Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma
Dhakal et al. Blood Cancer Journal
Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma
Binod Dhakal 0
Anita D'Souza 0
Mehdi Hamadani 0
Carlos Arce-Lara 0
Katrina Schroeder 0
Saurabh Chhabra 0
Nirav N. Shah 0
Katelyn Gauger 0
Taylor Keaton 0
Marcelo Pasquini 0
Parameswaran Hari 0
0 Division of Hematology/Oncology, Medical College of Wisconsin , Milwaukee, WI , USA
In this phase I/II trial, BID, bendamustine (70, 80, or 90 mg/m2), ixazomib (4 mg), and dexamethasone (40 mg), was administered to 28 patients with relapsed and/or refractory multiple myeloma (RRMM) exposed to bortezomib and lenalidomide and refractory to at least one. A 3 + 3 dose escalation based on dose-limiting toxicities (DLTs) was employed in phase I (total 15); 2/6 patients developed DLTs (neutropenia and thrombocytopenia) at dose level 3 establishing the recommended phase II dose as bendamustine 80 mg/m2, ixazomib 4 mg, and dexamethasone 40 mg. The median age was 67 years (range, 42-72), and 43% were females. Patients received a median of 4 (range, 4-9) prior lines of therapy, of which ~50% were double refractory. In phase II, total 19 patients were treated. With a median follow-up of 17 months, 11% achieved very good partial response, 50% achieved partial response, and 27% achieved stable disease. Median progression free (PFS) and overall (OS) survival were 5.2 months (95% CI, 1.96-8.3) and 23.2 months (95% CI 16.3-30.07). The most frequent adverse events were anemia, thrombocytopenia, leukopenia, nausea, diarrhea, and infections. Peripheral neuropathy was infrequent. BID is a well-tolerated and effective combination therapy for patients with RRMM.
With the introduction of several new classes of drugs,
the survival outcomes of patients with multiple myeloma
(MM) have improved considerably in the last decade1,2.
Despite these effective treatments, the disease invariably
relapses after a period, requiring continued intervention
for disease control. Identification of new targets and
development of novel agents against such targets are
extremely important for the discovery of more effective
treatments. Bendamustine, a bifunctional alkylator with
antimetabolite activity, is an attractive option in MM due
to its specific mode of activity, favorable toxicity profile,
lack of cross reactivity with other agents, and its
preclinical and clinical activity in patients resistant to
alkylating agents3–5. In MM, bendamustine has clinical
activity, both as a single agent6 and in combination with
immunomodulators (ImIDs): thalidomide, lenalidomide,
and pomalidomide7–9 or proteasome inhibitors (PI):
bortezomib and carfilzomib10,11.
Ixazomib is an orally available peptide boronic acid that
preferentially binds to the β5 subunit of the 20S
proteasome12. Ixazomib has shown clinical activity both as
single agent and in combination in newly diagnosed and
relapsed/refractory multiple myeloma (RRMM)13–15.
Ixazomib is approved in combination with lenalidomide
and dexamethasone in treatment of MM patients with 1
prior therapy based on a phase III trial demonstrating
improved progression free survival (PFS) compared to the
control arm16. Proteasome inhibition has emerged as an
important therapeutic strategy in MM; however, risk of
peripheral neuropathy associated with bortezomib17 and
cardiovascular toxicities18 associated with carfilzomib
limit the use of these two major PI for prolonged periods
of time among MM patients. Exploring the role of
alternative PIs with non-overlapping toxicities like ixazomib is
therefore a reasonable strategy for combination triplet
regimens. In this phase I/II study, we assessed the safety
and efficacy of the combination of bendamustine,
ixazomib and dexamethasone (BID) in RRMM patients
exposed to bortezomib and lenalidomide and refractory to
at least one of the agents.
Subjects and methods
This open-label, single-center phase I/II study was
designed to assess the safety, tolerability, and efficacy of
oral ixazomib combined with bendamustine and
dexamethasone when delivered together in a 28-day cycle in
patients with relapsed and/or refractory multiple
myeloma (RRMM) for a maximum of eight cycles. In the
phase I portion three doses of bendamustine 70 mg/m2,
80 mg/m2, and 90 mg/m2 days 1 and 2 were tested in
combination with ixazomib 4 mg and dexamethasone
40 mg (20 mg in patients ≥75 years) on days 1, 8, and 15,
respectively. In the phase II portion, bendamustine was
given at recommended phase II dose (RP2D) along with
ixazomib and dexamethasone in the same dose as phase I.
All patients were informed of the investigational nature of
the study and provided informed consent per institutional
and federal guidelines. This study was approved by the
Institutional Review Board from the Medical College
of Wisconsin and was registered at clinicaltrials.gov
The primary objective of the phase I portion of the
study was to determine the RP2D of bendamustine when
given in combination with ixazomib and
dexamethasone. The primary objectives of the phase II
portion were to estimate the overall response rates
(ORR) of the three-drug combination. The secondary
objectives included the estimation of the duration of
response, survival (overall, OS and PFS) and clinical
benefit rates (CBR).
In the phase I portion of the study, a 3 + 3 design was
employed, and dose escalation decisions were based on
the dose-limiting toxicities (DLTs) occurring in cycle 1.
DLTs were defined as any of the following events that
were considered by the investigator to be related to
therapy with bendamustine or ixazomib: grade 4
neutropenia or grade 3 neutropenia with fever ≥38.5 °C, grade
4 thrombocytopenia or grade 3 thrombocytopenia with
clinically significant bleeding; DLTs also included any
grade 3 or greater non-hematologic toxicity including
grade ≥3 nausea that occurred despite maximal
antiemetic prophylaxis; diarrhea occurring despite maximal
anti-diarrheal agents and delay in starting cycle 2 for
>7 days because of lack of adequate recovery of
hematologic and non-hematologic drug related toxicities.
Antiviral prophylaxis against herpes zoster was mandatory
throughout the study period.
The study enrolled patients of 18 years old or older
diagnosed with RRMM who had prior exposure to PI
(bortezomib and carfilzomib) and ImiDs (thalidomide,
lenalidomide, or pomalidomide). Patients also had to be
refractory to either of the bortezomib and lenalidomide
according to the International Myeloma Working Group
(IMWG) definition of refractory disease (progressive
disease on or within 60 days of stopping PI or ImIDs).
Patients were required to have measurable disease defined
as serum monoclonal protein (M-protein) of ≥1 g/dl of
IgG or IgM, ≥0.5 g/dl of IgA or IgD, urine M protein
≥200 mg/24 h, or involved serum-free light chain of
≥10 mg/dl, Eastern Cooperative Oncology Group of 0–2
and adequate hematologic (absolute neutrophil count
>1000/mm3, platelets ≥75,000 mm3), hepatic (total
bilirubin ≤1.5 upper limit of normal, alanine/aspartate
aminotransferase ≤3 times the upper limit of normal), and
renal (creatinine clearance ≥30 ml/minute) function.
Recipients of autologous or allogeneic stem cell transplant
were eligible as long as there were no ongoing transplant
related side effects.
Key exclusion criteria were grade >2 peripheral
neuropathy; gastrointestinal disease or history of procedure that
could interfere with the oral absorption of ixazomib;
systemic treatment with strong CYP1A2 inhibitors or
strong inhibitors/inducers within 14 days before the first
dose of ixazomib; evidence of current, uncontrolled
cardiovascular conditions; and ongoing/active systemic
infection, active hepatitis B or C infection or known HIV
positivity. Prior ixazomib was not allowed.
Disease and toxicities assessments
Responses were assessed using the International
Myeloma Working group (IMWG) criteria19. Refractory to
either bortezomib or carfilzomib and lenalidomide or
pomalidomide was defined as double refractory; refractory
to bortezomib, lenalidomide, carfilzomib, and
pomalidomide as quadruple refractory and to CD38 antibody was
defined as penta refractory. Adverse events (AEs) were
monitored throughout the study and were graded
according to the Common Terminology Criteria for
Adverse Events (CTCAE) v 4.03. The study investigators
assessed disease responses.
The phase I portion of the study was designed to
identify doses of bendamustine with ixazomib and
dexamethasone that were associated with an acceptable AE
profile when delivered together in a 28-day cycle. The
primary end point for the phase I was to assess the
maximum tolerated dose (MTD). For the phase II portion
of this trial, the primary end point was overall response
rate (ORR) of the combination. The null hypothesis that
the true response rates of <30% with weekly ixazomib and
dexamethasone in RRMM13 was tested at 10% one sided
significance level with 80% power. The sample size was
calculated using a Simon 2-stage design. The six patients
treated at the MTD in the phase I portion were also
included in the phase II portion for overall sample size
estimation. At stage I, 14 patients were enrolled on the
study with a plan to continue enrollment if the observed
response rate was at least 28.6% (4/14). At stage II,
additional five patients (19 total) were to be enrolled and
consider the combination “interesting” only if at least 6/19
(35.3%) patients achieved a response. Secondary end
points of the phase II portion were: duration of response
(defined as the first documented response to documented
disease relapse, progression or death whichever occurs
first), OS (defined as the time interval from the date of
first study drug to death of date from any cause), PFS
(defined as the time interval from the date of first study
drug to relapse, progression or death from any cause), and
CBR (defined as total responders and stable disease (SD)
divided by the number of evaluable patients).
Time-toevent measures were estimated using the Kaplan–Meier
A total of 28 patients were enrolled between October
2015 and January 2018; 15 in phase I (3 at 70 mg/m2, 6 at
80 mg/m2 and 3 at 90 mg/m2) and 13 in phase II. Median
age of patients was 67 years (range, 42–72); 43% were
females and 75% were White. The baseline characteristics
of these patients are described in Table 1. Patients
received a median 4 (range, 3–9) lines of therapy, which
included bortezomib (100%), lenalidomide (100%),
carfilzomib (43%), pomalidomide (21%), and alkylating agents
(36%). Eighty nine percent of patients had undergone
prior autologous stem cell transplant; 46% and 25% of
patients were double and quadruple refractory patients,
respectively. The refractory status to the last line of
treatment before enrollment was: 10 (35%) refractory to
lenalidomide, 5 (18%) to daratumumab-based regimen, 4
(14%) to carfilzomib-based regimen, 3 (11%) to
cyclophosphamide based regimen, 2 (7%) to elotuzumab-based
regimen, and 4 (14%) to others (1 pomalidomide, 1 to
pomalidomide and bortezomib and 2 to multi-agent
The median time from diagnosis to study enrollment
was 66.5 months (range, 28–166). At the time of data
cutoff, 11 (39%) of the patients had died and 17 (61%)
were alive with a median follow-up of 17 months (range,
No DLTs were observed in at dose level (DL) 1. Given
that none of the three patients experienced DLTs at the
dose level 1, dose level was escalated to level 2 at which
level 1 patient developed grade 4 thrombocytopenia
(DLT). Given that one of three patients experienced DLT,
an additional three patients were enrolled at this dose
level 2 and no further DLT was observed. Following a
review of toxicities on DL2, three patients were enrolled
on DL3. Among the first three patients, one patient
developed grade 4 thrombocytopenia. Per 3 + 3 design,
DL3 was expanded to enroll additional three patients; and
one patient developed grade 4 neutropenia and
thrombocytopenia. As two of six patients developed DLTs at
DL3, the recommended phase 2 dose (RP2D) was one
dose level below at DL2 (bendamustine 80 mg/m2,
ixazomib 4 mg, and dexamethasone 40 mg).
Of the 19 patients treated at the phase 2 dosing scheme,
18 patients were evaluable for response per study
definition, out of which seven completed all eight cycles. The
median number of cycles completed was 41–8. The most
frequent reason for discontinuation before eight cycles
was disease progression. The ORR was 61% with very
good partial response (VGPR) in 2 (11%), partial response
(PR) in 9(50%) and stable disease in (SD) 5 (27%) and
progressive disease in (PD) 2 (11%) (Table 2). One patient
completed less than one cycle and was not evaluable for
response. For patients treated at all dose levels, the ORR
N (%) (Phase II/all patients)
9 (50)/11 (41)
11 (61)/13 (48)
was 48% with VGPR in 2 (7%), PR in 11 (41%), SD in 11
(41%), and PD in 3 (11%) (Table 2). For responders, the
median duration of response was 5.2 months2–13. At a
median follow-up of 17 months, median PFS and OS was
5.2 months (95% CI, 1.96–8.3) and 23.2 months (95% CI
16.3–30.07), respectively (Fig. 1).
Response rates in PI exposed and refractory patients (for all dose levels)
Twelve (43%) of patients were exposed but not
refractory to PI of which two (16.5%) had achieved VGPR, eight
(67%) had PR, and two (16.5%) SD. Remaining 16 (57%)
were refractory to PI- 3 to bortezomib only and 14 to both
bortezomib and carfilzomib. For patients refractory to
bortezomib only, one (33%) had PR, and two (67%) had
SD. For those refractory to both bortezomib and
carfilzomib, eight (57%) had SD, three (21%) PD, and one (7%)
achieved PR while remaining one patient was not
evaluable for response.
Twenty-four (86%) patients were refractory to ImIDs of
which two (8%) had VGPR, nine (37%) had PR, 11 (46%)
had SD, and two (8%) had PD. Of 13 (46%) refractory to
both PI and ImIds, one (8%) had PR, nine (69%) had SD,
and three (23%) had PD.
Effect on high-risk cytogenetics
A total of 10 (35%) of patients had high-risk
cytogenetics defined as presence of any of the following: t (4:14),
t (14:16), t (14:20), 1q amplification, 1 p deletion, or 17p
deletion (Table 1). However, of 18 evaluable phase two
patients, only four (22%) had high-risk cytogenetics as
defined above. The disease response for these four
patients was as follows: one VGPR, one PR, and two SD.
At the time of last follow-up, one patient died of disease
progression and one died of progressive dementia, while
two were still alive.
An adverse event (AE) of any grade possibly related to
treatment was reported in 100% of patients (Table 3). No
treatment related deaths were observed. The most
common hematological toxicities were lymphopenia (92%),
thrombocytopenia (78.6%), leucopenia (61%), and anemia
(57%), while the most common non-hematological
toxicities included fatigue (64%), nausea (57%), diarrhea
(39%), anorexia (35%), hypophosphatemia (28%),
hypertension (28%), hyperglycemia (25%), hypoalbuminemia
(25%), and dizziness (25%). Table 3 shows the grade 3 and
4 AEs possibly related to drug combination. Peripheral
neuropathy was present in 17% of the patients and all
were grades 1–2. The most common causes of death were
disease progression 6(55%), pneumonia 3(27%), cardiac
arrest 1 (9%), and progressive dementia 1 (9%).
This prospective phase I/II trial with BID showed an
impressive ORR of 61%, and clinical benefit rate of 89% in
heavily treated patients with RRMM where almost half
(46%) of the patients were refractory to both bortezomib
and lenalidomide. The combination was well-tolerated,
with manageable toxicity profile. Given the tolerability
and efficacy of bendamustine alone or in combination in
RRMM, the combination with ixazomib and
dexamethasone required further evaluation, as it is an oral PI
with low risk of neurotoxicity compared to bortezomib.
Bendamustine is an active agent in several cancers.
Exvivo models using cell lines from mature B-cell
Dose level 1 (n = 3)
Dose level 2 (n = 19)
Dose level 3 (n = 6)
Peripheral sensory neuropathy
malignancies have demonstrated the efficacy of
bendamustine to trigger distinct apoptotic pathways even in
cells with defective DNA repair pathway (like p53
deficient cells)20. In MM, this observation forms a strong
rationale for bendamustine combination with drugs like
bortezomib, which have shown activity in high-risk
myeloma particularly 17p and t (4:14)21,22. Since the
majority of RRMM patients are already exposed to and/or
refractory to bortezomib, combining bendamustine with
another PI like ixazomib makes logical sense.
Additionally, ixazomib has a favorable profile including oral
administration and better tolerability. When combined
with bortezomib, the MTD of bendamustine ranged from
70 mg/m2 up to a maximum of 90 mg/m2 on days 1 and
2;6,11,23 MTD of 80 mg/m2 of bendamustine this study, is
thus, within the range observed previously. Likewise, the
dose of bendamustine varies when combined with
different ImiDs as well7,8. Lentzsch et al. established MTD of
bendamustine at 75 mg/m2 on days 1 and 2 in patients
with median 3 prior treatment lines in combination with
lenalidomide with an ORR of 50%8. The results of these
studies point to a potential synergism of bendamustine
with PI or ImiDs and formed the basis of our study.
The therapeutic efficacy of ixazomib in bortezomib
RRMM patients is understudied. In an experimental
in vivo model, ixazomib showed activity on cells from
bortezomib resistant patients24. This observation has been
corroborated in several clinical trials; however, the
variability in response observed across studies, and the
small-scale study designs preclude any definite
conclusions25,26. Responses observed in this study were
comparable to bortezomib-bendamustine-dexamethasone
which resulted in ORR of 60.8% in RRMM that included
patients with prior exposure, but not refractory to
bortezomib11. The slightly lower PFS and OS observed in our
study reflects the more heavily pretreated patients and a
high proportion dual refractory to novel agents.
Additionally, in a prespecified and post-hoc analysis of
TOURMALINE-MM1 trial, the addition of ixazomib was
found to overcome the poor PFS associated with high-risk
cytogenetics27. These observations provide an impetus for
further investigating the role of ixazomib in combination
with alkylators and other novel agents in heavily
pretreated high-risk patients.
Both bendamustine and ixazomib has been tested
separately in combination with pomalidomide in lenalidomide
refractory patients in phase I/II studies9,28. Bendamustine
(at MTD 120 mg/m2 total dose), in combination with
pomalidomide, resulted in ORR of 61% and CBR 63% in
patients with median 5 prior lines of therapy9. The median
PFS and OS of the combination was 9.6 months and
21.3 months, respectively; 18% of the patients being on
planned maintenance. When combined with
pomalidomide, ixazomib resulted in ORR of 53% in patients with
median 2 prior lines of therapy28. About 2/3rd of patients in
this study were refractory to bortezomib who achieved ≥PR
of 29% and CBR 71% with this combination. The median
PFS and OS of the combination was 8.6 months and not
reached, respectively. The ORR of 61% and CBR of 91%
achieved with BID regimen in this study compares favorably
with the previous two studies as 64% were bortezomib
refractory, 86% lenalidomide refractory, and 46% to both.
Additionally, planned maintenance therapy was not used in
this study and might be effective for prolonging the
response duration. Furthermore, three other novel
combinations reported in similar patient population are worth
discussing in this context—daratumumab, pomalidomide
and dexamethasone (DPd)29, clarithromycin, pomalidomide
and dexamethasone (ClaPd)30 and carfilzomib,
pomalidomide and dexamethasone (KPd)31. The ORR was 60% for
DPD, ClaPD and 50% for KPD with median 4–5 prior lines
of therapy. The responses observed with BID after 4 prior
lines is comparable, and future study combining this
regimen with CD38 monoclonal antibody is being considered.
The toxicity profile of this regimen has been similar to
that seen with previously reported bendamustine or
ixazomib combinations4,14. No grade 3 or higher peripheral
neuropathy was seen in this cohort, compared to 7% grade
3 and higher seen with the bortezomib combination11. As
seen in other ixazomib studies, we did observe
gastrointestinal toxicity, particularly nausea, but this was
managed with supportive care measures. Hematological
toxicity remains the most common category of AEs and
was similar with the ixazomib and pomalidomide28.
Compared to bendamustine and pomalidomide
combination, we observed lower rates of grade 3 and higher
infections despite the higher total dose of bendamustine
(160 mg/m2 vs. 120 mg/m2)9.
In conclusion, the combination of
bendamustineixazomib and dexamethasone is a well-tolerated and
effective combination that can be used in heavily pretreated
RRMM patients. These findings justify further study of this
combination in RRMM patients especially with continued
ixazomib maintenance in responders32. Our study could
also form a basis for future combination studies with
ultranovel agents like monoclonal antibodies given the lower
acquisition costs associated with bendamustine.
B.D., K.S., K.T., T.K. and P.H.: concept, data collection, data analysis. B.D., A.D., M.
H., S.C., N.S., M.P. and P.H.: clinical care and manuscript editing. B.D. and P.H.:
concept, study design, manuscript generation. B.D. wrote the first draft of the
manuscript and all authors approved the final version.
Conflict of interest
B.D. has served on the advisory board for Takeda and Amgen. P.H. has received
grant support and consulting honoraria from Takeda. A.D.—institutional funding:
Amgen, Celgene, Merck, Prothena, Takeda; Consultancy: Prothena; Advisory
board- Pfizer. M.H. reports Research Support/Funding: Takeda Pharmaceutical
Company; Otsuka Pharmaceutical; Spectrum Pharmaceuticals; Astellas Pharma.
Consultancy: MedImmune LLC; Janssen R &D; Incyte Corporation; ADC
Therapeutics; Cellerant Therapeutics; Celgene Corporation; Pharmacyclics &
DOVA Oncology. Speaker’s Bureau: Celgene Corporation (Inactive); Sanofi
Genzyme. N.N.S. reports research funding from Lentigen, A miltenyi biotech
company. He has served on the advisory boards for Kite, Juno, and Cellectar. The
remaining authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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