Phase 2study of dovitinib in patients with relapsed or refractory multiple myeloma with or without t(4;14) translocation

Abstract

Objectives:
Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation.

Methods:
Adult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2-stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5-days-on/2-days-off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non-responding patients, treatment could continue with the addition of low-dose dexamethasone.

Results:
In total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non-interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)-positive group and 3.7 weeks in the t(4;14)-negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)-positive group and 34.6% in the t(4;14)-negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%).

Conclusion:
Dovitinib showed no single-agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)-positive patients.

Full text

ORIGINAL ARTICLE
Phase 2 study of dovitinib in patients with relapsed or
refractory multiple myeloma with or without t(4;14)
translocation
Christof Scheid
1
, Donna Reece
2
, Meral Beksac
3
, Andrew Spencer
4
, Natalie Callander
5
,
Pieter Sonneveld
6
, Ghulam Kalimi
7
, Can Cai
7
, Michael Shi
7
, Jeffrey W. Scott
7
, A. Keith Stewart
8
1
University Hospital of Cologne, Cologne, Germany;
2
Princess Margaret Cancer Centre, Toronto, ON, Canada;
3
Ankara University School of
Medicine, Ankara, Turkey;
4
Alfred Health-Monash University, Melbourne, Vic., Australia;
5
University of Wisconsin, Madison, WI, USA;
6
Erasmus
Medical Center, Rotterdam, the Netherlands;
7
Novartis Pharmaceuticals, East Hanover, NJ;
8
Mayo Clinic, Scottsdale, AZ, USA
Abstract
Objectives: Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation,
which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor
receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro
inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14)
translocation. Methods: Adult patients with relapsed or refractory MM who had received ≥2 prior
regimens were enrolled in this multicenter, 2-stage, phase 2 trial. Patients were grouped based on their t
(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5-days-on/2-days-off schedule. The
primary endpoint was overall response rate by local investigator review (per International Myeloma
Working Group criteria). In non-responding patients, treatment could continue with the addition of low-
dose dexamethasone. Results: In total, 43 patients (median age, 63 years) were enrolled (13 t(4;14)
positive, 26 t(4;14) negative, and 4 t(4;14) status non-interpretable). Patients had received a median of 5
prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)-positive group and 3.7 weeks
in the t(4;14)-negative group. None of the patients on dovitinib had objective responses. The stable
disease rate was 61.5% in the t(4;14)-positive group and 34.6% in the t(4;14)-negative group. Overall, 39
patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea
(60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%). Conclusion: Dovitinib showed no single-
agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)-positive patients.
Key words phase 2; relapsed or refractory multiple myeloma; FGFR3; dovitinib; t(4;14) translocation
Correspondence Christof Scheid, MD, PhD, Department of Internal Medicine, University Hospital of Cologne, Kerpener Str. 62,
50924 Cologne, Germany. Tel: +49 221 478 6296; Fax +49 221 478 86712; e-mail: c.scheid@uni-koeln.de
Accepted for publication 13 November 2014 doi:10.1111/ejh.12491
Multiple myeloma (MM) is a neoplastic disorder of clonal B
cells characterized by uncontrolled and aberrant proliferation
of plasma cells within bone marrow, monoclonal protein in
the blood or urine, and associated organ dysfunction (1).
About 24 050 new cases of myeloma are estimated in 2014
in the United States (2), whereas the estimated number of
new MM cases in Europe was 33 000 in 2012 (3). Over the
past decade, the outcome of patients with MM has signifi-
cantly improved with the development of immunomodula-
tory drugs (thalidomide, lenalidomide, and pomalidomide)
and proteasome inhibitors (bortezomib and carfilzomib).
However, despite these advances, nearly all patients with
MM eventually relapse. Although patients can sometimes
achieve subsequent responses with additional treatment regi-
mens, these responses are often of shorter duration, necessi-
tating novel treatment options for MM (4, 5).
The fibroblast growth factor (FGF) receptor (FGFR) signal-
ing pathway is implicated in the pathogenesis of a variety of
cancers including MM (6); FGFR signaling promotes tumor
angiogenesis, and deregulated expression of FGFs leads to
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European Journal of Haematology 95 (316–324)

tumor cell proliferation, survival, and chemoresistance (7).
Approximately 15% of patients with MM exhibit a t(4;14)
translocation (8), which often results in FGFR3 expression.
FGFR3 is receptor tyrosine kinase (RTK) of the FGF family,
consisting of 3 immunoglobulin-like extracellular domains, a
transmembrane domain, and a split cytoplasmic tyrosine
kinase domain. Following ligand stimulation, it signals pri-
marily through the extracellular signal-regulated kinases 1
and 2, phosphatidylinositol 3-kinase, and phospholipase C-ɣ
pathways (9–11). Furthermore, somatic mutation may occur
after the translocation, resulting in the constitutive activation
of FGFR3 (12). Patients with t(4;14) translocation appear to
have a worse prognosis and shorter survival compared with
patients without this translocation (13, 14). About 25% of
patients lose FGFR3 protein expression over time, and Ras
mutations common to almost 50% of patients with MM may
circumvent FGFR3 signaling dependency (15, 16).
Dovitinib, an RTK inhibitor, has demonstrated in vitro
inhibitory activity against FGFR, vascular endothelial growth
factor receptor (VEGFR), and platelet-derived growth factor
receptor, with half minimal inhibitory concentration values
of approximately 10 nM(17).
Tumor growth inhibition was observed with dovitinib
treatment in xenograft tumor models of MM with activating
FGFR3 mutations (8, 18), resulting in significant improve-
ment in survival (8). Thus, the preclinical data established a
rationale for studying dovitinib in patients with MM. The
objective of this study was to evaluate the efficacy and
safety of dovitinib in patients with relapsed or refractory
MM with or without t(4;14) translocation.
Patients and methods
Patients
Adult patients (age ≥18 years), with cytopathologically or
histologically confirmed relapsed or refractory MM accord-
ing to International Myeloma Working Group (IMWG) cri-
teria (19), who had received ≥2 prior therapy regimens
including chemotherapy, autologous transplant, immunother-
apy, or other investigational agents, were included. Other
eligibility criteria were presence of measurable disease
(serum M-protein ≥1 g/dL and/or urine M-protein ≥200 mg/
24 h by protein electrophoresis) (20); World Health Organi-
zation (WHO) performance status of ≤2; and absolute neu-
trophil and platelet count ≥1000/mm
3
and ≥75 000/mm
3
,
respectively (or ≥750/mm
3
and ≥50 000/mm
3
, respectively,
if neutropenia and thrombocytopenia was clinically related
to progressive myeloma with bone marrow infiltration),
hemoglobin ≥8 g/dL, aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) ≤3.0 9upper limit of nor-
mal (ULN), serum bilirubin ≤1.5 9ULN, and serum creati-
nine ≤2.0 9ULN (or 24-hour creatinine clearance ≥50 mL/
min).
Patients were excluded if they had non-secretory or olig-
osecretory MM, symptomatic amyloidosis or plasma cell
leukemia, previous allogeneic stem cell transplant with evi-
dence of active graft-vs.-host disease requiring immunosup-
pressive therapy, history of another malignancy within
3 years prior to study entry (except cured basal cell carci-
noma of the skin or excised in situ carcinoma of the cervix),
impaired cardiac function or clinically significant cardiac dis-
eases, uncontrolled hypertension defined as systolic blood
pressure ≥160 mmHg and/or diastolic blood pressure
≥100 mmHg with or without antihypertensive medication(s),
treatment with therapeutic doses of warfarin, cirrhosis,
chronic active hepatitis, or chronic persistent hepatitis, and
other concurrent severe and/or uncontrolled concomitant
medical conditions that could have caused unacceptable
safety risks. Patients could not have undergone a major sur-
gery ≤2 weeks prior to starting the study drug.
Study design and treatment
This was a multicenter, non-randomized, open-label, 2-stage,
phase 2 trial. Efficacy and safety of the treatment was sepa-
rately evaluated in the t(4;14)-positive or t(4;14)-negative
groups of patients. The study objectives did not include
direct comparisons of the two groups. At the baseline visit,
the patients’bone marrow aspirate samples were analyzed
for t(4;14) translocation status by cytoplasmic immunoglobu-
lin-enhanced interphase fluorescent in situ hybridization
(FISH; Vysis; Abbott Laboratories, Abbott Park, IL, USA),
and they were assigned to either t(4;14)-positive or t(4;14)-
negative groups. Patients were considered assessable if at
least 100 clonal plasma cells from each slide could be
scored. Bone marrow aspirate samples were analyzed for
FGFR3 expression by flow cytometry, and the results were
qualitatively expressed as positive or negative. Patients were
assigned as t(4;14)-non-interpretable if there were too few
plasma cells in the samples to provide an accurate assess-
ment by FISH and flow cytometry and were not included in
the primary and secondary efficacy analyses.
All patients received dovitinib at a dose of 500 mg/day
orally on a 5-days-on/2-days-off schedule (dosing on days 1
to 5, 8 to 12, 15 to 19, and 22 to 26) every 28 days until pro-
gressive disease (PD), unacceptable toxicities, or patient’s/
investigator’s decision to discontinue. The 500 mg/day orally
on a 5-days-on/2-days-off dosing schedule was selected
based on the phase 1/2 study of dovitinib in metastatic renal
cell carcinoma (mRCC). In a Phase 1/2 dose escalation study,
dovitinib at the dose of 500 mg on a 5-days-on/2-days-off
schedule was generally well tolerated and showed antitumor
activity in heavily pretreated patients with mRCC. Also, the
pharmacodynamic analysis revealed VEGFR inhibition and
FGFR inhibition (21). Further, dovitinib (500 mg/day on a 5-
days-on/2-days-off schedule) was effective and tolerable in
patients with advanced or metastatic RCC enriched for
©2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd. 317
Scheid et al. Phase 2 dovitinib in multiple myeloma

patients previously treated with a VEGFR TKI and an mTOR
inhibitor (22).
As an exploratory objective, after disease progression on
dovitinib monotherapy, patients had the option to continue
treatment with the addition of low-dose dexamethasone
(40 mg every 7 days), with M-protein levels at the time of
progression considered as the new baseline.
Dose reductions [400 mg (first reduction) and 300 mg
(second reduction)] were permitted for patients unable to tol-
erate the protocol-specified dosing schedule of dovitinib. No
dose escalation was allowed once a patient was dose
reduced. Dose reductions for dexamethasone were not per-
mitted in the dexamethasone-supplemented dovitinib regi-
men.
All patients provided written informed consent. The study
protocol and its amendments were approved by the indepen-
dent ethics committees at each center. The study conformed
to Good Clinical Practices guidelines and the ethical princi-
ples of the Declaration of Helsinki. The study was designed
by the academic investigators and by representatives of the
sponsor, Novartis Oncology.
Efficacy and safety assessments
The primary endpoint was extended overall response rate
(ORR) by local investigator review. Extended ORR was
defined as the rate of patients with ORR [best overall
response of complete response (CR), very good partial
response (VGPR), or partial response (PR)], plus patients
with best overall response of minor response (MR) accord-
ing to IMWG criteria (19). Secondary endpoints included
safety and ORR and progression-free survival (PFS) by local
investigator review. PFS was defined as the time from the
start of treatment to the date of the first-documented PD or
death due to any cause, as assessed by the investigator. If a
patient had not progressed or died at the date of the analysis
cutoff or when he/she received any further antineoplastic
therapy, PFS was censored at the time of the last tumor
assessment before the cutoff date or the antineoplastic ther-
apy start date. Documentation of response in patients who
opted to continue on a dexamethasone-supplemented doviti-
nib regimen was an exploratory objective. Patients were
evaluated at the end of each cycle. Any response of MR or
better had to be confirmed by the next set of evaluations
4 weeks later. Any response of PD had to be confirmed as
soon as possible, preferably within 7 days after the observa-
tion.
Safety assessments consisted of collecting all adverse
events (AEs) and serious AEs (SAEs), including the regular
monitoring of laboratory tests, regular measurement of vital
signs, weight, performance status, physical examination, and
cardiac assessments (electrocardiogram, blood pressure, car-
diac enzymes, and multigated acquisition/echocardiogram).
All AEs were recorded using the National Cancer Institute
Common Terminology Criteria for Adverse Events version
4.0.
Statistical analysis
A 2-stage design (23) was used for each group to test the
null hypothesis that the extended ORR is ≤10% using a
1-sided test with 10% level of significance and 90%
power at the alternative extended ORR of 30%. The null
hypothesis of extended ORR =0.10 and the alternative of
extended ORR =0.30 were chosen with reference to the
outcomes of single-agent phase 2 studies of lenalidomide
and bortezomib in patients with relapsed or refractory
MM (24, 25). For stage 1 enrollment, a total of 20
patients were planned in each group. If ≥3 patients had a
response, an additional 20 patients were planned in stage
2 of that group. The null hypothesis was rejected at the
10% level of significance (1-sided) if there were ≥7
responders among all 40 patients at the end of stage 2.
Kaplan–Meier product-limit method was performed to esti-
mate median PFS.
Results
Patient characteristics
A total of 43 patients with relapsed or refractory MM were
enrolled between May 28, 2010, and December 29, 2011. As
of the latter date, only 13 patients were enrolled in the t(4;14)-
positive group. Enrollment in the t(4;14)-positive group was
closed due to lack of objective responses and slow rate of
enrollment. Twenty-six patients were enrolled in the t(4;14)-
negative group. The t(4;14) translocation status could not be
determined in 4 patients; these patients were summarized in a
non-interpretable group.
A majority of the patients were white (90.7%), had a
WHO performance status of 1 (58.1%), and were refractory
to last treatment (60.5%) (Table 1). Independent of translo-
cation status, 12 patients (27.9%) had FGFR3 expression (9
in the t(4;14)-positive group, 2 in the t(4;14)-negative group,
and 1 in t(4;14)non-interpretable group). Patients had
received a median of 5 (range, 2–10) prior antineoplastic
regimens.
Patient disposition
All 43 patients received dovitinib monotherapy (Table 2).
The median duration of exposure to the study drug was
8.7 weeks and 3.7 weeks for the patients enrolled in t
(4;14)-positive and t(4;14)-negative groups, respectively.
Of the 27 patients with PD on dovitinib monotherapy, 6
patients continued on dovitinib with dexamethasone added
[3 each in the t(4;14)-positive and t(4;14)-negative
groups].
318 ©2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.
Phase 2 dovitinib in multiple myeloma Scheid et al.

Table 1 Patient characteristics at baseline –dovitinib monotherapy
t(4;14)-Positive
n=13
t(4;14)-Negative
n=26
t(4;14)-
Non-interpretable
n=4
All patients
N=43
Median age (range), years 61 (47–69) 67 (29–84) 55 (40–66) 63 (29–84)
Sex, n(%)
Female 6 (46.2) 10 (38.5) 4 (100) 20 (46.5)
Male 7 (53.8) 16 (61.5) 0 23 (53.5)
Race, n(%)
White 12 (92.3) 23 (88.5) 4 (100) 39 (90.7)
Black 1 (7.7) 2 (7.7) 0 3 (7.0)
Asian 0 1 (3.8) 0 1 (2.3)
World Health Organization performance status, n(%)
0 4 (30.8) 9 (34.6) 0 13 (30.2)
1 8 (61.5) 15 (57.7) 2 (50.0) 25 (58.1)
2 1 (7.7) 2 (7.7) 2 (50.0) 5 (11.6)
Median time since diagnosis (range), months 49.3 (24.9–84.3) 64.3 (15.8–246.0) 62.1 (58.8–140.1) 58.8 (15.8–246.0)
Number of prior lines of therapy, n(%)
2 4 (30.8) 2 (7.7) 0 6 (14.0)
3 1 (7.7) 4 (15.4) 0 5 (11.6)
4 2 (15.4) 5 (19.2) 0 7 (16.3)
>4 6 (46.2) 15 (57.7) 4 (100) 25 (58.1)
Median prior lines of therapy (range) 4.0 (2–10) 5.0 (2–9) 7.0 (5–9) 5.0 (2–10)
Prior therapies, n(%)
Corticosteroids 13 (100) 26 (100) 4 (100) 43 (100)
Bevacizumab 1 (7.7) 1 (3.8) 0 2 (4.7)
Bortezomib 13 (100) 24 (92.3) 4 (100) 41 (95.3)
Vorinostat 1 (7.7) 2 (7.7) 0 3 (7.0)
Lenalidomide 11 (84.6) 21 (80.8) 4 (100.0) 36 (83.7)
Thalidomide 6 (46.2) 16 (61.5) 4 (100.0) 26 (60.5)
Patients relapsed or refractory from last treatment, n(%)
Refractory 7 (53.8) 16 (61.5) 3 (75.0) 26 (60.5)
Relapsed 6 (46.2) 10 (38.5) 1 (25.0) 17 (39.5)
FGFR3 expression, n(%)
Yes 9 (69.2) 2 (7.7) 1 (25.0) 12 (27.9)
No 0 19 (73.1) 2 (50.0) 21 (48.8)
Unknown 4 (30.8) 5 (19.2) 1 (25.0) 10 (23.3)
FGFR3, fibroblast growth factor receptor 3.
Table 2 Patient disposition
t(4;14)-Positive
n=13
t(4;14)-Negative
n=26
t(4;14)-Non-interpretable
n=4
All patients
N=43
Dovitinib monotherapy
EOT, n(%) 13 (100) 26 (100) 4 (100) 43 (100)
Primary reason for EOT, n(%)
Disease progression 7 (53.8) 20 (76.9) 0 27 (62.8)
Adverse event (s) 4 (30.8) 3 (11.5) 3 (75.0) 10 (23.3)
Subject withdrew consent 2 (15.4) 3 (11.5) 1 (25.0) 6 (14.0)
Dovitinib plus dexamethasone
EOT, n(%) 3 (23.1) 3 (11.5) 0 6 (14.0)
Primary reason for EOT, n(%)
Disease progression 2 (15.4) 3 (11.5) 0 5 (11.6)
Adverse event(s) 1 (7.7) 0 0 1 (2.3)
EOT, end of treatment.
©2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd. 319
Scheid et al. Phase 2 dovitinib in multiple myeloma

As of March 22, 2013 (final database lock), all patients
discontinued the study drug (including those receiving the
dovitinib/dexamethasone combination regimen). The most
frequently reported reasons for discontinuing dovitinib
monotherapy were disease progression in 27 patients
(62.8%) and AEs in 10 patients (23.3%). The reasons to stop
the dovitinib/dexamethasone regimen were disease progres-
sion for 5 patients and AEs for 1 patient.
Efficacy
None of the patients on dovitinib monotherapy had MR,
PR, VGPR, or CR (Table 3); hence, the ORR (≥PR) and
extended ORR (≥MR) were 0%. Overall, 20 patients
(46.5%) had stable disease (SD).
Eight patients (61.5%) in the t(4;14)-positive group had
SD. The median PFS per local investigator assessment
was 2.6 months [95% confidence interval (CI): 0.9–3.9] in
the t(4;14)-positive group in patients treated with dovitinib
monotherapy (Fig. 1).Of the 3 patients in the t(4;14)-positive
group who continued on the dexamethasone-supplemented
treatment regimen, 1 patient had SD, 1 patient had PD, and
the response was not evaluable for the remaining 1 patient.
Nine patients in the t(4;14)-negative group (34.6%) had
SD. The median PFS per local investigator assessment was
0.9 months (95% CI: 0.8–1.7) in the t(4;14)-negative group
in patients treated with dovitinib monotherapy (Fig. 1A). Of
the 3 patients in the t(4;14)-negative group, 1 patient had
PR and 2 patients had SD.
As the number of responders in each group failed to meet
the criteria for study continuation to stage 2 (≥3 responders
from stage 1), the study was terminated. Among the 12
patients with detectable FGFR3 expression, 58.3% had SD,
whereas the SD rate in the 21 patients without FGFR3
expression (excluding patients with unknown expression)
was 42.9%. The median PFS was 1.77 months [95% CI:
0.39–3.88]) in patients who had FGFR3 expression and
0.9 months [95% CI: 0.82–1.77] in patients who did not
have FGFR3 expression (Fig. 1B).
Safety
Overall, 39 patients (90.7%) treated with dovitinib mono-
therapy had AEs suspected to be related to study drug
(Table 4). The safety profiles were similar for the t(4;14)-
positive and t(4;14)-negative groups. The most frequently
reported AEs suspected to be related to study drug were
diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), fati-
gue (32.6%), and thrombocytopenia (20.9%). The most
frequently reported grade 3 or 4 treatment-related AEs
were diarrhea (20.9%), thrombocytopenia (16.3%), and
fatigue (14.0%). Diarrhea was the most commonly
reported grade 3 or 4 SAE occurring in 4 of the 8
patients (9.3%) with SAEs suspected to be related to
study drug. For the 6 patients who continued on the dovi-
tinib and dexamethasone combination, AEs and SAEs
were primarily gastrointestinal related.
In the overall population, the most common AEs leading
to discontinuation of dovitinib monotherapy were diarrhea
(11.6%), vomiting (7.0%), and fatigue (4.7%). Overall, 26
patients treated with dovitinib monotherapy had AEs requir-
ing a dose adjustment or study drug interruption, most com-
monly diarrhea (23.3%), nausea (9.3%), and vomiting
(9.3%). A total of 12 patients (27.9%) on dovitinib mono-
therapy had a dose change: 6 patients (14.0%) required 1
dose change, and 6 patients (14.0%) required ≥2 dose
changes. The median daily dose remained 500 mg/day in all
the groups.
In total, 4 patients died within 30 days following the last
treatment dose on dovitinib monotherapy; the reasons for
deaths were disease progression (3 patients) and cardiopul-
monary arrest (1 patient). The patient who died due to car-
diopulmonary arrest had discontinued study drug because of
disease progression on day 25 and started melphalan 2 days
later. The patient’s condition deteriorated; under mechanical
ventilation, cardiogenic shock was experienced 10 days after
last dose of the study drug, which was followed by cardio-
pulmonary arrest 24 days after the last dose of the study
drug. A total of 2 patients died within 30 days following the
Table 3 Overall response to dovitinib monotherapy, assessed by local review
Overall response, n(%)
t(4;14)-Positive
n=13
t(4;14)-Negative
n=26
t(4;14)-Non-interpretable
n=4
All patients
N=43
Complete response 0 0 0 0
Very good partial response 0 0 0 0
Partial response 0 0 0 0
Minor response 0 0 0 0
Stable disease 8 (61.5) 9 (34.6) 3 (75.0) 20 (46.5)
Progressive disease 4 (30.8) 13 (50.0) 1 (25.0) 18 (41.9)
Not determined 1 (7.7) 4 (15.4) 0 5 (11.6)
Extended overall response rate 0 0 0 0
Overall response rate 0 0 0 0
320 ©2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.
Phase 2 dovitinib in multiple myeloma Scheid et al.

last dose on dovitinib plus dexamethasone combination ther-
apy; 1 of these patients died due to disease progression, and
the other patient died due to intestinal perforation secondary
to disease progression. None of these 6 deaths were sus-
pected to be related to study drug.
There was no evidence of QTcF increase from baseline of
>60 ms. One patient experienced a >20% decrease in left
ventricular ejection fraction.
Hematologic abnormality shifts were mostly grade 1 or 2.
Eleven patients (25.6%) had grade 3 decreased neutrophils,
A
B
Figure 1 Kaplan–Meier median progression-free
survival by local investigator review –dovitinib
monotherapy by (A) t(4;14) translocation status
and (B) FGFR3 expression status.
Table 4 Adverse events suspected to be related to study drug –Dovitinib monotherapy (≥10% patients)
Preferred term
t(4;14)-Positive
n=13
t(4;14)-Negative
n=26
t(4;14)-Non-interpretable
n=4
All patients
N=43
Any grade
n(%)
Grade 3/4
n(%)
Any grade
n(%)
Grade 3/4
n(%)
Any grade
n(%)
Grade 3/4
n(%)
Any grade
n(%)
Grade 3/4
n(%)
Total 12 (92.3) 8 (61.5) 23 (88.5) 12 (46.2) 4 (100) 2 (50.0) 39 (90.7) 22 (51.2)
Diarrhea 7 (53.8) 3 (23.1) 16 (61.5) 6 (23.1) 3 (75.0) 0 26 (60.5) 9 (20.9)
Nausea 7 (53.8) 1 (7.7) 14 (53.8) 2 (7.7) 4 (100) 0 25 (58.1) 3 (7.0)
Vomiting 6 (46.2) 1 (7.7) 11 (42.3) 2 (7.7) 3 (75.0) 0 20 (46.5) 3 (7.0)
Fatigue 4 (30.8) 3 (23.1) 10 (38.5) 3 (11.5) 0 0 14 (32.6) 6 (14.0)
Thrombocytopenia 4 (30.8) 3 (23.1) 3 (11.5) 2 (7.7) 2 (50.0) 2 (50.0) 9 (20.9) 7 (16.3)
Decreased appetite 2 (15.4) 1 (7.7) 5 (19.2) 1 (3.9) 0 0 7 (16.3) 2 (4.7)
Dehydration 1 (7.7) 0 5 (19.2) 4 (15.4) 0 0 6 (14.0) 4 (9.3)
Anemia 2 (15.4) 2 (15.4) 2 (7.7) 1 (3.8) 1 (25.0) 0 5 (11.6) 3 (7.0)
Neutropenia 3 (23.1) 3 (23.1) 2 (7.7) 1 (3.8) 0 0 5 (11.6) 4 (9.3)
Dyspepsia 0 0 2 (7.7) 0 2 (50.0) 0 4 (9.3) 0
Asthenia 0 0 3 (11.5) 0 0 0 3 (7.0) 0
Rash 2 (15.4) 0 1 (3.9) 1 (3.8) 0 0 3 (7.0) 1 (2.3)
Weight decreased 0 0 3 (11.5) 0 0 0 3 (7.0) 0
©2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd. 321
Scheid et al. Phase 2 dovitinib in multiple myeloma

12 patients (27.9%) had grade 3 decreased hemoglobin, and
12 patients (27.9%) had grade 3 decreased white blood cells.
A total of 6 patients (14.0%) experienced grade 3 decreased
lymphocytes and 1 patient (2.3%) experienced grade 4
decreased lymphocytes. Furthermore, grade 3 and 4
decreased platelet count was reported in 9 patients (20.9%)
and 10 patients (23.3%), respectively.
Grade 3 increases in ALT and AST were reported in 3
patients (7.3%) and 2 patients (4.7%), respectively, while for
bilirubin, no increase of more than grade 1 was found.
Discussion
Approximately 15% of patients with MM exhibit a t(4;14)
translocation (8), which often results in FGFR3 expression.
Loss of FGFR3 expression is, however, evidenced during
disease progression in approximately 25% of patients, lead-
ing some to believe that the reciprocal of the t(4;14) translo-
cation that results in MMSET protein activation may be the
dominant molecular event (15, 16). Treatment of patients
with MM bearing the t(4;14) translocation (one of the ‘high-
risk’cytogenetic factors) is challenging, as early and aggres-
sive relapse is common (26). Although development of
immunomodulatory agents and proteasome inhibitors has
dramatically improved the outlook for patients with MM,
including t(4;14), prognosis in this MM subset remains poor
overall (27). Dovitinib, an RTK inhibitor, demonstrated in
vitro cytotoxicity and tumor growth inhibition in xenograft
tumor models of MM with activating FGFR3 mutations (8,
18). Based on these preclinical findings, we evaluated the
efficacy and safety of dovitinib in patients with relapsed or
refractory MM with and without t(4;14) translocation.
In the present study, although none of the patients on
dovitinib monotherapy had ORR (≥PR) or extended ORR
(≥MR), 20 patients (46.5%) had SD. Although the t(4;14)
translocation predicts poor prognosis in patients with MM
(28), it is of interest that the proportion of patients
with SD during study treatment was numerically higher in
the t(4;14)-positive group (61.5%) than the t(4;14)-negative
group (34.6%). These results need to be interpreted cau-
tiously as the sample size was small, and the study objec-
tives did not include direct comparison the t(4;14)-positive
or t(4;14)-negative groups of patients. Furthermore, the
median PFS in the t(4;14)-positive and t(4;14)-negative
group was 2.6 months and 0.9 months, respectively. These
results raise the possibility that dovitinib has some biologic
activity in relapsed or refractory MM patients with t(4;14)
translocation, a hypothesis that could be explored in com-
bination studies with other agents, such as proteasome
inhibitors or by studying similar agents earlier in the dis-
ease course. Although patient populations from different
studies cannot be compared, it is interesting to note that
carfilzomib as a single agent produced a median PFS of
3.5 months in patients with relapsed and refractory MM
with high-risk cytogenetics (29). In a randomized phase 2
study comparing pomalidomide plus low-dose dexametha-
sone vs. pomalidomide alone in patients with relapsed and
refractory MM, the median PFS was 2.7 months in patients
treated with pomalidomide alone (30), which is similar to
the median PFS in the t(4;14)-positive group in our study.
Monotherapy has generally not proven to be effective in
patients with MM; thus, combination regimens have been
the mainstay of effective therapy in MM. In this study,
results were perhaps more promising in patients with t(4;14)
or FGFR3 overexpression, and further in vitro and xenograft
studies may suggest a role for using dovitinib in combina-
tion regimens for t(4;14)-positive patients.
The safety results in our study were in line with the
known safety profile of dovitinib or were not unexpected in
patients with relapsed or refractory MM. The most com-
monly affected primary system organ class (≥10%) for AEs
suspected to be related to study drug was gastrointestinal
disorders. Gastrointestinal toxicity remains a challenge, and
timely monitoring and supportive care during dovitinib treat-
ment may alleviate these symptoms.
In summary, dovitinib was found to have no or minimal
single-agent activity in relapsed or refractory MM irrespec-
tive of t(4;14) status. However, the higher rate of disease
stabilization, the longer exposure duration, and longer PFS
in the t(4;14)-positive group may provide support for explor-
ing the inclusion of dovitinib in a combination therapy regi-
men in this high-risk patient population, particularly those
patients with earlier-stage disease who retain expression of
FGFR3 and lack Ras or other genomic mutations that render
FGFR3 redundant. Success is only likely in patients meeting
these criteria who are still at least partially dependent on
FGFR3 signaling.
Acknowledgements
We thank Peter J. Simon, PhD, Articulate Science (funded
by Novartis Pharmaceuticals Corporation) and Pushkar Nar-
vilkar, Novartis Healthcare Pvt. Ltd. for providing medical
editorial assistance with this manuscript.
Conflict of interest and sources of funding
CS has received honoraria from Novartis. DR has received
research funding from Novartis, Millennium, Janssen, and
Celgene; honoraria from Novartis, Janssen, and Celgene;
and consultancy from Janssen and Celgene. MB has served
on advisory boards for Novartis, Janssen-Cilag, Celgene,
Amgen, and Bristol-Myers Squibb; and speakers’bureau for
Janssen-Cilag, Celgene, and Amgen. AS has received per-
sonal fees from Novartis. NC has nothing to disclose. PS
has received grants and personal fees from Celgene, Janssen,
Millennium, and Onyx; and has served on advisory boards
for Novartis. GK, CC, MC, and JC are employees of
322 ©2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.
Phase 2 dovitinib in multiple myeloma Scheid et al.

Novartis Pharmaceuticals Corporation. AKS has served as
consultant for Novartis. This study was funded by Novartis
Pharmaceuticals Corporation.
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