Tinostamustine Conditioning and Autologous Stem Cell

Study Design (Methodology):

This is a 2-part, international, multi-center, open-label study of salvage treatment with
tinostamustine conditioning followed by ASCT in patients with relapsed/ refractory multiple
myeloma (MM). (ASCT is defined as salvage if the patient had already received a prior ASCT
and undergoes a second ASCT after evidence of progressive disease [PD].) Phase 1 of the study
employs a standard 3+3 dose escalation design with the objective of defining the DLTs of the
tinostamustine conditioning regimen and defining the MTD and RP2D for use in the Phase 2
portion of the study.

The Safety Review Committee can make a decision to stop dose escalation or explore
intermediary doses at any time. The total dose of tinostamustine will be administered on Day
-1. Phase 2 of the study employs a 2-step sequential design (Simon, 1989). In Stage 1 of
Phase 2, up to 31 patients initially will be enrolled. If ≤25 patients of these initial 31
patients experience a response, then no additional patients will be enrolled. However, if >25
patients in Stage 1 of Phase 2 experience a response, then enrollment in this cohort will
continue, with up to 71 patients enrolled. In Phase 2 of the study, all patients will receive
tinostamustine at the RP2D administered in Phase 1 according to the same schedule. After
provision of written informed consent, patients will be screened for study eligibility within
28 days before Day 1 (the day of ASCT). Patients who have a minimum of 2×106 CD34+ cells/kg
cryopreserved and are otherwise determined to be eligible, based on screening assessments,
will be enrolled and receive the tinostamustine conditioning regimen. The tinostamustine dose
will be administered 24 hours pre- ASCT (i.e., Day -1). On Day 1, ASCs will be administered
intravenously (IV) according to standard institutional practice.

Patients will receive supportive measures (including growth factor support post-ASCT,
antimicrobial prophylaxis, red blood cell and platelet transfusion, and treatment for
neutropenic fever) according to standard institutional practice.

Inclusion Criteria:

1. Patient has MM and:

1. Has received prior ASCT after standard first-line induction treatment.

2. Has evidence of PD, with progression-free interval ≥6 months in Phase 1 ≥18
months in Phase 2.

Progression Free Interval is defined as the time from date of ASCT to PD.

3. Received treatment with ≤3 prior lines of therapy. A line of therapy is defined
as 1 or more cycles of a planned treatment program. When patients have undergone
sequential phases of treatment without intervening progression, such as
induction, collection of peripheral blood stem cells, transplantation and
consolidation/maintenance, this is considered to be 1 line of treatment. A new
line of therapy is initiated as a result of PD or relapse (Garderet et al, 2017).

2. CR, VGPR, PR, or minimal response (MR) to latest of salvage chemotherapy at relapse,
as determined by the International Myeloma Working Group (IMWG) criteria.

3. Is, in the Investigator's opinion, a candidate for consolidation therapy with
tinostamustine followed by ASCT. (Note that patients planned to receive tandem ASCT
are not eligible for the Phase 1 portion of the study.)

4. Has available autologous peripheral blood stem cell (PBSC) product with CD34 cell dose
≥2×106 cells/kg. The product could be from a collection prior to first ASCT or later
second collection. (Note that, although not required, in Phase 1, the Investigator
should consider enrolling patient with a large number of available PBSCs to permit
subsequent ASCT, as patients in Stage 1 may received a dose lower than that determined
to be effective.)

5. Age 18-75 years.

6. Eastern Cooperative Oncology Group (ECOG) performance status score <3 at Screening.

7. Creatinine clearance ≥40 mL/min, as determined by a local laboratory using the
Cockcroft-Gault equation within 28 days before ASCT.

8. Left ventricular ejection fraction (LVEF) ≥40% within 28 days before ASCT.

9. Adequate pulmonary function, defined as forced expiratory volume in 1 second (FEV1),
forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) >50%
predicted within 28 days before ASCT.

10. Adequate liver function, as defined by an alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN) and bilirubin ≤1.5 × ULN
within 28 days before ASCT.

11. Potassium within the local laboratory's normal range. (Potassium supplementation is
permissible.)

Exclusion Criteria:

Patients meeting any of the following criteria are not eligible for study entry:

1. History of central nervous system (CNS) disease involvement.

2. Primary or secondary plasma cell leukemia at any time point prior to transplant

2. Myocardial infarction (MI) or stroke within 6 months before Screening. 3. Uncontrolled
acute infection. 4. HCT-CI >6 points. 5. Concurrent malignant disease with the exception of
treated basalioma/spinalioma of the skin or early-stage cervix carcinoma, or early-stage
prostate cancer. Previous treatment for other malignancies (not listed above) must have
been terminated at least 24 months before registration and no evidence of active disease
shall be documented since then.

6. Major coagulopathy or bleeding disorder. 7. Other serious medical condition that could
potentially interfere with the completion of treatment according to this protocol or that
would impair tolerance to therapy or prolong hematological recovery.

8. Lack of cooperation to allow study treatment as outlined in this protocol. 9. Pregnancy
or lactating female patients. 10. The use of any anti‐cancer investigational agents within
21 days prior to the expected start of trial treatment and interval of 14 days to last
administration of salvage treatment.

11. Receiving treatment with drugs known to prolong the QT/QTc interval. 12. QTc interval
(Fridericia's formula) >450 msec, based on the mean of triplicate Screening 12-lead ECGs.