Role of the Host Microbiota and Il-17 in Favoring Multiple Myeloma Progression

NCT ID: NCT05712967

Last Updated: 2024-03-01

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 62 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-06-14
• Study Completion Date: 2024-02-05

Brief Summary

Goal of this observational, non-interventional study is to demonstrate that in humans a correlation exists between bone marrow (BM) levels of the cytokine interleukin 17 (IL-17) and composition of the gut microbiota in patients affected by smoldering multiple myeloma (SMM) or multiple myeloma (MM).

Enrolled SMM/MM patients will be analyzed for their bone marrow levels of IL-17 together with the distribution of T helper 17 lymphocytes in their BM and peripheral blood. These analyses will be correlated with analyses of the patients' gut microbiome to identify commensal bacteria potentially involved in Th17 cell expansion.

Detailed Description

Each year, approximately 10% of asymptomatic smoldering multiple myeloma (SMM) patients progress to incurable multiple myeloma (MM), a neoplasm of plasma cells causing anemia, bone lesions, increased blood calcium levels and renal damage. Lack of consolidated predictive biomarkers of disease progression makes the selection of SMM candidates to early treatment difficult, and a watch and wait approach is still preferred for these patients. We have recently reported results from a retrospective clinical study showing that SMM patients with higher levels of bone marrow (BM) interleukin-17 (IL-17) were at higher risk to rapidly progress to MM than SMM patients with lower IL-17 levels. Several lines of evidence in autoimmune diseases and cancer link IL-17-producing T lymphocytes (Th17) with the gut microbiota, and evidence exists in patients affected by MM that the gut microbiota impacts disease progression and susceptibility to therapies. Such link has not been investigated in patients affected by SMM.

Goal of this observational, non-interventional study is to demonstrate that in humans a correlation exists between BM levels of IL-17 and composition of the gut microbiota.

Enrolled SMM/MM patients will be analyzed for their bone marrow levels of IL-17 together with the distribution of Th17 cells in their BM and peripheral blood. These analyses will be correlated with analyses of the patients' gut microbiome to identify commensal bacteria potentially involved in Th17 cell expansion. We will seek a direct link between gut microbiota, IL-17 and MM by transplanting mice affected by MM with stool samples from the enrolled SMM/MM patients. We expect a more aggressive disease in avatar mice transplanted with stools from IL-17-high patients when compared to IL-17-low patients. Because samples will be collected both in Italy and in the USA, the study will also allow investigating the impact of additional environmental factors (e.g. Mediterranean versus high-fat diet) on host microbiota and IL-17-driven MM. Thus, primary outcome of the study will be evidence of a correlation between BM levels of IL-17 and the composition of the gut microbiota in patients affected by SMM/MM.

The recruited patients will also be monitored for disease progression or relapse after therapy. The study has no statistical power to define correlates of disease progression in these patients. However, the gut microbiome and the levels of BM IL-17 in SMM patients will be correlated to time to MM progression. Additionally, microbiome and BM IL-17 levels in MM patients eligible for hematopoietic stem cell transplantation (HSCT) will be correlated with response to the induction phase, which is routinely evaluated within 3 months. We expect better responses in patients with low levels of BM IL-17. Additionally, based on recently published experience on the role of enteric microbiome in influencing the HSCT outcomes, we have begun collecting stool samples from MM patients before and after HSCT. Therefore, once we identify patients with early relapse, we will be able to determine if they were colonized with tumor-promoting commensal bacteria following the transplant.

Conditions

Multiple Myeloma

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

PATIENTS WITH MM

patients fulfilling the International Myeloma Working Group (IMWG) diagnostic criteria for MM

No interventions assigned to this group

PATIENTS WITH sMM

patients fulfilling the International Myeloma Working Group (IMWG) diagnostic criteria for SMM

No interventions assigned to this group

Controls

healthy controls

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

patients fulfilling the International Myeloma Working Group (IMWG) diagnostic criteria for SMM or MM, and 10 healthy controls older than 18 years and accepting to sign the informed consent

Exclusion Criteria

• Non-Caucasian subjects.
• Subjects younger than 18 years.
• Subjects that did not accept to sign the informed consent.
• Subjects reporting infectious diseases requiring antibiotic therapy in the previous three months, ongoing antibiotic therapy or prophylaxis.
• Subjects who already underwent HSCT or under pharmacologic therapy for MM.
• Subjects affected by autoimmune diseases with the exception of thyroiditis.
• Subjects affected by HIV, HBV or HCV.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

IRCCS San Raffaele

OTHER

Sponsor Role: lead

Responsible Party

Matteo Bellone, MD

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

matteo bellone, md

Role: PRINCIPAL_INVESTIGATOR

IRCCS Ospedale San Raffaele

Locations

IRCCS Ospedale San Raffaele

Milan, Milano, Italy

Countries

Italy

References

Anderson KC, Carrasco RD. Pathogenesis of myeloma. Annu Rev Pathol. 2011;6:249-74. doi: 10.1146/annurev-pathol-011110-130249.

Reference Type: BACKGROUND

PMID: 21261519 (View on PubMed)

Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, Rajkumar SV. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med. 2018 Jan 18;378(3):241-249. doi: 10.1056/NEJMoa1709974.

Reference Type: BACKGROUND

PMID: 29342381 (View on PubMed)

Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015 May 14;125(20):3069-75. doi: 10.1182/blood-2014-09-568899. Epub 2015 Apr 2.

Reference Type: BACKGROUND

PMID: 25838344 (View on PubMed)

Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. doi: 10.1001/jamaoncol.2015.2010.

Reference Type: BACKGROUND

PMID: 26181891 (View on PubMed)

Other Identifiers

Observational study

Identifier Type: -

Identifier Source: org_study_id