Background and rationale:
Due to demographic changes, multiple myeloma with its preferential manifestation in the
elderly population exerts increasing incidence worldwide. Since decades, autologous stem cell
transplantation (ASCT) after high-dose chemotherapy (HDCT) with melphalan is the standard
first-line consolidation option for patients with multiple myeloma considered fit for this
approach. Nevertheless, subsequent relapse despite this intensive treatment is inevitable in
most myeloma patients, emphasizing the unmet clinical need for improved conditioning
strategies to further enhance the effect of HDCT treatment.
The Inselspital in Bern represents one of the largest European centers for autologous stem
cell transplantation (ASCT) in myeloma, lymphoma and leukemia patients, and it is the largest
center in Switzerland for ASCT, with more than 150 ASCT performed annually. In parallel, the
transplant team at the Inselspital has a dedicated history of clinical trials aiming to
further improve tolerance and efficacy of HDCT with ASCT.
In a previous randomized phase 2 study performed at the department of medical oncology of the
Inselspital, the combination of the cytotoxic compound bendamustin in addition to the
standard melphalan dose as a novel HDCT regimen before autologous transplantation in 120
myeloma patients has been explored and established. This approach was successful in terms of
increased anti-myeloma efficacy, but the nephrotoxicity of high-dose bendamustin was relevant
in a significant subset of patients. This fact, ultimately, led to the propose of a novel
approach.
The present study aims to combine high-dose melphalan (Melphalan Ideogen) with treosulfan
(Trecondi® Ideogen), a well established bifunctional alkylating agent. Treosulfan has a
favorable toxicity profile, and it is used in patients with acute leukemias in the allogeneic
transplant setting as a standard approach in an increasing number of centers. However, no
study so far evaluated treosulfan combined with melphalan as high-dose chemotherapy in
patients with multiple myeloma. Consequently, this approach is unique and novel in patients
with multiple myeloma in the autologous transplant setting.
Compared to the closely related (and more known) compound busulfan, treosulfan compares
favorably in terms of decreased neurotoxicity (for busulfan, antiepileptic prophylaxis is
necessary), and it does not cause irreversible hair loss, which is often observed after
busulfan treatment. The team at the Inselspital performed a pilot study in 25 patients with
relapsed myeloma undergoing second-line HDCT/ASCT therapy. Treosulfan (14 mg/m2 i.v. at days
-4, -3, and -2) combined with standard dose melphalan (day -1) had promising anti-myeloma
activity and was well tolerated as expected from the previous studies. Standardized
measurement of treosulfan serum levels by mass spectrometry (Metabolomics, University
Institute of Clinical Chemistry, Inselspital Bern) in these patients demonstrated consistent
pharmacokinetic profiles with peak levels within the therapeutic range and with low
interindividual differences. Consequently, no modifications of the treosulfan dosage were
needed during these initial experiences. With the clinical trial outlined in this protocol,
the study team aim to gain insights into the use of treosulfan as part of the high-dose
chemotherapy regimen before ASCT in myeloma patients. The study will be performed as an
open-label, randomized phase 2 study, involving multiple recruiting regional Swiss centers,
with all high-dose treatments being performed at the University Hospital Inselspital Bern.
Patients will first undergo standardized induction therapy (e.g. VRD regimen, with or without
Daratumumab), followed by a 1:1 randomization to two treatment arms:
Arm B, the experimental ("TreoMel") arm, combines treosulfan at three days at 14 g/m2
followed by 200 mg/m2 melphalan given on two days at 100 mg/m2. Arm A, the standard arm,
comprises standard 200 mg/m2 melphalan ("Mel"), split into two days à 100 mg/m2.
The stem cell transplantation is identical in both arms, as is the post-transplant
management.
In patients with reduced renal function (creatinine clearance <50 mL/min and ≥ 35 ml/min),
the melphalan total dose will be lowered to 140 mg/m2, split into two doses at 70 mg/m2.
Treosulfan will be administered in a dosage of 14 mg/m2 i.v. on days -5, -4, and -3 in Arm A
("TreoMel"). The autologous cells will be transfused on day 0.
Patients will be stratified 1) according to the myeloma remission status as assessed based on
the last available remission status: complete (CR) and very good partial remission (VGPR)
versus partial remission (PR), minimal remission (MR), no change (NC) and progressive disease
(PD); and 2) according to renal function: Renal function: creatinine clearance ≥ 50 ml/min
versus < 50 ml/min.
Based on a previous cohort of 122 myeloma patients at the Inselspital (2010-2013), a CR1 rate
in the standard (Mel) arm of 50% is anticipate.
The primary endpoint is to show an improvement of the CR rate after ASCT (before initiation
of maintenance treatment) in the standard arm A using melphalan only ("Mel") from 50% to 65%
in the experimental arm B combining treosulfan and melphalan ("TreoMel").
Therefore, the study is considered successful if the experimental treosulfan/melphalan arm is
superior by 15% points. With a statistical power of 80% and one-tailed significance level of
5%, 60 patients are required for cohorts A and B each. Thus, the total number of patients for
the trial needed amounts to 120 patients. As the yearly number of myeloma patients undergoing
HDCT/ASCT therapy at the Inselspital Bern is close to 80 patients, the recruitment of a
sufficient number of patients in the planned study duration of 36 months appears feasible.
Patients can be included with a diagnosis of multiple myeloma after standard first-line
induction therapy, commonly being the VRD regimen with or without additional daratumumab. In
the case of refractory myeloma, one or several additional alternative induction regimens can
be applied before the study treatment. Further preconditions are clinical fitness for
HDCT/ASCT and age of at least 18 years, ECOG less than 3, and creatinine clearance of at
least 35 mL/min or more (for additional incl./excl. criteria see the entire protocol).
The measurement of the endpoints of the study will be as follows: Primary endpoint is the
complete remission (CR) rate after ASCT (before initiation of maintenance treatment)
following measurement of myeloma parameters in the peripheral blood including M-gradient,
quantitative immunoglobulins, kappa/lambda light chain ratio, and immunofixation. Secondary
endpoints are: time to neutrophil and thrombocyte engraftment, progression-free and overall
survival, toxicities, infectious complications, hospitalization duration, minimal residual
disease (MRD) load determined by next-generation immunophenotyping. Treosulfan serum levels
will be assessed by pharmacokinetic drug monitoring based on mass spectrometry. Bone marrow
punction for defining the response will be performed in all patients after neutrophil
engraftment before hospital discharge around 15 days after ASCT. Bone marrow analyses
comprise cytomorphology, histopathology, and flow cytometry at a sensitivity level of 10(-5)
for MRD assessment.
The trial will be performed at the Department of Oncology at the Inselspital, University
Hospital Bern. The CTU of the University of Bern will perform the on-site monitoring of the
study.
