Annals of Hematology

https://doi.org/10.1007/s00277-021-04404-3

ORIGINAL ARTICLE

Treatment of relapsed/refractory multiple myeloma

in the bortezomib and lenalidomide era: a systematic review
and network meta-analysis
Leonardo Javier Arcuri 1 & Andre Dias Americo 2

Received: 5 March 2020 / Accepted: 3 January 2021

# The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021

Abstract
Multiple myeloma (MM) is an incurable disease, and patients usually receive multiple lines of therapy. Due to the abundance of novel
treatments for MM, we conducted a network meta-analysis to identify combinations that could fare better than others in relapsed/
refractory MM, in the setting of novel drugs. We searched PubMed and Cochrane databases for phase III trials in previously treated
MM that had lenalidomide or bortezomib in the control arm. The primary endpoint was progression-free survival (PFS), extracted as
hazard-ratio. We used the P score to rank treatments. Thirteen studies were included. All but two studies compared one novel agent
against two, with or without dexamethasone. Based on the P score, daratumumab and pegylated liposomal doxorubicin had a higher
probability of achieving better PFS, followed by isatuximab, carfilzomib, pomalidomide, and panobinostat. Although most overall
survival data were not mature enough, the addition of a second or third novel agent to either immunomodulatory (IMID) or proteasome
inhibitor (PI) backbone seemed to improve survival (HR = 0.84, 95CI 0.77–0.92). Severe adverse events were more frequent with
isatuximab, panobinostat, and pomalidomide. In summary, in the absence of trials directly comparing two novel agents-based therapies,
we provide a tool that indirectly compares these newer therapies and that can help physicians to prioritize some regimens over others.

Keywords Relapsed/refractory multiple myeloma . Network meta-analysis . Novel agents

Introduction “category 1,” which means that these recommendations are

Multiple myeloma (MM) is an incurable disease. Newly diag-
nosed patients are usually classified into transplant eligible or
transplant-ineligible, and it is expected that almost all patients
will need additional courses of therapy due to poor disease
control or relapse [1]. A large number of novel agents became
available over the last 15 years: bortezomib, carfilzomib,
ixazomib, lenalidomide, pomalidomide, daratumumab,
elotuzumab, and panobinostat, just to cite a few [2].
The National Comprehensive Cancer Network guideline for
MM, version 1.2020, recommends a triplet regimen for previous-
ly treated MM. Currently, there are 9 triplet regimens labeled as
“based upon high-level evidence, (and) there is uniform NCCN
consensus that the intervention is appropriate.” There are no direct
comparisons between these 9 triplet regimens, and treatment se-
lection for relapsed MM is based on drug availability, prior drug
exposure, adverse events profile, and physician’s familiarity.
Due to the abundance of new treatment options for MM
and the fact that direct comparisons are unlikely (at least in the
short term), we conducted a network meta-analysis to review
the available evidence of novel treatments for relapsed/
refractory MM, in the setting of new drugs, and to identify
combinations that could fare better than others. This indirect
comparison might assist physicians when it comes to select
the best treatment in the relapsed/refractory setting.

* Leonardo Javier Arcuri

leonardojavier@gmail.com
Methods
Andre Dias Americo
andrediasamerico@hotmail.com We followed the PRISMA Statement for this systematic review
and meta-analysis. We searched PubMed and Cochrane data-
1
Hospital Isrealita Albert Einstein, Sao Paulo, Brazil bases. This meta-analysis was registered at PROSPERO,
2
A Beneficiencia Portuguesa, Sao Paulo, Brazil #CRD42020153121. The research question was which

treatments yield the highest progression-free survival for
relapsed/refractory multiple myeloma, compared with other nov-
el treatment-based (lenalidomide or bortezomib) therapies?
The search strategy was the following: (refractory OR re-
lapsed OR refractory/relapsed) “multiple myeloma”
(lenalidomide OR bortezomib) ((“phase III”) OR (“phase 3”)
OR randomized OR randomized), limited to Title/Abstract,
and from 1st Jan 2007 to 21st Dec 2020.
We only included phase III randomized controlled trials of
previously treated multiple myeloma with a control arm that
included either lenalidomide or bortezomib. Both are consid-
ered equivalent therapies [3]. After discussion, two studies
Fig. 1 PRISMA diagram
Ann Hematol
with pomalidomide and one with carfilzomib in the control
arm were also included. We excluded sub-studies or study
updates already that have been already included and studies
in smoldering myeloma.
Hazard ratios (HR) for progression-free (PFS, primary end-
point) and overall survival (OS, secondary endpoint) were ex-
tracted and log-converted for the analyses. Standard errors (SE)
of the logHR were estimated by the P value or by the log-
converted confidence interval. If HR was not extractable, we
extracted the relative risk (RR) and its SE based on the number
of events [4] or using methods described by Tierney et al. [5].
The number of serious adverse events (SAE) was extracted and
Table 1 Characteristics of the included studies
Ann Hematol

Nome Author Intervention Control Ni Nc Median follow-up PFSi PFSc Age Previous
(months) (months) (months) range therapy

VANTAGE 088 Dimopoulos, 2013 Bortezomib and vorinostat Bortezomib 317 320 14,2 7,63 6,83 29-86 1-3
POLLUX Dimopoulos, 2016a Daratumumab, lenalidomide, and Lenalidomide and dexamethasone 286 283 13,5 NR 18,4 34-89 1+
dexamethasone
ENDEAVOR Dimopoulos, 2016b Carfilzomib and dexamethasone Bortezomib and dexamethasone 464 465 11,9 18,7 9,4 NA 1+
TOURMALINE-MM1-China How, 2017 Ixazomib, lenalidomide, and Lenalidomide and dexamethasone 57 58 20,5 6,7 4 NA 1-3
dexamethasone
NCT00813150 Kropf, 2017 Cyclophosphamide, bortezomib, Bortezomib and dexamethasone 46 47 24 12,6 9,9 NA 1+
and dexamethasone
ELOQUENT-2 Lonial, 2015 Elotuzumab, lenalidomide, and Lenalidomide and dexamethasone 321 325 24,5 19,4 14,9 37-91 1-3
dexamethasone
KEYNOTE-183 Mateos, 2019 Pembrolizumab, pomalidomide, and Pomalidomide and dexamethasone 125 124 8,1 5,6 8,4 NA 2+
dexamethasone
TOURMALINE-MM1 Moreau, 2016 Ixazomib, lenalidomide, and Lenalidomide and dexamethasone 360 362 14,7 20,6 14,7 30-91 1-3
dexamethasone
DOXIL-MMY-3001 Orlowski, 2007 Pegylated liposomal doxorubicin Bortezomib 324 322 7,2 9 6,5 NA 1+
and bortezomib
CASTOR Palumbo, 2016 Daratumumab, bortezomib, and Bortezomib and dexamethasone 251 247 7,4 NR 7,2 30-88 1+
dexamethasone
OPTIMISMM Richardson, 2019 Pomalidomide, bortezomib, and Bortezomib and dexamethasone 281 278 15,9 11,2 7,1 NA 1-3
dexamethasone
PANORAMA1 San Miguel, 2014 Panobinostat, bortezomib, and Bortezomib and dexamethasone 387 381 6 11,99 8,08 NA 1-3
dexamethasone
ASPIRE Stewart, 2015 Carfilzomib, lenalidomide, and Lenalidomide and dexamethasone 396 396 31,9 26,3 17,6 1-3
dexamethasone
BELLINI Kumar, 2020 Venetoclax, bortezomib, and Bortezomib and dexamethasone 194 97 18.7 22.4 11.5 NA 1-3
dexamethasone
GMMG ReLApsE Goldschmidt, 2020 ASCT, lenalidomide, and Lenalidomide and dexamethasone 139 138 36.8 20.7 18.8 NA 1-3
dexamethasone
BOSTON Grosicki, 2020 Selinexor, bortezomib, and Bortezomib and dexamethasone 195 207 14.9 13.93 9.46 NA 1-3
dexamethasone
CANDOR Dimopoulos, 2020 Daratumumab, carfilzomib, Carfilzomib and dexamethasone 312 154 17 NR 15.8 NA 1-3
and dexamethasone
ICARIA-MM Attal, 2020 Isatuximab, pomalidomide, Pomalidomide and dexamethasone 154 153 11.6 11.5 6.5 NA 1-3
and dexamethasone

*
At least 12 months after the first high-dose chemotherapy; Ni and Nc: number of patients in investigational and control arms; PFSi and PFSc: median progression-free survival in investigational and
controls arms; NA: not available; NR: not reached

Fig. 2 Graph of the evidence network
analyzed as a binomial outcome. If SAE was not available, we
extracted grades III-IV adverse events (AE), which happened in
one study.
Screening, full-text review, and data extraction were inde-
pendently carried out by two reviewers (L.JA. and A.D.A).
Discrepancies between the two were settled by discussion.
A network meta-analysis with fixed effect, or random effects
if I2 was higher than 40%, was carried out and presented as table
and forest plots. We grouped the control arms into a single con-
trol group based on a phase III study [6] that concluded that the
lenalidomide and dexamethasone combination is equivalent to
bortezomib and dexamethasone for relapsed MM. The risk of
bias assessment was based on the Cochrane Handbook of
Systematic Reviews of Interventions. Treatments were ranked
according to P score [7]. Heterogeneity was measured by the I
square.
This systematic review received no funding.
Results
A total of 735 abstracts were screened, and 32 articles were
selected for full-text review (Fig. 1). Of these, 17 were
Fig. 3 Network meta-analysis
forest plot for PFS
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excluded for not having a control arm treated with
lenalidomide or bortezomib (4), being studies in newly diag-
nosed patients (7), sub-analyses or updates of other included
studies (4), phase II trial (1), or in smoldering multiple mye-
loma (1). We also added three studies found in the NCCN
guidelines. Therefore, we included 18 studies [8–25] in the
qualitative and quantitative analyses (Fig. 1).
Study profiles are detailed in Table 1. In brief, all but three
had lenalidomide (6) or bortezomib (8) in the control arm with
or without dexamethasone; one had carfilzomib and two had
pomalidomide in the control arm. Intervention arms included
vorinostat (1), panobinostat (1), pomalidomide (1), pegylated
doxorubicin (1), cyclophosphamide (1), elotuzumab (1),
pembrolizumab (1), autologous stem cell transplantation
(ASCT, 1), venetoclax (1), carfilzomib (2), ixazomib (2),
daratumumab (3), isatuximab (1), and selinexor (1).
Intervention arms were combinations of three drugs except
for two, which were a combination of carfilzomib and dexa-
methasone, and bortezomib and vorinostat without dexameth-
asone. In total, 4609 patients were included in the intervention
arms, and 4357 in the control arms. The graph of the evidence
network is depicted in Fig. 2.
Forest plots for PFS show most investigational therapies are
better than the control ones (Fig. 3) and suggest that triplet reg-
imens containing daratumumab achieve better progression-free
survival. Pembrolizumab was an outlier, and PFS was actually
worse with pembrolizumab. Table 2 shows the hazard ratios for
all comparisons. Based on the P score, therapies that have a
higher probability of being better are, in descending order,
daratumumab and pegylated liposomal doxorubicin, followed
by isatuximab, carfilzomib, pomalidomide, and panobinostat.
Worst therapies include pembrolizumab, vorinostat, and high-
dose chemotherapy (Table 3).
The combined result for OS shows that more potent thera-
pies lead to better survival (HR = 0.83; 95CI 0.76–0.90; Fig.
 Ann Hematol

Table 2 Hazard ratios for PFS

Carfilzomib . . . . . . . . . . . . . .

0.61 [0.45; Control . . . . . . . . . . . . .

0.81]
0.85 [0.43; 1.41 [0.76; Cy . . . . . . . . . . . .
1.69] 2.63]
1.34 [0.90; 2.21 [1.68; 1.57 [0.79; Dara . . . . . . . . . . .
2.00] 2.92] 3.11]
0.86 [0.52; 1.43 [0.95; 1.01 [0.48; 0.65 [0.39; Elotuzumab . . . . . . . . . .
1.43] 2.16] 2.14] 1.06]
0.70 [0.40; 1.15 [0.72; 0.82 [0.38; 0.52 [0.30; 0.80 [0.43; High-dose . . . . . . . . .
1.20] 1.82] 1.77] 0.89] 1.49] chemo
1.02 [0.58; 1.68 [1.04; 1.19 [0.54; 0.76 [0.44; 1.17 [0.63; 1.46 [0.75; Isatuximab . . . . . . . .
1.77] 2.70] 2.61] 1.32] 2.20] 2.83]
0.88 [0.56; 1.45 [1.02; 1.03 [0.50; 0.66 [0.42; 1.02 [0.59; 1.26 [0.71; 0.86 [0.48; Ixazomib . . . . . . .
1.38] 2.06] 2.11] 1.02] 1.74] 2.25] 1.56]
0.96 [0.58; 1.59 [1.06; 1.13 [0.54; 0.72 [0.44; 1.11 [0.62; 1.38 [0.75; 0.95 [0.51; 1.09 [0.64; Pano . . . . . .
1.58] 2.38] 2.37] 1.17] 1.98] 2.56] 1.77] 1.87]
1.10 [0.65; 1.82 [1.17; 1.29 [0.60; 0.82 [0.49; 1.27 [0.70; 1.58 [0.84; 1.08 [0.57; 1.25 [0.71; 1.15 [0.63; Pegylated . . . . .
1.87] 2.83] 2.77] 1.39] 2.33] 3.00] 2.08] 2.20] 2.09] liposomal
doxorubicin
0.40 [0.22; 0.65 [0.39; 0.46 [0.21; 0.30 [0.16; 0.46 [0.24; 0.57 [0.28; 0.39 [0.19; 0.45 [0.24; 0.41 [0.21; 0.36 [0.18; Pembro . . . .
0.72] 1.10] 1.04] 0.53] 0.89] 1.14] 0.79] 0.84] 0.80] 0.71]
0.99 [0.59; 1.64 [1.07; 1.16 [0.55; 0.74 [0.45; 1.15 [0.64; 1.43 [0.76; 0.98 [0.52; 1.13 [0.65; 1.03 [0.57; 0.90 [0.49; 2.51 [1.28; Poma . . .
1.66] 2.51] 2.48] 1.23] 2.07] 2.67] 1.85] 1.96] 1.86] 1.66] 4.91]
0.86 [0.50; 1.43 [0.90; 1.01 [0.47; 0.65 [0.38; 1.00 [0.54; 1.24 [0.65; 0.85 [0.44; 0.98 [0.55; 0.90 [0.49; 0.78 2.19 0.87 Selinexor . .
1.48] 2.26] 2.20] 1.10] 1.85] 2.38] 1.65] 1.75] 1.66] [0.42;1.48] [1.09;4.3- [0.47;1.6-
6] 3]
0.96 [0.54; 1.59 [0.96; 1.13 [0.51; 0.72 [0.40; 1.11 [0.58; 1.38 [0.70; 0.95 [0.47; 1.09 [0.59; 1.00 [0.52; 0.87 [0.45; 2.43 [1.18; 0.97 [0.50; 1.11 [0.56; Venetoclax .
1.72] 2.63] 2.51] 1.28] 2.13] 2.74] 1.89] 2.02] 1.91] 1.70] 5.01] 1.87] 2.19]
0.79 [0.48; 1.30 [0.86; 0.92 [0.44; 0.59 [0.36; 0.91 [0.51; 1.13 [0.61; 0.77 [0.41; 0.90 [0.52; 0.82 [0.46; 0.71 [0.39; 1.99 [1.03; 0.79 [0.44; 0.91 [0.49; 0.82 [0.43; Vorinostat
1.30] 1.95] 1.94] 0.96] 1.62] 2.09] 1.45] 1.53] 1.46] 1.30] 3.85] 1.43] 1.68] 1.56]

Comparisons are columns against rows. For example, HR of carfilomib, compared with control, is 0.61 (first column, second row). Cy: cyclophosphamide; Dara: daratumumab; Panobino: panobinostat;
Poma: pomalidomide; HDT: high-dose therapy (aulologous stem-cell transplantation); Pembro: pembrolizumab; Poma: pomalidomide. In bold are statistically significant results
 Ann Hematol

Table 3 Ranking of
investigational agents Treatment P score for PFS P score for OS P score for SAE

Daratumumab 0.924 #1 0.769 #2 0.377 #8

Pegylated liposomal doxorubicin 0.735 #2 0.766 #3 0.552 #7
Isatuximab 0.651 #3 0.787 #1 0.044 #14
Carfilzomib 0.648 #4 0.639 #4 0.377 #8
Pomalidomide 0.631 #5 0.310 #12 0.198 #12
Panobinostat 0.597 #6 0.476 #11 0.134 #13
Venetoclax 0.593 #7 0.019 #15 0.821 #2
Ixazomib 0.495 #8 0.549 #7 0.819 #3
Selinexor 0.483 #9 0.534 #8 NA
Elotuzumab 0.481 #10 0.595 #5 0.412 #10
Cyclophosphamide 0.476 #11 0.522 #9 0.743 #5
Vorinostat 0.380 #12 0.501 #10 0.832 #1
High-dose chemotherapy 0.273 #13 0.580 #6 0.688 #6
Control 0.120 #14 0.235 #13 0.762 #4
Pembrolizumab 0.015 #15 0.218 #14 0.240 #11

The P score of treatment should be interpreted as the certainty that one treatment is better than another one. It
ranges from 0 (worst) to 1 (best). PFS: progression-free survival; OS: overall survival; SAE: serious adverse
event; NA: not available

4). The interventions that have a higher probability of achiev-
ing better overall survival than others are, also in descending
order, isatuximab, daratumumab, and pegylated liposomal
doxorubicin, followed by carfilzomib, elotuzumab, and
high-dose chemotherapy.
Seventeen studies reported data on SAE and one only one,
grade III-IV AE. The most toxic treatments were isatuximab,
panobinostat, and pomalidomide. Other regimens most com-
monly associated with SAE were pembrolizumab,
daratumumab, elotuzumab, and carfilzomib. All other regi-
mens had an incidence of SAE comparable to placebo/obser-
vation, especially cyclophosphamide, vorinostat, ixazomib,
and venetoclax (Table 3 and Fig. 5).
Heterogeneity, measured by the I2, was 64% for PFS, 0%
for OS, and 0% for SAE.
Sensitivity analysis
We performed a sensitivity analysis categorizing the control
arms by immunomodulatory agent-based (IMiD/
lenalidomide or pomalidomide) or proteasome-inhibitor-
based (bortezomib or carfilzomib). Daratumumab remained
the best treatment regarding PFS, followed by pegylated lipo-
somal doxorubicin, carfilzomib, and isatuximab. For the over-
all survival, the best treatments, in order, were pegylated
doxorubicin, daratumumab, isatuximab, and carfilzomib.
The results are in the supplemental file. HR for bortezomib
in the control arms, compared with lenalidomide or
pomalidomide in the control arms, was 1.02 (95CI 0.62–
1.70) for PFS and 1.06 (95CI 0.76–1.47). There was no evi-
dence of inconsistency.
The risk of bias table can be found in the supplemental
material.
Discussion
Our results show that triplet regimens containing
daratumumab or pegylated liposomal doxorubicin could be
preferred over other regimens in relapsed/refractory MM.
Moreover, both have a favorable toxicity profile.
Most multiple myeloma patients receive up-front high dose
chemotherapy, and nearly all patients with multiple myeloma
will require additional therapy due to disease relapse or pro-
gression. In our analysis, two treatments appeared to fare bet-
ter at prolonging progression-free survival: daratumumab and
pegylated liposomal doxorubicin. Both daratumumab and
pegylated liposomal doxorubicin have a favorable toxicity
profile.
Although some authors claimed their survival data were
not mature enough, we were able to perform a standard
meta-analysis that showed that overall survival is improved
when a more potent regimen is administered. Therefore,
adding a third drug (except for pembrolizumab) or substituting
carfilzomib for bortezomib in relapsed/refractory MM patients
will likely improve not only disease control but also survival.
This is in accordance with the NCCN recommendation that
triplet drug therapy should be preferred in relapsed/refractory
multiple myeloma.
Ann Hematol
Fig. 4 Standard forest plot for OS
Two other network meta-analyses have been performed
recently in the relapsed/refractory setting [26, 27]. However,
both included control arms treated only with dexamethasone,
which is not considered an acceptable treatment nowadays.
Moreover, Luo et al. found that ixazomib is the most effective
treatment regarding overall survival. We came to a different
conclusion, and the reason for this discrepancy is unknown.
Botta et al. created treatment groups based on the classes of
drugs, while we built our groups based on the intervention
itself. It is now known that lenalidomide+dexamethasone
and bortezomib+dexamethasone are equally effective in
relapsed/refractory MM, and this allowed us to create a single
control group, making the path for indirect comparisons
shorter, which increases the power to detect differences.
Fig. 5 Network meta-analysis
forest plot for SAE
Our study has some limitations. We were not able to ac-
count for treatment duration in our analysis. It has been shown
that prolonged treatment may lead to increased PFS and
higher rates of near-complete and complete responses [28,
29]. However, only one study offered fixed duration therapy
for the control arm and continuous therapy with daratumumab
for the intervention arm. The result was comparable to the
other study with daratumumab that offered continuous therapy
for all patients, so it seems unlikely that this could have biased
our results. Likewise, we were not able to assess cross-
resistance or prior therapy exposure. It has been reported
cross-resistance for carfilzomib and bortezomib [30], and we
cannot rule out some degree of cross-resistance with ixazomib
[31]. As a matter of fact, almost 70% of the patients in the

ixazomib study had been previously exposed to bortezomib or
carfilzomib. The conclusion, however, would not be different:
ixazomib-based rescue might not be the best option in the
relapsed/refractory population. In the study that compared au-
tologous stem-cell transplantation with conventional therapy
for relapsed/refractory patients, only 29% of the patients ran-
domized to autologous transplantation received the treatment,
and the results were significantly better for those who actually
received transplantation. Indeed, if we included only the data
of patients who underwent transplantation, the P score (0.890)
would be the highest for transplantation (data not shown).
Finally, the study that tested venetoclax has shown paradoxi-
cal results: even though there was a significant benefit in PFS,
OS was in fact poorer. Unfortunately, despite promising re-
sults with anti-BCMA therapy, including CAR-T cells, ran-
domized controlled trials using this kind of medication have
not been published yet.
On the other hand, this study is the first network meta-
analysis that included only studies that had novel drug-based
treatment in the control arm, making it more representative of
the current management of relapsed/refractory multiple myelo-
ma. In addition, the way we grouped the control group in-
creased the effectiveness of the analyses. We performed a sen-
sitivity analysis categorizing the control arms into two groups:
immunomodulatory-based (lenalidomide and pomalidomide)
or bortezomib-based, and we were able to show that both treat-
ments are equivalent, supporting our decision to group these
categories into a single one. All NCCN category-1 triplet reg-
imens were included in our analysis, and it is unlikely that there
will be a direct head-to-head comparison between these triplet
novel treatments in the following years.
In conclusion, here, we have provided indirect evidence for
prioritizing some treatments that are more effective than
others in patients with relapsed/refractory multiple myeloma.
We hope this study will help centers to optimize treatment
selection decisions for this group of patients.
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s00277-021-04404-3.
Authors’ contributions L.J.A. was responsible for protocol writing. Both
L.J.A. and A.D.A. were responsible for data extraction, data analysis, and
manuscript writing.
Data availability This study did not produce any new data
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.
Ethics approval This meta-analysis does not require the approval of the
ethics committee
Code availability Upon request, we will provide the R code used
Ann Hematol
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