycles 1,3,5,7,12, and 24: Predose on Day 1; end of treatment (28 days after the last daratumumab dose), and 8 weeks after the last daratumumab dose (up to approximately 3 years and 8 weeks)	Participant's plasma samples will be collected and screened for antibodies binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary for the rHuPH20 immunogenicity assessment.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score	Baseline, Weeks 12, 24, and 60, every year until end of treatment (EOT)/active monitoring, pre-PD follow-up (every year until end of study or PD), PD, and Months 3, 6, 12, and 18 post-PD (up to approximately 8 years)	EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer participants. It is composed of 30 items, multiitem measure (28 items) and 2 single-item measures. For the multiple item measure, 4 point scale is used and the score for each item range from "1 = not at all" to "4 = very much". Higher scores indicate worsening. The 2 single-item measure involves question about the overall health and overall quality of life which will be rated on a 7 point scale ranging from "1 = very poor" to "7 = excellent". Lower scores indicate worsening. Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale	Baseline, Weeks 12, 24, and 60, every year until end of treatment (EOT)/active monitoring, pre-PD follow-up (every year until end of study or PD), PD, and Months 3, 6, 12, and 18 post-PD (up to approximately 8 years)	EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. EORTC QLQ-MY20 includes two scales: disease symptoms (6 questions) and future perspective (3 questions). Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the future perspective scale, a higher score indicates a better perspective of the future; and higher score for the disease symptoms scale indicates higher level of symptomatology.
Change From Baseline in European Quality (EuroQoL) 5-Dimension 5-Level Health Status (EQ-5D-5L) Questionnaire	Baseline, Weeks 12, 24, and 60, every year until end of treatment (EOT)/active monitoring, pre-PD follow-up (every year until end of study or PD), PD, and Months 3, 6, 12, and 18 post-PD (up to approximately 8 years)	The EQ-5D questionnaire is a brief, generic health-related quality of life assessment (HRQOL) that can also be used to incorporate participant preferences into health economic evaluations. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and as overall health using a "thermometer" visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health).
Duration of Response	From the date of initial documentation of a response to the date of first documented evidence of PD (up to approximately 8 years)	Duration of response is defined as date of onset of first response (PR or better \[VGPR, CR, sCR\]) until date of disease progression or death. PR: \>=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>=90% or to \<200 mg/24 hours; if the serum and urine M-protein are not measurable, \>=50% decrease in difference between involved and uninvolved free light chain (FLC) levels; if serum and urine M-protein and serum free light assay is not measurable, a \>=50% reduction in bone marrow PC, with baseline bone marrow PC percentage \>=30%. VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. CR: negative immunofixation on serum and urine, and \<5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Time to Response	Up to End of Treatment (up to approximately 39 cycles [each cycle of 28 days] or 36 months, whichever occurs first)	Time to response is defined as the time from randomization until onset of first response (PR or better \[VGPR, CR, sCR\]). PR: \>=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>=90% or to \<200 mg/24 hours; if the serum and urine M-protein are not measurable, \>=50% decrease in difference between involved and uninvolved free light chain (FLC) levels; if serum and urine M-protein and serum free light assay is not measurable, a \>=50% reduction in bone marrow PC, with baseline bone marrow PC percentage \>=30%. VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. CR: negative immunofixation on serum and urine, and \<5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.

Trial Locations

Locations (162)

Arthur J E Child Comprehensive Cancer Centre; 🇨🇦 Calgary, Alberta, Canada

Arizona Oncology Associates, PC - HAL; 🇺🇸 Phoenix, Arizona, United States

Innovative Clinical Research Inc; 🇺🇸 Whittier, California, United States

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

University of Iowa Hospitals and Clinics; 🇺🇸 Iowa City, Iowa, United States

East Jefferson General Hospital; 🇺🇸 Metairie, Louisiana, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

VA Southern Nevada Healthcare; 🇺🇸 North Las Vegas, Nevada, United States

New York Oncology Hematology; 🇺🇸 Albany, New York, United States

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

University of North Carolina; 🇺🇸 Chapel Hill, North Carolina, United States

Levine Cancer Institute, Carolinas HealthCare System; 🇺🇸 Charlotte, North Carolina, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

The Ohio State University; 🇺🇸 Columbus, Ohio, United States

OHSU/CHM; 🇺🇸 Portland, Oregon, United States

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Texas Oncology P A; 🇺🇸 Tyler, Texas, United States

VA North Texas Health Care System; 🇺🇸 Dallas, Texas, United States

University of Washington; 🇺🇸 Seattle, Washington, United States

Hospital Aleman; 🇦🇷 Buenos Aires, Argentina

Hospital Italiano de Buenos Aires; 🇦🇷 Buenos Aires, Argentina

CEMIC Saavedra; 🇦🇷 Ciudad de Buenos Aires, Argentina

Hospital das Clinicas de Porto Alegre; 🇧🇷 Porto Alegre, Brazil

Instituto de Educacao, Pesquisa e Gestao em Saude Instituto Americas (COI); 🇧🇷 Rio de Janeiro, Brazil

Hospital Sao Rafael; 🇧🇷 Salvador, Brazil

Hospital Privado - Centro Medico de Cordoba; 🇦🇷 Cordoba, Argentina

Hospital Italiano de La Plata; 🇦🇷 La Plata, Argentina

Sanatorio Britanico de Rosario; 🇦🇷 Rosario, Argentina

Austin Hospital; 🇦🇺 Heidelberg, Australia

Calvary Mater Newcastle Hospital; 🇦🇺 Waratah, Australia

The Perth Blood Institute; 🇦🇺 West Perth, Australia

Queen Elizabeth Hospital; 🇦🇺 Woodville, Australia

ZNA; 🇧🇪 Antwerpen, Belgium

AZ St.-Jan Brugge-Oostende AV; 🇧🇪 Brugge, Belgium

UZBrussel; 🇧🇪 Brussel, Belgium

UZ Gent; 🇧🇪 Gent, Belgium

Virga Jessa Ziekenhuis; 🇧🇪 Hasselt, Belgium

Az Groeninge; 🇧🇪 Kortrijk, Belgium

Centro de Pesquisa e Ensino em Oncologia de Santa Catarina CEPEN; 🇧🇷 Florianopolis, Brazil

Universidade Federal de Goias - Hospital das Clinicas da UFG; 🇧🇷 Goiania, Brazil

Instituto Joinvilense de Hematologia e Oncologia Ltda Centro de Hematologia e Oncologia; 🇧🇷 Joinville, Brazil

Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto Hospital de Base; 🇧🇷 Sao Jose do Rio Preto, Brazil

Instituto de Ensino e Pesquisa São Lucas; 🇧🇷 Sao Paulo, Brazil

Clinica Sao Germano; 🇧🇷 São Paulo, Brazil

Hospital Santa Cruz; 🇧🇷 São Paulo, Brazil

Cross Cancer Institute; 🇨🇦 Edmonton, Alberta, Canada

Lakeridge Health Oshawa; 🇨🇦 Oshawa, Ontario, Canada

Fakultni nemocnice Hradec Kralove; 🇨🇿 Hradec Kralove, Czechia

Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni; 🇨🇿 Plzen, Czechia

Fakultni Nemocnice Ostrava; 🇨🇿 Ostrava, Czechia

Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie; 🇨🇿 Praha 2, Czechia

Aarhus University Hospital; 🇩🇰 Aarhus N., Denmark

Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Odense Universitetshospital; 🇩🇰 Odense C, Denmark

Ålborg Universitetshospital; 🇩🇰 Ålborg, Denmark

CHU de Limoges - Fédération Hépatologie; 🇫🇷 Limoges, France

Chu Hotel Dieu; 🇫🇷 Nantes cedex 01, France

CHU de Bordeaux - Hospital Haut-Leveque; 🇫🇷 Pessac cedex, France

Centre hospitalier Lyon-Sud; 🇫🇷 Pierre Benite cedex, France

CHU De Poitiers; 🇫🇷 Poitiers, France

l'Hôpital Pontchaillou; 🇫🇷 Rennes, France

CHU Bretonneau; 🇫🇷 Tours Cedex 9, France

Helios Kliniken Berlin Buch Gmbh; 🇩🇪 Berlin, Germany

St. Barbara-Klinik Hamm GmbH; 🇩🇪 Hamm, Germany

Universitaetsklinikum Heidelberg Medizinische Klinik V; 🇩🇪 Heidelberg, Germany

Medizinische Klinik A; 🇩🇪 Muenster, Germany

Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,; 🇩🇪 Tübingen, Germany

Universitaetsklinikum Ulm; 🇩🇪 Ulm, Germany

Alexandra General Hospital of Athens; 🇬🇷 Athens Attica, Greece

Semmelweis Egyetem, I. Belgyogyaszati Klinika; 🇭🇺 Budapest N/a, Hungary

Semmelweis Egyetem I.Belgyogyaszati Klinika; 🇭🇺 Budapest, Hungary

Del Pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet Szent Laszlo Telephely; 🇭🇺 Budapest, Hungary

Debreceni Egyetem Klinikai Kozpont; 🇭🇺 Debrecen, Hungary

Haemek; 🇮🇱 Afula, Israel

Barzilai Medical Center; 🇮🇱 Ashkelon, Israel

Bnai Zion Medical Center; 🇮🇱 Haifa, Israel

Carmel Medical Center; 🇮🇱 Haifa, Israel

Rambam Medical Center; 🇮🇱 Haifa, Israel

Hadassah Medical Center; 🇮🇱 Jerusalem, Israel

Galilee Medical Center; 🇮🇱 Nahariya, Israel

Rabin Medical Center; 🇮🇱 Petah-Tiqva, Israel

Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

Sourasky Medical Center; 🇮🇱 Tel-Aviv, Israel

Policlinico Sant'Orsola Malpighi; 🇮🇹 Bologna, Italy

Businco Cancer Hospital; 🇮🇹 Cagliari, Italy

A.O. Santa Croce e Carle; 🇮🇹 Cuneo, Italy

Ospedale S. Eugenio; 🇮🇹 Roma, Italy

Università di Roma 'La Sapienza' - Ospedale Umberto 1°; 🇮🇹 Roma, Italy

A.O.U. Città della Salute e della Scienza di Torino- Divisione di Ematologia; 🇮🇹 Torino, Italy

ASST dei Sette Laghi, Ospedale di Circolo e Fonazione Macchi; 🇮🇹 Varese, Italy

Fukuoka University Hospital; 🇯🇵 Fukuoka, Japan

Chugoku Central Hospital; 🇯🇵 Fukuyama, Japan

Ogaki Municipal Hospital; 🇯🇵 Gifu, Japan

Kagoshima University Hospital; 🇯🇵 Kagoshima, Japan

Kanazawa University Hospital; 🇯🇵 Kanazawa, Japan

National Hospital Organization Osaka Minami Medical Center; 🇯🇵 Kawachi Nagano, Japan

National Hospital Organization Kumamoto Medical Center; 🇯🇵 Kumamoto-shi, Japan

Kobe City Medical Center General Hospital; 🇯🇵 Kobe City, Japan

Kurume University Hospital; 🇯🇵 Kurume, Japan

Kyoto Kuramaguchi Medical Center; 🇯🇵 Kyoto, Japan

National Hospital Organization Matsumoto Medical Center; 🇯🇵 Matsumoto, Japan

Matsuyama Red Cross Hospital; 🇯🇵 Matsuyama, Japan

Nagoya City University Hospital; 🇯🇵 Nagoya, Japan

Niigata Cancer Center Hospital; 🇯🇵 Niigata, Japan

National Hospital Organization Okayama Medical Center; 🇯🇵 Okayama, Japan

National Hospital Organization Sendai Medical Center; 🇯🇵 Sendai-City, Japan

National Hospital Organization Shibukawa Medical Center; 🇯🇵 Shibukawa, Japan

Japanese Red Cross Medical Center; 🇯🇵 Shibuya, Japan

iBiomed Research Unit; 🇲🇽 Aguascalientes, Mexico

JM Research, SC; 🇲🇽 Cuernavaca, Mexico

Centro de Investigación Farmacéutica Especializada; 🇲🇽 Guadalajara, Mexico

Centro de Atención e Investigación Clínica en Oncología; 🇲🇽 Merida, Mexico

Hospital Universitario de Nuevo León; 🇲🇽 Monterrey, Mexico

Gelre Ziekenhuis; 🇳🇱 Apeldoorn, Netherlands

Haga ziekenhuis; 🇳🇱 Den Haag, Netherlands

Albert Schweitzer Ziekenhuis; 🇳🇱 Dordrecht, Netherlands

ETZ TweeSteden; 🇳🇱 Tilburg, Netherlands

Oslo University Hospital HF Ulleval sykehus; 🇳🇴 Oslo, Norway

Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im Ks B Markiewicza; 🇵🇱 Brzozow, Poland

Szpital Uniwersytecki nr 2 im. Jana Biziela w Bydgoszczy; 🇵🇱 Bydgoszcz, Poland

Wojewodzki Szpital Specjalistyczny w Legnicy; 🇵🇱 Legnica, Poland

Clinical Research Center Sp z o o Medic R Sp k; 🇵🇱 Poznan, Poland

Instytut Hematologii i Transfuzjologii; 🇵🇱 Warszawa, Poland

Emergency Hospital of Dzerzhinsk; 🇷🇺 Dzerzhinsk, Russian Federation

City clinical hospital n.a. S.P.Botkin; 🇷🇺 Moscow, Russian Federation

City Clinical Hospital # 40; 🇷🇺 Moscow, Russian Federation

Nizhniy Novgorod Region Clinical Hospital; 🇷🇺 Nizhny Novgorod, Russian Federation

Perm Medical Sanitary Unit#1; 🇷🇺 Perm, Russian Federation

Republican Hospital n.a.V.A.Baranov; 🇷🇺 Petrozavodsk, Russian Federation

Ryazan Regional Clinical Hospital; 🇷🇺 Ryazan, Russian Federation

Clinical Research Institute of Hematology and Transfusiology; 🇷🇺 St-Petersburg, Russian Federation

Oncology Dispensary of Komi Republic; 🇷🇺 Syktyvkar, Russian Federation

Hosp. Univ. Germans Trias I Pujol; 🇪🇸 Badalona, Spain

Hosp Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Hosp Univ Vall D Hebron; 🇪🇸 Barcelona, Spain

Hosp. Gral. Univ. Gregorio Maranon; 🇪🇸 Madrid, Spain

Hosp. Univ. Infanta Leonor; 🇪🇸 Madrid, Spain

Hosp. Univ. Ramon Y Cajal; 🇪🇸 Madrid, Spain

Clinica Univ. de Navarra; 🇪🇸 Pamplona, Spain

Hosp. Quiron Madrid Pozuelo; 🇪🇸 Pozuelo de Alarcon, Spain

Hosp Clinico Univ de Salamanca; 🇪🇸 Salamanca, Spain

Hosp. Univ. Dr. Peset; 🇪🇸 Valencia, Spain

Falu Lasarett; 🇸🇪 Falun, Sweden

Sunderby Sjukhus Medicinkliniken; 🇸🇪 Luelå, Sweden

Karolinska Universitetssjukhuset Huddinge; 🇸🇪 Stockholm, Sweden

Ankara Numune Egitim ve Arastirma Hastanesi; 🇹🇷 Ankara, Turkey

Ankara University Medical Faculty; 🇹🇷 Ankara, Turkey

Trakya University Hospital; 🇹🇷 Edirne, Turkey

Istanbul University Istanbul Medical Faculty; 🇹🇷 Istanbul, Turkey

Erciyes University Medical Faculty; 🇹🇷 Kayseri, Turkey

Ondokuz Mayis University; 🇹🇷 Samsun, Turkey

Heart of England NHS Foundation Trust; 🇬🇧 Birmingham, United Kingdom

University Hospitals Bristol NHS Trust; 🇬🇧 Bristol, United Kingdom

Kent and Canterbury Hospital; 🇬🇧 Canterbury, United Kingdom

St Bartholomew's Hospital; 🇬🇧 London, United Kingdom

Christie Hospital NHS Trust; 🇬🇧 Manchester, United Kingdom

Nottingham University Hospitals NHS Trust; 🇬🇧 Nottingham, United Kingdom

Royal Stoke University Hospital; 🇬🇧 Stoke-On-Trent, United Kingdom