Critical Reviews in Oncology / Hematology 159 (2021) 103211

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Critical Reviews in Oncology / Hematology

journal homepage: www.elsevier.com/locate/critrevonc

Daratumumab-based induction therapy for multiple myeloma: A systematic

review and meta-analysis
Lip Leong Chong a, 1, Yu Yang Soon b, 1, Cinnie Yentia Soekojo a, Melissa Ooi a, d,
Wee Joo Chng a, c, d, Sanjay de Mel a, *
a
Department of Haematology Oncology, National University Cancer Institute Singapore, National University Health System Singapore, Singapore
b
Department of Radiation Oncology, National University Cancer Institute Singapore, National University Health System Singapore, Singapore
c
Cancer Science Institute of Singapore, National University of Singapore, Singapore
d
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

A R T I C L E I N F O A B S T R A C T

Keywords: This study aims to evaluate the efficacy and safety of Daratumumab-based induction therapy (DBI) in newly
Daratumumab diagnosed multiple myeloma (MM). We identified four eligible RCTs including 2735 patients. The primary
Induction therapy outcomes of RCTs involving transplant eligible (TEMM) and non-transplant eligible MM (NTEMM) were stringent
Newly diagnosed multiple myeloma
complete response (sCR) and progression-free survival (PFS) respectively. Meta-analysis was performed using
High cytogenetic risk
Meta-analysis
random-effects models. DBI improved sCR rates for standard risk (SR) (OR 1.86, 95 % CI 1.41–2.46) but not HiR
(high risk) (OR 0.78, 95 % CI 0.41–1.48) (interaction P = 0.01) TEMM. In NTEMM, DBI improved PFS in SR (HR
0.44, 95 % CI 0.35–0.55) but not HiR patients. (HR 0.81, 95 % CI 0.52–1.27) (interaction P = 0.02). In
conclusion, while DBI is efficacious in SR patients, there is insufficient data to support a benefit in HiR-MM.

1. Introduction mechanisms (Plesner and Krejcik, 2018). Dara has demonstrated

Multiple myeloma (MM) is the second most common haematologic
malignancy worldwide (Rajkumar, 2018). MM is characterized by a
clonal proliferation of plasma cells usually associated with a monoclonal
protein and specific clinical features (Rajkumar, 2018). Proteasome in­
hibitor (PI) and immunomodulator (IMID) based triplet induction fol­
lowed by high-dose melphalan and autologous stem-cell transplantation
is the standard of care for transplant eligible MM (TEMM) (Rajkumar,
2018; Laubach and Kumar, 2016). Depending on their fitness,
non-transplant eligible MM (NTEMM) patients are treated with PI
and/or IMID based triplet or doublet regimens (Piechotta et al., 2019).
Despite the development of potent novel therapeutics, MM remains
incurable with the outlook for patients with high cytogenetic risk (HiR)
MM being particularly poor (Rajkumar, 2018; Sonneveld et al., 2016).
There is hence a need to improve on currently available targeted
therapy.
Daratumumab (Dara) is an anti-CD38 human IgGk monoclonal
antibody which targets malignant plasma cells through a variety of
remarkable efficacy both as a single agent and in combination with
conventional therapies in relapsed or refractory MM (Lonial et al., 2016;
Dimopoulos et al., 2016; Bahlis et al., 2020; Palumbo et al., 2016). More
recently, Dara has been investigated in the upfront setting in combina­
tion with standard induction regimens. In TEMM, Dara was combined
with bortezomib, thalidomide, dexamethasone (VTD) in the CASSIO­
PEIA trial and with bortezomib, lenalidomide, dexamethasone (VRD) in
the GRIFFIN trial (Moreau et al., 2019; Voorhees et al., 2020a). Both
phase III randomized controlled trials (RCT) showed a benefit for
Dara-VTD (DVTD) and Dara-VRD (DVRD) over VTD and VRD respec­
tively in terms of stringent complete response (SCR) rate and
progression-free survival (PFS) (Moreau et al., 2019; Voorhees et al.,
2020a).
In NTEMM, Dara combined with bortezomib, melphalan, predniso­
lone (VMP) resulted in a superior PFS when compared to VMP (Mateos
et al., 2017; Mateos et al., 2020). The addition of Dara to lenalidomide
and dexamethasone (RD) also produced a significant PFS benefit
compared to RD (Facon et al., 2019). These RCTs strongly suggest the

* Corresponding author at: Department of Haematology Oncology, National University Cancer Institute Singapore, National University Health System Singapore,
1E Kent Ridge Road, 119228, Singapore.
E-mail address: sanjay_widanalage@nuhs.edu.sg (S. de Mel).
1
These authors contributed equally.

https://doi.org/10.1016/j.critrevonc.2020.103211
Received 3 July 2020; Received in revised form 13 December 2020; Accepted 20 December 2020
Available online 30 December 2020
1040-8428/© 2020 Elsevier B.V. All rights reserved.
L.L. Chong et al.
superiority of Dara-based induction over conventional regimens. The
benefit of Dara-based induction is however, less certain in patients with
HiR MM and these trials were not adequately powered to assess out­
comes in this patient subset. We conducted a systematic review and
meta-analysis to evaluate the efficacy and safety of Dara-based induc­
tion overall, and in specific subgroups of newly diagnosed MM (NDMM).
2. Materials / subjects and methods
2.1. Research objective and study eligibility criteria
This systematic review included RCTs comparing the effects of Dara-
based induction regimens versus standard treatment in patients with
treatment naïve, TEMM and NTEMM. Inclusion criteria were as follows:
patients with newly-diagnosed multiple myeloma (NDMM), comprising
either TEMM or NTEMM, who received standard induction regimens or
daratumumab-based induction treatment. The primary efficacy out­
comes were stringent complete response (sCR) for TEMM and
progression-free survival (PFS) for NTEMM. Secondary efficacy out­
comes were overall response rate (ORR) and the rates of very good
partial response (VGPR), partial response (PR), complete response (CR),
negative minimal residual disease (MRD), stable disease (SD) and pro­
gressive disease (PD). Safety and side effect profiles were additional
secondary outcomes analysed in this study.
2.2. Search strategy
We identified eligible trials by searching MEDLINE, EMBASE and
Cochrane Register of Controlled Trials from the date of inception on­
ward to April 2020. The search strategy included search terms such as
“Multiple Myeloma” and “Daratumumab”. The results were then hand
searched for eligible trials. In addition, the reference list of selected trials
and conference proceedings from American Society of Clinical Oncology
(ASCO), American Society of Hematology (ASH), European Hematology
Association (EHA) and International Myeloma Working Group (IMWG)
between 2010 and 2019 were reviewed for any other eligible trials.
2.3. Selection of trials and data extraction
Three reviewers independently assessed the eligibility of the ab­
stracts identified by the search. The full text articles that appeared to
meet the inclusion criteria was retrieved for closer review. Disagree­
ments were resolved by consensus.
The same reviewers extracted the data independently using stan­
dardized data collection forms. Data retrieved from the articles include
publication details, methodological components, trial characteristics
such as sample size, interventions, duration of follow up and outcome
measures.
2.4. Risk of bias assessment
We assessed the risk of bias using the Cochrane RoB2 tool which
assess the risk of bias in five domains, namely: randomization process,
deviations from the intended interventions, missing outcome data,
measurement of the outcome and selection of the reported result. An
overall risk of bias was determined based on the reviewers’ judgement
for each of the domains. An overall “low risk of bias “score is given when
the study is judged to be at low risk of bias for all domains. An overall
“some concerns” score is given when the study is judged to raise some
concerns in at least one domain, but not to be at high risk for any
domain. An overall “high risk of bias” score is given when the study is
judged to be at high risk of bias in at least one domain.
2.5. Outcome measures
The primary outcome was sCR for trials involving patients with
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Critical Reviews in Oncology / Hematology 159 (2021) 103211
TEMM (CASSIOPEIA and GRIFFIN) and PFS for trials involving patients
with NTEMM (ALCYONE and MAIA). Given the differing primary
outcome measures for the trials evaluating TEMM and NTEMM, we used
sCR rate and PFS respectively when analysing the TEMM and NTEMM
trials.
The secondary outcomes for the CASSIOPEIA trial were OS, PFS,
response after induction (sCR, VGPR or better and overall response
rates), and response after consolidation (MRD negativity and CR). The
GRIFFIN trial considered OS, ORR and sCR rates at specific time points,
time to response, duration of response as well as rates of PD, SD and
MRD-negativity after consolidation as its secondary outcomes.
Meanwhile, the secondary outcomes for NTEMM studies from MAIA
and ALCYONE were ORR (including rates of VGPR, CR and MRD
negativity), time to response, duration of response, safety and side effect
profiles.
2.6. GRADE assessment
We assessed the overall certainty of the summarized evidence
focusing on the primary outcomes using the GRADE approach. The
GRADE approach involves grading of five domains including study
design, study’s overall risk of bias, inconsistency and imprecision of
studies’ results, and indirectness of the evidence. The GRADE system
classifies the certainty of the summarized evidence in one of the four
grades: High, Moderate, Low and Very Low. A high grade score suggests
that further research is very unlikely to change our confidence in the
estimate of effect and very low grade score indicates that any estimate of
effect is very uncertain.
2.7. Subgroup analyses
Subgroup analyses were performed to determine if the estimates of
effect for the primary outcomes were influenced by cytogenetic profiles,
age, gender, race, international staging system (ISS) stage, heavy chain
subtype, ECOG performance status, baseline creatinine clearance and
hepatic function.
2.8. Statistical analyses
The log hazard ratios (HR) and their variances for time to event data
(i.e. PFS and OS) were estimated using published methods when
appropriate summary statistics or Kaplan-Meier curves were reported.
The individual trial log HR and their variances were combined using the
generic inverse variance method. A HR of less than 1 indicates an
advantage of using Dara-based treatment regimens.
The restricted mean survival time (RMST) for both PFS and OS were
estimated at 6, 12, 24 and 36 months from randomisation. We recon­
structed the individual patient data from the published Kaplan Meier
curves using methods developed by Wei and colleagues (Wei and Roy­
ston, 2017). We estimated the RMST using the methods developed by
Cronin and colleagues (Cronin et al., 2016). We calculated the differ­
ences in RMST and its standard deviation between the two treatment
arms at the pre-specified time points. The individual trial differences in
RMST and its standard deviations were combined using the generic in­
verse variance method. A mean difference of more than zero indicates an
advantage of using Dara-based treatment.
The odd ratios for dichotomous data (i.e. disease response and
adverse events) were calculated from the number of patients who
experienced the event and the number of patients who did not experi­
ence the event. The individual trial odds ratios were combined using the
Mantel-Haenszel method. An odds ratio of more than 1 for disease
response outcomes and less than 1 for adverse events indicates an
advantage of using Dara-based treatment.
The chi-square Cochrane Q test was used to detect any heterogeneity
across the different trials and between subgroups. A P value of less than
0.05 would indicate a statistically significant difference between the
L.L. Chong et al.
subgroups i.e. a statistically significant heterogeneity among the trial
results. The I2 statistics is used to judge the magnitude of heterogeneity.
An I2 statistic of more than 25 % would signify that at least moderate
level of heterogeneity is present among the trial results. The random
effects meta-analysis model was used in the analysis.
Statistical analysis for reconstruction of individual patient data from
the Kaplan Meier curves and restricted mean survival time were per­
formed using Stata version 16.0 (Statacorp, TX). The meta-analysis was
performed using the Cochrane Collaboration software (RevMan version
5.30; http://www.cochrane.org)
3. Results
3.1. Results of search strategy
We identified 267 records from our search strategy. After screening
through the titles and abstracts, we retrieved the full text articles of ten
records for further evaluation. We included a total of five articles on two
RCTs that include TEMM and two RCTs including NTEMM (Fig. 1).
3.2. Characteristics of included studies
A total of 2735 patients were included from four RCTs analysed
(ALCYONE 2018, MAIA 2019, CASSIOPEIA 2019 and GRIFFIN 2020).
Patient demographics and baseline disease characteristics were gener­
ally well-balanced based on available data (Table 1). Dara-based in­
duction treatment was given for 50.1 % (n = 647) of TEMM and 49.8 %
(n = 718) of NTEMM, respectively. Overall, 388 patients (14 %) had
high-risk cytogenetics and were equally distributed between the Dara-
based induction and standard treatment groups. 1491 patients (55 %)
were classified as IgG subtype and 681 patients (24 %) had ISS stage III
disease. The average median follow-up time for all patients was 21.4
months (range 16.5–28.0 months). The risk of bias of the included
Fig. 1. PRISMA flowchart for screening and identification of appropriate studies.
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Critical Reviews in Oncology / Hematology 159 (2021) 103211
studies was judged to be low (Supplementary Table 1).
3.3. Stringent Complete Response for trials on transplant eligible multiple
myeloma
Dara-based treatment was associated with a clinically and statisti­
cally significant improvement in sCR rate compared with standard
treatment (Odds ratio 1.59, 95 % CI 1.24–2.05, P value = 0.0003,
Fig. 2). There was no statistically significant heterogeneity in the odd
ratios for SCR from individual trials (chi square P value = 0.96, I2 = 0%).
The GRADE score was judged to be of high certainty (Supplementary
Table 2).
3.4. Subgroup analyses on Stringent Complete Response for trials on
transplant eligible multiple myeloma
Patients with standard risk cytogenetic profiles treated with Dara-
based regimen demonstrated a statistically significant effect on sCR
compared to HiR MM. The pooled odds ratio was 1.86, 95 % CI
(1.41–2.46) for patients with the standard risk cytogenetic profile and
was 0.78, 95 % CI (0.41–1.48) for patients with HiR MM. The test for
subgroup differences showed a P value of 0.01 (Fig. 3). The effects on
sCR were similar between subgroups defined by gender, ISS disease
stage, heavy chain isotype and ECOG performance status (Supplemen­
tary Table 3).
3.5. Other efficacy outcomes for trials on transplant eligible multiple
myeloma
Dara-based induction was associated with a clinically substantial and
statistically significant improvement in PFS compared to standard
treatment (Hazard Ratio 0.47, 95 % CI 0.33–0.66, Fig. 4). The gain in
RMST for PFS was observed at the 24-month time point (2.39 months, 95
L.L. Chong et al. Critical Reviews in Oncology / Hematology 159 (2021) 103211

Table 1 1.74, 95 % CI 1.38–2.20), minimal residual disease (MRD) negative

Patient demographics and baseline disease characteristics among the patients regardless of response (odds ratio 2.83, 95 %CI 1.64–4.90) and MRD
included in the clinical trials (N = 2735). NDMM, newly diagnosed multiple negative with CR or better (odds ratio 2.66, 95 % CI 1.42–5.01)
myeloma. compared to standard treatment. There was no significant difference
Transplant Eligible NDMM Transplant Ineligible NDMM between Dara-based and standard treatment regimens for outcomes
Daratumumab- Standard Daratumumab- Standard including overall response, CR, VGPR or better, VGPR and PR. (Sup­
Characteristics
based Induction Induction based Induction Induction plementary Table 4).
(n = 647) (n = 645) (n = 718) (n = 725)

Age, years
Median, range 59 (22–70) 60 (26–70) 72 (40–93) 73 3.6. Adverse events for trials on transplant eligible multiple myeloma
(45–91)
Dara-based treatment was associated with increased odds of adverse
Gender events in terms of neutropenia (any grade) (odds ratio 2.17, 95 % CI
Male 374 (57.8 %) 379 (58.8 349 (48.6 %) 362 (49.9
%) %)
1.67–2.81), neutropenia (G3 or 4) (odds ratio 2.28, 95 % CI 1.74–3.00)
Female 273 (42.2 %) 266 (41.2 369 (51.4 %) 363 (50.1 and lymphopenia (any grade) (odds ratio 1.48, 95 % CI 1.10–1.98)
%) %) compared with standard treatment. There was no difference between the
two arms in terms of lymphopenia (G3 or 4), peripheral neuropathy (any
Performance score grades), peripheral neuropathy (G3 or 4), constipation (any grades),
Total 644 644 718 725
constipation (G3 or 4), nausea (any grades), nausea (G3 or 4), pyrexia
0 304 (47.0 %) 297 (46.0 205 (28.6 %) 222 (30.6
%) %) (any grades), pyrexia (G3 or 4), peripheral oedema (any grades) and
1 276 (42.7 %) 282 (43.7 360 (50.1 %) 360 (49.7 peripheral oedema (G3 or 4). These data are summarised in Supple­
%) %) mentary Table 5.
2 64 (9.9 %) 65 (10.0 153 (21.3 %) 143 (19.7
%) %)

3.7. Progression-free survival for trials on non-transplant eligible multiple

Type of measurable disease
IgG 386 (59.7 %) 366 (56.7 368 (51.3 %) 371 (51.2 myeloma
%) %)
Non-IgG 261 (40.3 %) 279 (43.3 350 (48.7 %) 354 (48.8 Dara-based treatment was associated with a clinically substantial
%) %) and statistically significant improvement in PFS compared with stan­
dard treatment (Hazard Ratio 0.48, 95 % CI 0.36 – 0.63, P value <
ISS disease stage
Total 646 643 718 725
0.0001) (Fig. 4). There was moderate level of heterogeneity among the
I 253 (39.1 %) 278 (43.1 167 (23.2 %) 170 (23.4 results with chi-square P value of 0.09 and I2 statistic of 65 %. The
%) %) GRADE score was judged to be high certainty (Supplementary Table 1).
II 295 (45.6 %) 270 (41.9 302 (42.1 %) 316 (43.6 The gain in RMST in PFS was observed at the 12-month (0.49 months, 95
%) %)
% CI 0.04–0.94 months), 24-month (2.30 month, 95 % CI 1.09–3.51
III 98 (15.1 %) 95 (14.7 249 (34.7 %) 239 (33.0
%) %) months) and 36-month (5.16 months, 95 % CI 2.39–7.93 months) time
points but not at the 6-month time point (Supplementary Fig. 2).
Cytogenetics classification
High risk 98 (15.1 %) 100 (15.5 101 (14.1 %) 89 (12.3
%) %) 3.8. Subgroup analyses on progression-free survival for trials on non-
Standard risk 542 (83.8 %) 537 (83.2 532 (74.1 %) 536 (73.9
transplant eligible multiple myeloma
%) %)
Not done 7 (1.1 %) 8 (1.2 %) 85 (11.8 %) 100 (13.8
%) The effect on PFS was statistically significantly greater in the patients
with standard risk cytogenetic profile compared with HiR MM. The
Median time since initial diagnosis of myeloma pooled hazard ratio was 0.44, 95 % CI (0.35–0.55) for patients with the
Month, range 0.81 (0.0–12.0) 0.91 0.88 (0.1–13.3) 0.85
standard risk cytogenetic profile and was 0.81, 95 % CI (0.52–1.27) for
(0.0–61.0) (0.0–25.3)
HiR MM patients. The test of subgroup differences showed a P value of
0.02 (Fig. 5). However, these studies were not powered to detect dif­
% CI 0.97–3.81 months), but not at the 6- and 12-month time points ferences in efficacy for HiR MM. The effects on PFS were similar between
(Supplementary Fig. 1). Dara-based treatment was also associated with subgroups defined by gender, age, race, baseline creatinine clearance,
improvement of other efficacy outcomes for CR or better (odds ratio hepatic function, ISS disease stage and heavy chain isotype (Supple­
mentary Table 6).

Fig. 2. Odds ratios (ORs) for stringent complete response (sCR) in transplant eligible newly diagnosed MM (NDMM). The ORs for each trial are represented by the
squares, with the size of each square corresponding to the size of the individual study. The confidence interval (CI) is a function of the overall sample size. The
diamonds represent the estimated overall effect, based on the meta-analysis fixed-effect method. All statistical tests were 2-sided.

4
L.L. Chong et al. Critical Reviews in Oncology / Hematology 159 (2021) 103211

Fig. 3. Odds ratios (ORs) for stringent complete response (sCR) in transplant eligible newly diagnosed (NDMM), by cytogenetic subgroup.

Fig. 4. Progression-free survival (PFS) analysis (intent-to-treat population) in both transplant eligible and ineligible newly diagnosed MM (NDMM). (a) Hazard ratios
(HRs) for PFS by individual study. (b) Pooled Kaplan-Meier estimates of PFS combining the data from CASSIOPEIA and GRIFFIN trials for TEMM and ALCYONE and
MAIA trials for NTEMM.

3.9. Other efficacy outcomes for trials on non-transplant eligible multiple
myeloma
Dara-based treatment was associated with a clinically substantial
and statistically significant improvement in OS compared with standard
treatment (Hazard Ratio 0.67, 95 % CI 0.52–0.86, Supplementary
Fig. 3). The gain in RMST for OS was observed at 36 months (1.04
months, 95 % CI 0.06–2.03 months) but not at the 6-, 12- and 24-month
time points (Supplementary Fig. 4). Dara-based treatment was associ­
ated with improvement in other efficacy outcomes for overall response
(odds ratio 3.28, 95 % CI 2.38–4.53). CR or better (odds ratio 2.51, 95 %
CI 2.00–3.14), sCR (odds ratio 3.01, 95 % CI 2.23–4.06), VGPR or better

5
L.L. Chong et al.
Fig. 5. Hazard ratios (HRs) for progression free survival (PFS) in transplant ineligible newly diagnosed myeloma (NDMM), by cytogenetic subgroup.
(odds ratio 2.90, 95 % CI 2.14–3.92). Patients treated with Dara-based
regimens had lower odds of having stable disease (odds ratio 0.20, 95
% CI 0.13− 0.30) compared to standard treatment. There was no dif­
ference between the two arms in terms of VGPR rates or progressive
disease (Supplementary Table 4).
3.10. Adverse events for trials on transplant ineligible multiple myeloma
Dara-based treatment was associated with increased odds of adverse
events in terms of infections (any grade) (odds ratio 2.21, 95 % CI
1.74–2.81), infections (G3 or 4) (odds ratio 1.64, 95 % CI 1.27–2.10),
pneumonia (any grade) (odds ratio 2.59, 95 % CI 1.48–4.53) and
pneumonia (G3 or 4) (odds ratio 2.29, 95 % CI 1.39–3.77). There was no
difference in terms of neutropenia (any grade), neutropenia (G3 or 4),
anaemia (any grade), diarrhoea (any grade), diarrhoea (G3 or 4), nausea
(any grade), nausea (G3 or 4) and G5 toxicities. These data are sum­
marised in Supplementary Table 7.
4. Discussion
Our meta-analysis demonstrates that Dara-based induction is asso­
ciated with significant improvement in the primary outcomes of sCR rate
for TEMM and PFS for NTEMM compared with standard regimens.
Although Dara-based induction led to marked improvements for pa­
tients with standard risk cytogenetics, there was no clear benefit in terms
of sCR or PFS for patients with HiR MM. The key strengths of our study
include the use of the most up to date published data as well as validated
tools to evaluate the quality of the individual studies and summarized
evidence on this topic. Importantly, our meta-analysis has more statis­
tical power than individual trials for examining the impact of cytoge­
netic profiles as an effect modifier for analysis of the primary outcomes.
In a systematic review and network meta-analysis (NMA) comparing
a variety of induction regimens to RD as a reference, D-RD and D-VMP
emerged as the most potent combinations for NTEMM (Cao et al., 2019).
Sekine and colleagues also demonstrated in a NMA that D-VMP is su­
perior to standard PI and IMID based triplet induction regimens in terms
of PFS for NTEMM (Sekine et al., 2019). A NMA comparing induction
regimens reported in six clinical trials of NTEMM similarly demon­
strated that Dara-based regimens were superior to standard treatment
(Xu et al., 2019). Interestingly, this analysis suggested that DRD may be
superior to DVMP. Gil-Sierra and colleagues performed a similar NMA
on NTEMM which also demonstrated a benefit for Dara-based induction
compared to conventional regimens (Gil-Sierra et al., 2020). This study
suggested that VRD may be equivalent to DRD in terms of efficacy. Given
that the GRIFFIN trial showed superiority of D-VRD over VRD, this
suggests that the incorporation of a PI contributes significantly to the
efficacy of induction therapy in NTEMM (Voorhees et al., 2020b). The
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Critical Reviews in Oncology / Hematology 159 (2021) 103211
results of these NMAs are largely consistent with our findings showing
that Dara-based regimens are beneficial for NDMM patients on the
whole. The impact of Dara-based induction by cytogenetic subgroups
was not however evaluated in any of these studies.
It is noteworthy that the benefit of Dara-based induction in our study
did not differ when patients were sub grouped by gender, age, ISS stage
and heavy chain isotype. This highlights the importance of high risk
cytogenetics as a predictor of treatment response in MM. It is note­
worthy that rates of MRD negativity were lower in HiR patients. Given
the correlation of MRD negativity with long term outcomes in MM, this
is likely to be a key factor explaining the discrepancy in outcomes (Paiva
et al., 2020).
Our study has several limitations. Firstly, we did not have individual
patient data of each trial, thus we were unable to identify which patients
with HiR MM will benefit from Dara-based induction or determine the
impact of cytogenetic profiles on the secondary efficacy outcomes.
Secondly, as these RCTs excluded patients with ECOG performance
status greater than 2 and multiple co-morbidities, these results should
not be extrapolated to this frail group of patients who are commonly
seen in real world practice. The relatively short median follow up time is
also an important limitation of our analysis and longer term results of
these trials would be of significant importance.
It is also noteworthy that the maintenance randomisations of the
CASSIOPEIA and GRIFFIN studies were different (Moreau et al., 2019;
Voorhees et al., 2020a). Specifically, CASSIOPEIA randomised patients
between Dara maintenance and observation, while GRIFFIN compared
Dara-lenalidomide maintenance with single agent lenalidomide main­
tenance. The different maintenance randomisation means the mainte­
nance arms of these trials and the magnitude of PFS benefit may not be
directly comparable. The primary end point of both these studies was
however SCR rate which was assessed before maintenance and therefore
remains a valid point of comparison.
In conclusion, we propose that although Dara-based induction is
clearly beneficial in standard risk patients, there is currently insufficient
data to demonstrate a benefit in HiR MM. Given that some HiR patients
do benefit from Dara-based induction, clinical trials focusing on this
subgroup are required to determine which HiR patients may benefit
from Dara-based induction and the basis for this response. A better
understanding of the biology of HiR MM is required to design more
potent targeted therapeutics to address this unmet clinical need.
Funding sources
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
L.L. Chong et al.
Ethical approval and consent to participate
None required.
Consent to publication
All authors have provided consent for publication.
CRediT authorship contribution statement
Lip Leong Chong: Conceptualization, Data curation, Formal anal­
ysis, Methodology, Writing - original draft, Writing - review & editing.
Yu Yang Soon: Conceptualization, Data curation, Formal analysis,
Methodology, Writing - original draft, Writing - review & editing. Cin­
nie Yentia Soekojo: Writing - review & editing. Melissa Ooi: Writing -
review & editing, Supervision. Wee Joo Chng: Writing - review &
editing, Supervision. Sanjay de Mel: Conceptualization, Data curation,
Formal analysis, Methodology, Writing - original draft, Writing - review
& editing, Supervision.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
None.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.critrevonc.2020.10
3211.
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Lip Leong Chong: Senior resident in haematology at the national university cancer
institute Singapore.
Yu Yang Soon: Consultant radiation oncologist at the national university cancer institute
Singapore.
Cinnie Yentia Soekojo: Associate consultant haematologist at the national university
cancer institute Singapore.
Melissa Ooi: Consultant haematologist at the national university cancer institute
Singapore.
Wee Joo Chng: Senior Consultant haematologist at the national university cancer institute
Singapore.
Sanjay de Mel: Consultant haematologist at the national university cancer institute
Singapore