Bortezomib-bendamustine-melphalan vs Melphalan for Multiple Myeloma

Bortezomib-bendamustine-melphalan vs High-dose Melphalan in Autologous Hematopoietic Stem Cell Transplantation for Relapsed Multiple Myeloma - a Single Center Retrospective Cohort Study

This project will evaluate the efficacy and safety of the conditioning regimen bortezomib-bendamustine-melphalan (BBM) in combination with autologous hematopoietic stem cell transplantation (ASCT) in relapsed multiple myeloma given from 2011 to 2018 at Uppsala University Hospital. This approach will be retrospectively compared to high dose melphalan (HDM) in the same setting in the years prior to, and following the BBM-period. Data on efficacy and safety data will be collected through systematic analysis of electronic medical records and from the Swedish Cancer Registry.

Study Overview

• Status: Recruiting
• Conditions: Myeloma Multiple
• Intervention / Treatment: Drug: Bortezomib-bendamustine-melphalan

Detailed Description

Study design This is a retrospective single center cohort study comparing the new conditioning regimen bortezomib-bendamustine-melphalan to standard high-dose melphalan. The data sources will be electronic medical records and prospectively collected data from the Swedish Cancer Registry. The comparison will be analyzed in two parts. First, each patient will be its own control, comparing time to next treatment (TNT) for the first ASCT (always HDM, referred to as ASCT1) and second ASCT (BBM or HDM, referred to as ASCT2), and compare the mean difference between the two cohorts. Secondly, the difference in efficacy and severe adverse events between BBM and HDM at ASCT2 will be compared.

Study population Fifty consecutive patients, who were referred to Uppsala University Hospital (UUH) for a second ASCT after relapse in multiple myeloma following HDM and ASCT between 1 Nov 2011 and 30 Oct 2018 and who received conditioning with bortezomib-bendamustine-melphalan will be included in this study. As a control group, 25 consecutive patients who were treated with HDM prior to 1 Nov 2011 and 25 consecutive patients following 30 Oct 2018. The patients will be identified through the local European Society for Blood and Marrow Transplantation (EBMT) registry at UUH.

UUH is the referral hospital for seven Swedish regions with a total population of 2 151 353 at Dec 31 2022, which constitutes roughly one fifth of the population of Sweden.

Data collection Study data will be collected through systematic analysis of medical records from UUH and all the hospitals referring patients to UUH and from the Swedish Cancer Registry. All severe adverse events (AEs) will be collected until day 100 after ASCT2 according to National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Primary endpoints

• Mean TNT after ASCT1 and ASCT2 for each individual patient (each patient as its own control), for BBM and HDM-treated patients

Secondary endpoints

• Median time to next treatment (TNT) after ASCT2
• Median progression free survival (PFS) after ASCT2
• Depth of best response (stable disease (SD), partial response (PR), very good partial response (VGPR), complete remission (CR), stringent complete remission (sCR)) after ASCT2
• Median Overall survival after ASCT2
• Treatment related mortality rate at ASCT2
• Mean duration of neutropenia (ANC < 0,5) at ASCT2
• Mean time until engraftment
• Mean duration of hospitalization after stem cell infusion at ASCT2
• The frequency of all serious adverse events according to version 5.0 of National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) during hospitalization and until day +100 after ASCT2.

Prespecified subgroups will include depth of best response prior to ASCT2, any specific maintenance therapies following ASCT2, patients receiving Granulocyte Colony Stimulating Factor (G-CSF) following ASCT, and patients receiving daratumumab as a part of induction or maintenance therapy at ASCT2.

In addition, an exploratory subgroup analysis is planned for patients with high-risk cytogenetics including p53-aberrations and patients with early relapse after ASCT1 (less than 3 years), although missing data is expected to be high.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Thomas Silfverberg, MD; Phone Number: +4623492000; Email: thomas.silfverberg@regiondalarna.se

Study Locations

• Sweden
  • Uppsala, Sweden
    • Recruiting
    • Akademiska Sjukhuset
    • Contact: Kristina Carlson, MD, PhD
    • Principal Investigator: Thomas Silfverberg, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Fifty consecutive patients, who were referred to UUH for a second ASCT after relapse in multiple myeloma following HDM and ASCT between 1 Nov 2011 and 30 Jun 2018 and who received conditioning with bortezomib-bendamustine-melphalan will be included in this study. As a control group, 25 consecutive patients who were treated with HDM prior to 1 Nov 2011 and 25 consecutive patients following 30 Jun 2018. The patients will be identified through the local European Society for Blood and Marrow Transplantation (EBMT) registry at UUH.

Description

Inclusion Criteria:

• Diagnosis of first relapse after previous ASCT for multiple myeloma according to the International Myeloma Working Group.
• Treated with a second ASCT (ASCT2) as part of second line treatment at UUH.
• Conditioning at ASCT2 with bortezomib-bendamustine-melphalan or high-dose melphalan only.

Exclusion Criteria:

• Double (tandem) ASCT in first or second line treatment
• Allogenic haematopoietic stem cell transplantation as part of first or second line therapy
• Failure to meet the minimal dataset, defined as: (date of ASCT1 and ASCT2, date of start of induction treatment for relapsed myeloma prior to ASCT2, medical records from hospitalization for ASCT2, at least one follow-up visit (unless early death before first follow-up visit), date of progression and first treatment of relapsed multiple myeloma after ASCT2.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Bortezomib-bendamustine-melphalan; Myeloma patients receiving bortezomib-bendamustine-melphalan at autologous hematopoietic stem cell transplantation first relapse.	Drug: Bortezomib-bendamustine-melphalan; The aim of this retrospective cohort study is to evaluate the efficacy and safety of the conditioning regimen BBM compared to HDM in the setting of relapsed multiple myeloma.; Other Names: High-dose melphalan
high-dose melphalan; Myeloma patients receiving high-dose melphalan at autologous hematopoietic stem cell transplantation at first relapse.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean difference in time to next treatment (TNT) after ASCT1 and ASCT2 for each individual patient	Average time to next myeloma treatment within each individual patient making each patient as its' own control	0.2-18 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment related mortality	Death due to any transplantation-related cause other than disease progression.	0-12 months
Median time to next treatment after ASCT2	Time to start of next myeloma treatment after ASCT2	0-18 years
Median progression free survival (PFS) after ASCT2	Time to progression or death after ASCT2	0-18 years
Median overall survival after ASCT2	Survival until death from any cause	0-18 years
Depth of best response after ASCT2	Best result after given treatment for myeloma	0-24 months
Mean duration of neutropenia at ASCT2	Absolute neutrophil count (ANC) <0.5 x10^9	7-50 days
Mean time until engraftment at ASCT2	Days from ASCT until ANC of 0.5 x 109/L or higher and total platelet count of 20 x 109/L and rising, without transfusion of thrombocytes.	5-50 days
Mean duration of hospitalization at ASCT2	Days from ASCT until discharge	7-50 days
Frequency of severe adverse events at ASCT2	All serious adverse events according to version 5.0 of National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) during hospitalization and until day +100 after ASCT2.	100 days

Collaborators and Investigators

• Sponsor: Uppsala University
• Collaborators: Dalarna County Council, Sweden; Uppsala County Council, Sweden
• Investigators: Principal Investigator: Honar Cherif, MD, PhD, Uppsala University

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2024
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): November 30, 2025

Study Registration Dates

• First Submitted: September 26, 2023
• First Submitted That Met QC Criteria: January 29, 2024
• First Posted (Actual): February 7, 2024

Study Record Updates

• Last Update Posted (Actual): November 29, 2024
• Last Update Submitted That Met QC Criteria: November 25, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Bortezomib; Bendamustine; Melphalan; Autologous hematopoietic stem cell transplantation
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Bendamustine Hydrochloride; Bortezomib; Melphalan
• Other Study ID Numbers: 2023-04134-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, (text, tables, figures and appendices), will be available together with the study protocol after de-identification beginning 9 months and ending 5 years following article publication to researchers who provide a methodologically sound proposal. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Time Frame: from 9 months after published article until 5 years.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No