Clinical trial NCT05712967: Role of the Host Microbiota and Il-17 in Favoring Multiple Myeloma Progression
Official title: Role of the Host Microbiota and Il-17 in Favoring Multiple Myeloma Progression
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Multiple Myeloma
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
First posted: 2023-02-06
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: 52 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

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.

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.

Primary outcomes:
measure: the role of microbiota and IL17 in MM
timeFrame: 5YRS
Secondary outcomes:
Other outcomes:
Locations:
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
state: Milano
Study officials:
affiliation: IRCCS Ospedale San Raffaele
name: matteo bellone, md
role: PRINCIPAL_INVESTIGATOR
References:
citation: Anderson KC, Carrasco RD. Pathogenesis of myeloma. Annu Rev Pathol. 2011;6:249-74. doi: 10.1146/annurev-pathol-011110-130249.
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citation: 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.
citation: 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.