Articles

Ixazomib, daratumumab and low-dose dexamethasone in

intermediate-fit patients with newly diagnosed multiple
myeloma: an open-label phase 2 trial
Kaz Groen,a,b,z Claudia A. M. Stege,a,b,z Kazem Nasserinejad,c,d Koen de Heer,e Roel J. W. van Kampen,f Rineke B. L. Leys,g Noortje Thielen,h
Matthijs Westerman,i Ka-Lung Wu,j Inge Ludwig,k Djamila E. Issa,l Gerjo A. Velders,m Marie-Christiane Vekemans,n Gert-Jan Timmers,o
Fransien de Boer,p Lidwine W. Tick,q Annelies Verbrugge,c Danny Buitenhuis,c Sonia M. Cunha,c Ellen van der Spek,r Esther G. M. de Waal,s
Maaike Sohne,t Pieter Sonneveld,u Inger S. Nijhof,t Saskia K. Klein,v,w Niels W. C. J. van de Donk,a,b Mark-David Levin,x Paula F. Ypma,y and
Sonja Zweegmana,b,∗
a
Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands
b
Cancer Center Amsterdam, Treatment and Quality of Life, Amsterdam, the Netherlands
c
HOVON Data Center, Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
d
Innovative Statistical Consulting, Therapeutics Development Team, Cytel Inc., Massachusetts, USA
e
Department of Internal Medicine, Flevoziekenhuis, Almere, the Netherlands
f
Department of Internal Medicine, Zuyderland Hospital, Sittard-Geleen, the Netherlands
g
Department of Internal Medicine, Maasstad Hospital, Rotterdam, the Netherlands
h
Department of Internal Medicine, Diakonessenhuis, Utrecht, the Netherlands
i
Department of Internal Medicine, Northwest Clinics, Alkmaar, the Netherlands
j
Department of Hematology, ZNA Stuivenberg, Antwerpen, Belgium
k
Department of Internal Medicine, Ziekenhuis Bernhoven, Uden, the Netherlands
l
Department of Internal Medicine, Jeroen Bosch Hospital, Den Bosch, the Netherlands
m
Department of Internal Medicine, Gelderse Vallei, Ede, the Netherlands
n
Department of Hematology, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium
o
Department of Internal Medicine, Amstelland Hospital, Amstelveen, the Netherlands
p
Department of Internal Medicine, Ikazia Hospital, Rotterdam, the Netherlands
q
Department of Internal Medicine, Maxima Medical Center, Eindhoven, the Netherlands
r
Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands
s
Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, the Netherlands
t
Department of Internal Medicine, Antonius Ziekenhuis, Nieuwegein, the Netherlands
u
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
v
Department of Internal Medicine, Meander Medical Center, Amersfoort, the Netherlands
w
Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands
x
Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands
y
Department of Internal Medicine, Haga Hospital, Den Haag, the Netherlands

Summary eClinicalMedicine
2023;63: 102167
Background The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is
heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy Published Online 29
August 2023
and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients.
https://doi.org/10.
1016/j.eclinm.2023.
Methods In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were 102167
treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The
primary endpoint was overall response rate on induction treatment. Patients were included from October 2017
until May 2019. Trial Registration Number: NTR6297.

Findings Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early
mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months
and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9%
due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of
ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively),

*Corresponding author. Department of Hematology, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
E-mail address: s.zweegman@amsterdamumc.nl (S. Zweegman).
z
Contributed equally.

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mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone.
Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance
treatment.

Interpretation Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM

patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced
toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious
and tolerable regimens improving the outcome in vulnerable intermediate-fit patients.

Funding Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.

Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Multiple myeloma; Elderly; Daratumumab; Ixazomib; Intermediate-fit; IMWG frailty index

Research in context

Evidence before this study months with VMP, HR 0.37, 95% CI 0.27–0.50, p < 0.0001)
The outcome of older newly diagnosed multiple myeloma and fit (NR with D-VMP vs 22.2 months with VMP, HR 0.34,
(NDMM) patients is heterogeneous. The International 95% CI 0.20–0.57, p < 0.0001). Accordingly, in the MAIA trial,
Myeloma Working Group (IMWG) developed a frailty index the addition of daratumumab to lenalidomide-
(FI) in a pooled analysis of 869 individual older NDMM dexamethasone, led to a superior PFS, independent of frailty
patient data from 3 prospective trials. This prognostic score level. Again, the outcome of frail and intermediate patients
classifies patients as fit, intermediate-fit, or frail based on age, was still inferior to fit patients; frail patients (NR vs 30.4
co-morbidities and patient reported (instrumental) activities months, HR 0.62, 95% CI 0.45–0.85, p = 0.003),
of daily living. The IMWG-FI predicts mortality and non- intermediate-fit (NR in both arms, HR 0.53, 95% CI
haematologic toxicity. 0.35–0.80, p = 0.0024) and fit (NR vs 41.7 months, HR 0.41,
In order to identify prospective clinical studies investigating 95% CI 0.22–0.75, p = 0.0028). The outcome with
anti-myeloma treatment in intermediate-fit patients, we lenalidomide-dexamethasone in this post-hoc analysis of
performed a Pubmed search, containing “multiple myeloma” intermediate-fit patients of the MAIA trial using a simplified
AND “intermediate-fit”, in May 2023, and found 29 articles. frailty index (projected to be more than 40 months) is
Only 1/29 described a prospective randomized clinical trial in considerably higher than with exactly the same regimen in
intermediate-fit patients based on the IMWG frailty index. In the prospective clinical study in intermediate fit patients
this study continuous treatment with lenalidomide (25 mg) according to the IMWG-FI. This indicates that both indexes
and dexamethasone (Rd) was compared with 9 cycles of may identify different levels of frailty.
lenalidomide (25 mg) and dexamethasone followed by
Added value of this study
lenalidomide (10 mg) without dexamethasone (Rd-R) in 199
Our study is the first study investigating daratumumab as
NDMM patients. The primary endpoint was event-free
part of first line treatment in a solely intermediate-fit patient
survival (EFS), a composite endpoint of grade 4 haematologic
population. Furthermore, it is the second prospective study
adverse events, grade 3 and 4 non-haematologic events,
globally to employ the IMWG-FI, the gold standard, in
discontinuation of lenalidomide, progression, or death. Dose
identifying intermediate-fit patients.
reduction of lenalidomide and limited duration of
dexamethasone therapy was found to improve EFS (Rd-R 10.4 Implications of all the available evidence
months vs Rd 6.9 months), without compromising Newly diagnosed intermediate-fit patients have an inferior
progression-free survival (20.2 vs 18.3 months). PFS compared to fit non-transplant eligible patients. This
In 2 studies a simplified frailty index, using a physician-instead might be caused by the fact that treatment regimens
of patient-reported performance status (WHO-PS) was used induce more toxicity in a vulnerable population, leading
to categorize patients, which was used in a non-planned post- to early and higher levels of treatment discontinuation.
hoc frailty analyses. In the ALCYONE trial, patients were Therefore, in future studies endpoints including feasibility
treated with bortezomib-melphalan-prednisone, with or should be used, such as EFS incorporating efficacy and
without daratumumab (D-VMP vs VMP). The addition of toxicity, and knowing that even low grade toxicity
daratumumab led to an increase in median PFS independent hampers continuation of treatment, early adaptation of
of frailty level, however the outcome was inferior in frail and therapy could be implemented. Furthermore, the use of
intermediate fit as compared to fit; frail patients (32.9 with D- the IMWF-FI to identify intermediate-fit patients is
VMP vs 19.5 months with VMP, HR 0.51, 95% CI 0.39–0.68, encouraged, to enable better cross trial comparisons.
p < 0.0001), intermediate-fit (40.1 with D-VMP vs 18.3

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Introduction Methods
The prognosis of non-transplant eligible (NTE) patients Patients
with newly diagnosed multiple myeloma (NDMM) The HOVON-143 (NTR6297) is a multicenter, prospec-
has significantly improved over the last decade, with an tive phase II trial, that included patients with a previ-
unprecedented duration of progression-free survival ously untreated symptomatic MM with measurable
(PFS) and overall survival (OS) with daratumumab, disease12 and who were intermediate-fit or frail accord-
added to either bortezomib-melphalan-prednisone ing to the IMWG-FI (Supplemental Methods). This
(VMP, ALCYONE trial) or lenalidomide-dexamethasone analysis concerns the intermediate-fit patients, for
(Rd, MAIA trial).1,2 However, the question is whether further details see statistical analysis. Exclusion criteria
this applies to all NTE patients, irrespective of frailty consisted of non-secretory MM; severe organ dysfunc-
level. The level of frailty by the International Myeloma tion (cardiac dysfunction NYHA III-IV; COPD with
Working Group Frailty Index (IMWG-FI), that includes FEV1 <50%; hepatic dysfunction (bilirubin or trans-
age, comorbidities and patient-reported daily activities aminases ≥3 times normal); renal dysfunction (creati-
was not determined in the ALCYONE and MAIA trials.3 nine clearance <20 ml/min)); neuropathy grade 1 with
To date, only two prospective trials have specifically pain or grade ≥2; active/uncontrolled infections; and an
examined the outcomes of intermediate-fit and frail pa- active malignancy (for complete in- and exclusion see
tients.4,5 In the HOVON 143 study, IMWG-FI based frail Supplemental Methods). All patients provided written
patients were treated with ixazomib, daratumumab and informed consent. The study was conducted in accor-
low dose dexamethasone (Ixa-Dara-dex), resulting in a dance with the Declaration of Helsinki and principles of
median PFS of 13.8 months and a 12-month overall good clinical practice and approved by the ethics
survival of 78%.4 Larocca and colleagues performed a committees.
randomized clinical trial in intermediate fit patients
comparing dose-adjusted Rd vs standard Rd, the latter Study design and treatment
being administered according to the same treatment Patients received nine 28-day induction cycles consist-
schedule as in MAIA, allowing a non-head to head ing of ixazomib 4 mg (orally; days 1, 8, 15), dar-
comparison. A pronounced difference in PFS was atumumab 16 mg/kg (intravenous administration;
observed; 18.3 months vs 35 months in the MAIA trial.1,5 cycles 1–2: days 1, 8, 15, 22; cycles 3–6: days 1, 15; cycles
A post-hoc analysis of the MAIA trial, using a simplified 7–9: day 1) and dexamethasone (on the days dar-
frailty index (SFI) based on physician-reported perfor- atumumab was administered; cycle 1–2: 20 mg; subse-
mance status instead of patient-reported daily activities, quent cycles 10 mg). This was followed by maintenance
showed that 51.7% of the intermediate-fit patients were therapy, consisting of 8-week cycles with ixazomib (days
progression-free at 36 months with Rd treatment.6,7 1, 8, 15, 29, 36, 43) and daratumumab (day 1) until
These data show that in patients, who are defined progression for a maximum of 2 years. In accordance
intermediate-fit using the IMWG-FI, the clinical with the protocol, dose adaptations for the combination
outcome is inferior as compared to NTE-NDMM and of ixazomib, daratumumab and dexamethasone were
intermediate-fit patients using the S-FI. However, performed in case of toxicity. The study protocol rec-
whether the negative impact of being intermediate-fit ommended antibiotic- and antiviral prophylaxis with
according to the IMWG-FI would be overcome by dar- trimethoprim/sulfamethoxazole and valaciclovir, and
atumumab is currently unknown, as no trials investi- vaccinations were advised according to national guide-
gating daratumumab in this specific patient population lines. Myeloid growth factor use was permitted accord-
are available. We prospectively investigated the novel ing to local practice.
daratumumab-containing triplet; Ixa-Dara-dex in
intermediate-fit patients according to the IMWG-FI. At Study endpoints
the time the study was developed it was known that the The primary endpoint was overall response rate (ORR)
toxicity of daratumumab was limited, being mainly on induction treatment, defined as at least a partial
infusion-related. The combination with bortezomib- response (≥PR).13 Secondary endpoints included PFS,
dexamethasone (Dara-Vd) was superior and did not progression-free survival 2 (PFS2; defined as time from
lead to an excess of treatment discontinuation due to registration to date of objective disease progression or
toxicity, compared to Vd alone in the relapsed-refractory death from any cause after second line therapy), overall
setting,8,9 therefore we decided to investigate a survival (OS), tolerability (defined as treatment discon-
daratumumab-proteasome inhibitor combination. The tinuation), and safety ((severe) adverse events ((S)AEs)).
oral proteasome inhibitor ixazomib was selected because In addition, event-free survival (EFS) was assessed post-
of inducing less peripheral neuropathy (PNP) than hoc, defined as time to treatment discontinuation, pro-
bortezomib, with limited severe PNP only, allowing gressive disease (PD), death, hematological toxicity
long-term administration.9,10 We used a low dose of grade 4 or non-hematological toxicity grade 3 or 4 (see
dexamethasone as previous studies observed superior Supplemental Objectives). Secondary endpoints during
outcomes when sparing steroids.5,11 maintenance included the improvement of response

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during maintenance and discontinuation due to had ISS3 and 14% had high-risk cytogenetic abnor-
treatment-related toxicity of ixazomib and dar- malities.14,15 Patients were defined intermediate-fit based
atumumab. Quality of life, as defined by the EORTC on age 76–80 years in 57%, based on comorbidities
QLQ-C30 was assessed during induction and mainte- (Charlson Comorbidity Index (CCI) ≥2) in 29%, and
nance treatment. Other secondary endpoints are due to iADL-dependency (iADL ≤ 5) in 14%. None of
described in the Supplemental Methods. the patients were intermediate-fit because of ADL de-
pendency (ADL ≤ 4) (Table 1). Specific details regarding
Statistical analysis specific iADL-dependencies and comorbidities are
It was predefined in the protocol that the intermediate- defined in Table S1.
fit and frail patients would be analysed separately, and
that the results would not be formerly compared, nor Efficacy
would the results of both populations be pooled together The ORR during induction treatment was 71% (95%
(Supplemental Methods). For sample size calculation, confidence interval (CI) 63–73), including 24 (37%) pa-
the optimal Simon 2-stage design was used. An ORR of tients with a very good partial response or better
50% was considered to be insufficient and an ORR of (Table 2). The median time to first response was 2
65% sufficient. With an alpha of 0.1, a power of 80% months (range 1–5) and the median duration of
and taking into account a 10% ineligibility rate, 66 response was 20.8 months (95% CI 12.0–36.7).
intermediate-fit patients had to be included At a median follow-up of 41.0 months (IQR 36–46
(Supplemental Methods). There were 2 interim ana- months), 47/65 (72.3%) patients had progressed or died.
lyses, one for safety and one for efficacy. Patients were The median PFS was 18.2 months (95% CI 10.5–28.1)
analyzed on a modified intention-to-treat basis, i.e. only (Fig. 2a). Both the median PFS2 and OS were not
eligible patients were included in analyses. Time-to- reached (NR) (95% CI 37.9-NR, Fig. 2c) and (95% CI
event endpoints were estimated using the Kaplan– 47.2-NR, Fig. 2b), respectively). The 36-month OS was
Meier method and 95% confidence interval (CI). 83% (95% CI 71–90%) (Fig. 2b). No differences in PFS,
Global health status/quality of life (GHS) was assessed PFS2 or OS were observed between patients defined
using the European Organisation for Research and intermediate-fit based on age 76–80 years vs based on
Treatment of Cancer Quality of Life Questionnaire C30 other frailty parameters (either comorbidities or iADL-
(EORTC-QLQ-C30) at baseline (T0), after induction cy- dependency; Figure S1a and b).
cles 3 and 9 (T1 and T2, respectively), and after 6, 12 and Relapse-related mortality occurred in 7/65 (11%)
24 months of maintenance treatment (T3, T4 and T5, patients and non-relapse mortality in 10/65 patients
respectively) for patients who were still on protocol. (15%), including 1 patient who died within 60 days of
Health Related Quality of Life (HRQoL) course over registration (early death rate 1.5%). Reasons for non-
time was assessed by a linear-mixed-effects model and relapse mortality were three secondary primary
whether cross-sectional changes from baseline were malignancies (SPMs) (small cell lung carcinoma, mye-
clinically meaningful was evaluated using calculated lodysplastic syndrome with excessive blasts-2 and me-
minimal important difference (MID), of which the sothelioma), two cardiac events (heart failure and
definition is described in the Supplemental Methods. ventricular arrhythmia), two infections and three with
Finally, the percentage of patients improving/deterio- an unknown cause of death.
rating clinically relevant from baseline (i.e. more than The median EFS was 5.1 months (95% CI 2.8–7.2)
the MID) were reported. Statistical analyses were per- (Fig. 2d). At data cut-off, only five patients (8%) were
formed by Stata version 15.1 and R version 3.6.1. Ob- event-free. The most common event was non-
servations were censored on June 15, 2022. hematological AEs grade 3 or 4 (40/65; 62%), followed
by PD (14/65; 22%), treatment discontinuation of the
Role of the funding source whole treatment regimen (3/65; 5%), hematological AEs
The study was funded by Janssen Pharmaceuticals and grade 4 (2/65; 3%) and death (1/65; 2%) (see Table S2
Takeda Pharmaceutical Company Limited. The funders for a detailed description of events). No difference in
had no role in study design, data collection, data anal- EFS was observed between patients defined
ysis, data interpretation or writing of the report. intermediate-fit based on age 76–80 years vs based on
other frailty parameters (Figure S1c).
Thirty-five out of 65 (54%) patients completed in-
Results duction treatment and started with maintenance treat-
From October 2017 to May 2019, 66 intermediate-fit ment. The median follow-up of the patients who
patients were enrolled of whom 1 was excluded due to reached maintenance is 41.3 months (range 34.6–53.8).
ineligibility (Fig. 1, CONSORT diagram). The de- Improvement of response during maintenance was
mographics of the 65 eligible patients are described in observed in 12/35 (34%) patients. One patient changed
Table 1. Median age was 76 years (range 65–80), 14% from a minimal response (MR) to a partial response
had a WHO performance status (WHO-PS) ≥2, 18% (PR), four patients from a PR to a VGPR and 7 patients

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Registraon n=66
Ineligible n=1 Start maintenance n=35

Ind 1 n=65 Maintenance 1-2 n=35

Toxicity n=11 Toxicity n=14
Intercurrent death n=1I Progression n=3
Incompliance n=1 Other n=1d
Ind 2 n=62 Maintenance 3-4 n=30

Toxicity n=15
Progression n=4
Ind 3 n=62 Intercurrent death n=1II
Maintenance 5-6 n=24
Progression n=1
Other n=1a Progression n=2
Other n=1e
Ind 4 n=60
Maintenance 7-8 n=21
Progression n=3
Toxicity n=12 Progression n=1
Other n=1b Other n=1f

Ind 5 n=55 Maintenance 9-10 n=19

Progression n=2
Progression n=2
Incompliance n=1
Toxicity n=13
Maintenance 11-12 n=16
Ind 6 n=52
Incompliance n=1
Progression n=3
Toxicity n=13 Normal compleon of
Ind 7 n=48 protocol n=15

Progression n=4

Ind 8 n=44

Progression n=3

Ind 9 n=41
Progression n=3
Incompliance n=2
Other n=1c
Maintenance n=35 (54%)

Fig. 1: CONSORT diagram—patient flow and causes of treatment discontinuation. Consort diagram of the number of intermediate-fit patients
participating in the HOVON 143 study, flow through the induction and maintenance phase and timing and reason for treatment
discontinuation.
Reasons for treatment discontinuation:
– Toxicity: 1cardiac decompensation; 2PNP grade 3 with pain; 3acute renal failure; 4 PNP grade 2; 5 Orthostatic hypotension grade 3
– Intercurrent death: I sudden death; II unknown cause of death
– Other reasons: a hypothyroidism related to amiodarone; b increase in M-protein not formally meeting criteria of progressive disease (PD); c
progressive vascular dementia; d Squamous cell carcinoma grade 3; e PNP grade 2 and increase in M-protein (not formally meeting criteria of
PD) during COVID19 pandemic; f Physician decision (increasing M-protein not formally meeting criteria of PD).

from a VGPR to (s)CR (Table 2). The ORR during in- In addition, dose reductions and/or interruptions
duction and maintenance treatment was 72%. occurred during induction therapy (Table S3). Twenty-four
out of 65 (37%) patients had at least one dose modification
Tolerability of ixazomib. In 10/65 (15%) the dose of dexamethasone
Thirty out of 65 (46%) patients did not proceed to was modified. In 11/65 (17%) patients one or more dar-
maintenance (Fig. 1), of whom 63% (19/30) due to PD, atumumab doses were skipped. Six out of 65 (9%) patients
13% (4/30) due to toxicity, 10% (3/30) due to incom- discontinued ixazomib, while continuing treatment with
pliance, 3% (1/30) due to sudden death and 10% (3/30) daratumumab and dexamethasone. The median relative
due to other reasons (see Fig. 1 for more details). dose intensity (RDI) (with interquartile range) was 0.96

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Ixa-Dara-dex N = 65 Response status,13 During induction During induction and

n (%) maintenance
Male (%) 35 (54)
Overall response 46 (71) 47 (72)
Median age (years) [range] 76 [65–80]
rate (≥PR)
≤75 years 28 (43)
(s)CR 1 (2) 8 (12)
76–80 years 37 (57)
VGPR 23 (35) 20 (31)
WHO performance (%)
PR 22 (34) 19 (29)
0 25 (38)
MR 11 (17) 10 (15)
1 28 (43)
SD 7 (11) 7 (11)
2 6 (9)
NE 1 (2) 1 (2)
3 3 (5)
MR: minimal response; n: number; NE: not evaluable; PR: partial response; SD:
Unknown 3 (5)
stable disease (s) CR: (stringent) complete response; VGPR: very good partial
Charlson Comorbidity Index (CCI) response.
≤1 (%) 46 (71)
Table 2: Best response on induction and maintenance treatment with
≥2 (%) 19 (29)
Ixa-Dara-dex (n = 65).
Activities of Daily Living (ADL)
≥5 (%) 65 (100)
≤4 (%) –
Of the 35 patients who started maintenance therapy,
Instrumental ADL (iADL)
20 (57%) discontinued therapy, the majority (13/20,
≥6 (%) 56 (86)
65%) due to PD. Other reasons were patient choice
≤5 (%) 9 (14)
(2/20, 10%), toxicity (2/20, 10%), death (1/20, 5%) or
Type of measurable disease (%)
other reasons (2/20, 10%; 1 physician decision, 1
IgG 45 (69)
squamous cell carcinoma) (Fig. 1, CONSORT diagram).
IgA 13 (20)
Ixazomib dose modifications during maintenance
FLC 7 (11)
occurred in 19/36 (53%) patients, of whom 8 patients
ISS disease stage (%)
did not have dose modifications of ixazomib during
I 16 (25)
induction treatment. Six out of 35 (17%) patients skip-
II 37 (57)
ped one or more doses of daratumumab and 4/35 (11%)
III 12 (18)
of patients received ≥1 dose modification of dexameth-
LDH (%)
asone during maintenance treatment, for all new onset
Normal 61 (94)
(full dose during the induction treatment). Eight out of
Elevated 3 (5)
35 (23%) patients discontinued treatment with ixazo-
Unknown 1 (2)
mib, while continuing with daratumumab and dexa-
Cytogenetic results by FISH/array (%)
methasone once every eight weeks (Table S3).
t (4; 14) 0/60 (0)
Full doses of ixazomib, daratumumab and dexa-
del (17p) 5/58 (9)
methasone during maintenance were administered in
t (14; 16) 3/58 (5)
13/36 (36%) patients. Six out of 65 patients (9%)
High risk cytogenetic diseasea 8/56 (14)
completed induction and two year maintenance treat-
R-ISS disease stage (%)
ment without any dose modification.
I 10 (15)
II 49 (75)
Toxicity
III 3 (5)
Adverse events (AEs) during induction treatment are
Unknown 3 (5)
described in Table 3. Cumulative hematological toxicity
Median hemoglobin (g/dl) [range] 10.3 [8.1–16.0]
Median creatinine (mg/dl) [range] 0.96 [0.53–2.68]
grade ≥3 during induction occurred in 12% of patients,
with neutropenia being most commonly reported (6%).
FISH: fluorescence in situ hybridization; FLC: free light chain; IQR: interquartile Cumulative non-hematological toxicity grade ≥3
range; (R-)ISS: (Revised) International Staging System; LDH: lactate
dehydrogenase; WHO: World Health Organisation. aHigh risk cytogenetic
occurred in 51% of patients, predominantly grade 3 AEs
disease: presence of t (4; 14) and/or t (14; 16) and/or del17p13.14,15 (91%). The most common non-hematological AEs were
gastro-intestinal AEs (14%, mainly diarrhea) and central
Table 1: Demographics at registration of eligible intermediate-fit
nervous system AEs (14%), which were diverse (for
patients.
details see legend Table 3). In addition, a total of 42% of
patients developed any grade PNP, including 5 (8%)
(0.87–1.00), 0.99 (0.94–1.00) and 1.00 (0.97–1.00), for ixa- patients with grade 3 PNP. The occurrence of grade 3
zomib, daratumumab and dexamethasone, respectively. infections was 8%.
During protocol induction treatment, full doses of ixazo- During maintenance, 1/35 (3%) patients experienced
mib, daratumumab and dexamethasone, were adminis- grade 3 thrombocytopenia. Non-hematologic AEs
tered in 37/65 (57%) of patients (Table S3). occurred in 16/35 (46%) patients, of which the most

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Fig. 2: Survival outcomes of intermediate-fit patients A) Progression-free survival (PFS), B) overall survival (OS), C) progression-free survival 2
(PFS2) and D) event-free survival (EFS). For further specification of EFS reasons, please be referred to Table S2 in the Supplemental data. No
differences in PFS, OS or EFS were observed between patient subgroups defined intermediate-fit based on age 76–80 vs based on another frailty
parameter (comorbidities or iADL dependency) (Figure S1).

common were gastro-intestinal AEs (3 patients grade 3, 1 Seventy-nine SAEs were reported in 41/65 (63%) of
grade 4) and infections (3 patients grade 3). There was no patients on protocol, of which the majority (78%) were
new onset grade ≥3 PNP during maintenance (Table 4). due to (prolongation of) hospitalization. Four SAEs

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Fig. 2: (Continued).

resulted in death, of which all four were unlikely related in 40 of 42 patients (95%). This was comparable in
to study treatment. patients who went off protocol because of progressive
disease (30/31, 97%), premature treatment discon-
Second line treatment tinuation due to toxicity (3/3, 100%), incompliance
Of the patients who had progressive disease (either (3/3, 100%), other reasons (2/2) or after disease pro-
on- or off protocol), second line treatment was started gression after normal completion of protocol (2/3,

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compliance was 60/62 (97%) after 3 cycles, 39/41 (95%)

CTCAE grade n (%) 2 3 4
after 9 cycles, 29/30 (97%) after 6 months (C12), 20/23
Any hematologic AE 17 (26) 6 (9) 2 (3)
(87%) after 12 months (C15) and 15/15 (100%) after 24
Anemia 7 (11) 2 (3) –
months (C21) of maintenance treatment. Mean HRQoL
Thrombocytopenia 8 (12) 3 (5) –
score of Global Health Status/QoL (GHS/QoL) at baseline
Neutropenia 15 (23) 2 (3) 2 (3)
and five follow-up time points during induction and
Any non-hematologic AE 28 (43) 30 (46) 3 (5)b
maintenance treatment are presented in Table S5.
Cardiac 3 (5) 1 (2) 2 (4)a
During treatment, patients on protocol reported a
Central nervous system 7 (11) 7 (11)d –
statistically significant improvement in GHS/QoL,
Gastro-intestinal 14 (22) 9 (14) –
which was clinically relevant (i.e. reached the threshold
Infections 18 (28) 6 (9) –
for MID of 8.49) from 9 induction cycles onwards
Infusion related reactions 2 (3) 2 (3) –
(Figure S2). At all time points, the number of patients
Pain 14 (22) 4 (6) –
experiencing a clinically relevant (> MID of 8.49 points
Peripheral neuropathyc 10 (15) 5 (8) –
from baseline) improvement in their GHS/QoL, was
Secondary primary malignancy 3 (5) 2 (3) 1 (2)a
numerically higher than whom who reported a deteri-
AEs of grade ≥3 that occurred in at least 5% of patients and AEs of special oration (Figure S3).
interest are reported. aIncluding 1 patient with grade 5 AE. bIncluding 2 patients
with grade 5 AE. cGrade 1 peripheral neuropathy was observed in 12 (18%)
patients. d2 gait disturbance, 2 syncope, 1 Guillain-Barré syndrome, 1 brain stem
infarction, 1 carpal tunnel syndrome AE: adverse event; CTCAE: National Cancer Discussion
Institute Common Terminology Criteria for Adverse Events, version 4.016; n:
number.
Frailty levels have a pronounced effect on the outcome of
treatment, even in equally aged patient populations with
Table 3: Adverse events grade 2–4 during induction treatment. comparable performance status.3 We here report the sec-
ond prospective study specifically designed for
intermediate-fit patients with NDMM. Treatment with
67%). The remaining 23 patients were still free of ixazomib-daratumumab-low dose dexamethasone resulted
progression (18) or died before progressive disease in an ORR of 72% and was safe, reflected by a low early
was documented (5). mortality of 1.5%. Moreover, patients reported a clinically
The most common initiated second-line treatment relevant improvement in GHS/QoL from the end of in-
was lenalidomide-based (35/40, 88%). For a complete duction that persisted during maintenance. However, the
overview of second-line regimens please be referred to median PFS of 18.2 months was limited, irrespective of
Table S4. being intermediate-fit based on age or based on having
comorbidities or being dependent in iADL.
HRQoL Our data confirm the inferior outcome of
All 65 patients completed the baseline HRQoL question- intermediate-fit patients identified as such by the IMWG-
naires and were included in HRQOL analysis. Overall FI. Although cross-trial comparisons have inherent lim-
itations due to differences in treatment, trial design and
methodology, in the study of Larocca and colleagues, a
comparable PFS of 18.3 months was found when using
CTCAE grade n (%) 2 3 4 treatment with Rd.5 Treatment with a 3-drug regimen,
Hematologic AE 5 (14) 1 (3) – consisting of ixa-dara-dex, did not result in a superior
Anemia 1 (3) – – outcome. A higher level of frailty in our study is not a
Thrombocytopenia 1 (3) 1 (3) – likely explanation as in both studies intermediate-fit pa-
Neutropenia 4 (11) – – tients according to the IMWG-FI were included and we
Non-hematologic AE 14 (40) 14 (40) 2 (6) found no differences in outcome in patients defined
Cardiac 2 (6) – – intermediate-fit based on age or based on either comor-
Central nervous system 1 (3) – 1 (3) bidities or impairments in iADL. Furthermore, patient
Gastro-intestinal 6 (17) 3 (9) 1 (3) populations were comparable with regards to disease
Infections 8 (23) 3 (9) – characteristics. Both studies show inferior results as
Infusion related reactions – – – compared with a post-hoc frailty analysis of the
Pain 8 (23) 1 (3) – ALCYONE trial and the MAIA trial, comparing VMP
Peripheral neuropathya 4 (11) – – with Dara-VMP and Rd with Dara-Rd respectively.7,17 In
Secondary primary malignancy – 3 (9) – both trails the median PFS was considerably longer than
AEs of grade ≥3 that occurred in at least 5% of patients and AEs of special
in the trial of Larocca et al. and our trial, ranging from
interest are reported. aGrade 1 peripheral neuropathy was observed in 3 (9%) 40.1 months to not reached, except for patients treated
patients. with VMP; 18.3 months.5,7,17 The longer PFS might be
Table 4: Adverse events grade 2–4 during maintenance treatment.
explained by the fact that patients were defined
intermediate-fit based on the S-FI instead of the gold

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standard; the IMWG-FI, using physician-reported vs third reason for limited efficacy of our regimen, as the
patient-reported performance.6 The S-FI probably iden- added value of daratumumab every 8 weeks in the main-
tifies a less vulnerable intermediate-fit patient popula- tenance phase might be limited. Accordingly, results of the
tion, which is not unreasonable to hypothesize as in CASSIOPEIA study showed no benefit of daratumumab
general more fit patients tend to be included in trials maintenance every 8 weeks in patients who were treated
investigating non-registered drugs. We would like to with daratumumab in induction, like in our study.25
make plea for the incorporation of the IMWG-FI, which Whether this is caused by the treatment schedule of dar-
is the gold standard, in clinical trial design, in order to atumumab (q8W) or that benefit is lacking irrespective of
enable future cross-trial comparisons. the density of the maintenance scheme has not been
Almost half of the patients did not proceed to main- clarified yet.
tenance therapy, of which the majority because of pro- Taken into account that many older, vulnerable pa-
gression, for which there are several explanations. Firstly, tients may prioritize other outcomes than disease control,
the effectiveness of the regimen was undermined by study endpoints should not only reflect survival but also
vulnerability of intermediate-fit patients, with almost a tolerability and toxicity.20 Therefore, we investigated the
third of patients discontinuing induction therapy because EFS, incorporating the same events as in the study of
of toxicity, sudden death and incompliance. In addition, a Larocca et al.; next to progression and death, also hema-
third of the patients needed dose modifications of ixazo- tological toxicity grade 4, non-hematological toxicity grade
mib during induction treatment, and even more than half 3 or 4 or treatment discontinuation.5 We confirmed that
of the patients during maintenance, mainly due to the EFS was considerably shorter than the PFS; 5.3
neurotoxicity. The occurrence of PNP was higher than months vs 18.2 months, indicating the importance of
expected from earlier studies.10,18 The level of frailty or endpoints reflecting benefit–risk profiles. In both studies,
known risk factors for PNP, such as diabetes of high BMI, grade 3–4 non-hematologic toxicities were the most com-
might play a role, however cannot be substantiated mon events. In our study gastro-intestinal complaints and
because the data to make such comparisons are lacking. peripheral neuropathy, being attributed to ixazomib, led to
Importantly, discontinuation due to toxicity occurred even a 9% discontinuation of ixazomib during induction treat-
with mild toxicity, indicating that patients prioritize ment, which was even 23% during maintenance treat-
maintaining independence over prolonging their life. This ment. Actually, such patients were treated with
emphasizes the importance of reporting all levels of daratumumab alone, hampering efficacy. This stresses the
toxicity and the impact on feasibility, not just severe need for reducing non-hematologic toxicity, especially as
toxicity.19,20 Secondly, the regimen itself might have limited grade ≥3 non-hematologic toxicity (especially cardiac,
efficacy. This is supported by several observations. There is gastro-intestinal events, and infections) has been linked to
less improvement in PFS with ixazomib maintenance reduced overall survival within the first 6 months of its
therapy following stem cell transplantation than lenalido- occurrence.26 Secondly, utilizing composite endpoints will
mide although not head to head compared.21,22 In non- be necessary for directing treatment in vulnerable patients,
transplant eligible patients there is heterogeneous results and we advocate for including these in all future clinical
on the added value of ixazomib maintenance; in the trials for non-fit patients.27 Furthermore, in future studies
TOURMALINE-MM04 an improvement was observed, a frailty-adjusted approach should be implemented, which
however we found that ixazomib maintenance did not is currently under investigation in the FiTNEss trial, in
result in an improvement in PFS compared to placebo.18,23 order to improve outcome.28
In addition, the addition of ixazomib to lenalidomide was Almost all patients with progressive disease were
found to significantly increase PFS only in the relapsed able to receive second line treatment (40/42, 95%). This
setting but not in newly-diagnosed non-transplant eligible is in contrast to other studies showing that older pa-
patients.10,24 tients are less likely to receive subsequent treatment
Moreover, the combination of daratumumab with a lines.2,7 Therefore, we demonstrate that the combination
proteasome inhibitor might be less effective than with an of daratumumab in first-line treatment, along with
IMiD. This is supported by non-head to head compared carefully monitored dose adjustments of ixazomib and
regimens (Dara-Rd, Dara-VMP and dara-Vd) both in first dexamethasone, does not hinder subsequent treatment.
line and later lines of therapy.1,2,9 Whether this is caused by Interestingly, the PFS2 (not reached after a median
the longer duration of lenalidomide treatment vs bortezo- follow-up of 41.0 months) was considerably longer
mib treatment is unknown. By replacing bortezomib with compared to the PFS1 (18.2 months). The majority of
ixazomib we aimed to prolong proteasome inhibitor patients received a second line regimen including
treatment in combination with daratumumab. However, lenalidomide. Probably lenalidomide has a more
this was found to be less feasible than expected in a favourable risk-benefit ratio, compared to a PI in a
vulnerable population, with limited efficacy as a result. vulnerable patient population. Additionally, lenalido-
Therefore, 8/35 (23%) patients received only dar- mide might have enhanced the immunomodulatory ef-
atumumab once every eight weeks during maintenance fect of daratumumab knowing to remain for several
due to discontinuation of ixazomib. This might be the months after discontinuation.29,30

10 www.thelancet.com Vol 63 September, 2023

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In conclusion, we here show that the outcome of Paula F. Ypma.

intermediate-fit NDMM patients is limited, even with a Payment or honoraria for presentations: Janssen.
Support for attending meetings and/or travel: Janssen.
3-drug regimen. Treatment with ixazomib-
Sonja Zweegman.
daratumumab-dexamethasone was found to be safe Consulting or Advisory Role: Janssen-Cilag, Takeda, Celgene/Bristol
and enhance overall quality of life. However, feasibility Myers Squibb, Sanofi, Oncopeptides (no personal funding).
of ixazomib was limited reflected by frequent dose ad- Research Funding: Janssen, Takeda.
justments and discontinuation due to, often low grade, No other potential conflicts of interest were reported.
toxicity. We propose to design studies with composite or Acknowledgements
even co-primary endpoints, that include feasibility and The authors would like to thank all participating patients and centers,
all grade toxicity. In addition, the reasons for adapting the HOVON data center and the Data Safety Monitoring Board (Dr
and discontinuation of therapy should be investigated in Maria-Victoria Mateos, Dr Philippe Moreau and Dr Jerome Lambert).
more detail. This will allow the identification of less Scientific category
toxic partner drugs for daratumumab, paving the way multiple myeloma; clinical trials.
for optimization of therapy of this vulnerable patient
Appendix A. Supplementary data
population. Supplementary data related to this article can be found at https://doi.
org/10.1016/j.eclinm.2023.102167.
Contributors
KN, PS, M-DL, and SZ designed the research.
AV, DB and SC collected the data.
KN accessed and verified the data. References
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