Giri 2020

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Research

JAMA Oncology | Original Investigation

Evaluation of Daratumumab for the Treatment of Multiple Myeloma


in Patients With High-risk Cytogenetic Factors
A Systematic Review and Meta-analysis
Smith Giri, MD, MHS; Alyssa Grimshaw, MSLIS; Susan Bal, MD; Kelly Godby, MD; Prakash Kharel, MD; Benjamin Djulbegovic, MD, PhD;
Meletios A. Dimopoulos, MD; Thierry Facon, MD; Saad Z. Usmani, MD; María-Victoria Mateos, MD, PhD; Luciano J. Costa, MD, PhD

Supplemental content
IMPORTANCE The addition of daratumumab to backbone multiple myeloma (MM) regimens
is associated with improved response rates and progression-free survival (PFS). Whether
improved outcomes are also associated with this regimen among patients with
cytogenetically defined high-risk MM (HRMM) remains unclear.

OBJECTIVE To measure PFS associated with adding daratumumab to backbone MM regimens


among patients with HRMM.

DATA SOURCES For this systematic review and meta-analysis, MEDLINE, Embase, PubMed,
Scopus, Web of Science Core Collection, Cochrane Library, clinical trials registries, and
meeting libraries were searched from inception to January 2, 2020, using terms reflecting
multiple myeloma and daratumumab.

STUDY SELECTION Included studies were phase 3 randomized clinical trials that compared
backbone MM regimens with the same regimen plus daratumumab in newly diagnosed or
relapsed or refractory MM, such that the only difference between the intervention and
control groups was use of daratumumab and reported outcomes by cytogenetic risk.
High-risk MM was defined as the presence of t(4;14), t(14;16), or del(17p).

DATA EXTRACTION AND SYNTHESIS Using the Preferred Reporting Items for Systematic
Reviews and Meta-analyses (PRISMA) reporting guideline, 2 investigators independently
extracted study data, with disagreements resolved by a third investigator. Quality was
assessed by the Cochrane risk-of-bias method.

MAIN OUTCOMES AND MEASURES Data on effectiveness were extracted using hazard ratios
(HRs) for PFS. Relative log-HRs were pooled using a DerSimonian-Laird random-effects
model. Heterogeneity was assessed using the Cochran Q and the I2 statistic.

RESULTS Of 5194 studies screened, 6 phase 3 trials were eligible, including 3 trials for newly
diagnosed MM (2528 patients; 358 with HRMM) and 3 trials for relapsed or refractory MM
(1533 patients; 222 with HRMM). Among patients with newly diagnosed HRMM, the addition
of daratumumab to backbone regimens was associated with improved PFS (pooled HR, 0.67;
95% CI, 0.47-0.95; P = .02), with little evidence of heterogeneity (Cochran Q, P = .77;
I2 = 0%). Similar results were seen among patients with relapsed or refractory HRMM
(pooled HR, 0.45; 95% CI, 0.30-0.67; P < .001), again with little evidence of heterogeneity
(Cochran Q, P = .63; I2 = 0%).

CONCLUSIONS AND RELEVANCE This study suggests that incorporating daratumumab to


backbone regimens may be associated with improved PFS among patients with newly
diagnosed HRMM or relapsed or refractory HRMM.

Author Affiliations: Author


affiliations are listed at the end of this
article.
Corresponding Author: Smith Giri,
MD, MHS, Institute for Cancer
Outcomes and Survivorship,
Division of Hematology and
Oncology, University of Alabama at
Birmingham, 1600 7th Ave South,
JAMA Oncol. doi:10.1001/jamaoncol.2020.4338 Lowder 500, Birmingham, AL 35294
Published online September 24, 2020. (smithgiri@uabmc.edu).

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Research Original Investigation Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors

M
ultiple myeloma (MM) has great variability in clini-
cal presentation and biological characteristics. Key Points
Several features are associated with worse out-
Question Is there a benefit associated with adding daratumumab
comes, including high β2-microglobulin levels,1 high lactate to backbone myeloma treatment regimens among patients with
dehydrogenase levels,2 gene expression profile,3 and recur- cytogenetically defined high-risk multiple myeloma (HRMM)?
rent cytogenetic abnormalities.4-6 For instance, the presence
Findings This systematic review and meta-analysis identified 6
of t(4;14), t(14;16), or del(17p) is uniformly accepted as a marker
clinical trials involving 4061 patients, of which 580 had HRMM.
of worse prognosis4-6 and is incorporated in the Revised In- The addition of daratumumab to backbone multiple myeloma
ternational Staging System for MM.2 regimens was associated with significantly improved
Although the biological heterogeneity of MM has long been progression-free survival among patients with newly diagnosed
recognized, clinical trials are rarely performed to study the ef- HRMM or relapsed or refractory HRMM.
fect of a new agent or intervention in patients with a specific Meaning The findings suggest that addition of daratumumab to
biological subset of MM. Instead, trials are designed with eli- established myeloma regimens may be associated with improved
gibility dictated by prior therapies for relapsed or refractory outcomes among patients with HRMM.
MM or, in the case of newly diagnosed MM, by age and suit-
ability for high-dose therapy and autologous hematopoietic cell
transplantation.7 with “daratumumab OR Darzalex OR HuMax CD38.” Our
Daratumumab is a human immunoglobulin Gκ monoclo- search result was limited to English-language studies. No fil-
nal antibody that targets CD38, which is present ubiquitously ters or hedges for publication type were used. The search
on the surface of MM cells and normal plasma cells. Daratu- strategy was peer reviewed by a second librarian using Peer
mumab has reasonable single-agent activity among patients Review for Electronic Search Strategies (PRESS).21 In addi-
with MM8 and has been combined successfully with several tion, we performed a search of the gray literature through
backbone MM regimens both in newly diagnosed9-13 and in re- manual hand search of (1) bibliographies of identified ran-
lapsed or refractory disease.14-18 However, a subset analysis of domized clinical trials, (2) trial registries (ClinicalTrials.gov,
patients with cytogenetically defined high-risk MM (HRMM) World Health Organization International Clinical Trials Reg-
did not show improvement of progression-free survival (PFS) istry Platform search portal, controlled-trials.com, and the
in 4 studies,11-13,16 whereas 2 studies18,19 showed improved PFS National Institutes of Health database of funded studies for
in this subgroup of patients. As a result, there is reasonable ongoing or unpublished trials), and (3) conference proceed-
concern that daratumumab may not improve outcomes among ings and abstracts of the American Society of Hematology,
patients with HRMM, particularly in the context of newly di- American Society of Clinical Oncology, European Hematol-
agnosed disease. ogy Association, and European Society for Medical Oncology
Given the additional toxic effects and costs associated with from 2016 to 2019. Details of the search strategy are pro-
daratumumab, we sought to clarify its role among patients with vided in the eMethods in the Supplement.
HRMM. We performed a systematic review and meta- Citations from all databases were imported into an End-
analysis of randomized clinical trials to evaluate the associa- Note X9 database (Clarivate Analytics). After removing dupli-
tion of daratumumab treatment with progression-free sur- cates in EndNote, the remaining set of articles was imported
vival among patients with newly diagnosed HRMM or relapsed into Covidence, a screening and data extraction tool.22 Two in-
or refractory HRMM. dependent screeners performed title and abstract review (S.G.
and P.K.), and a third screener (L.J.C.) resolved ties. Overall,
there was excellent agreement between the 2 screeners, with
a Cohen κ statistic of 0.85.
Methods
This systematic review and meta-analysis was performed in Selection Criteria
a c c o rd a n c e w it h a p r e v i o u s l y p u b l i s h e d p r o t o c o l After preliminary screening, the full text of potentially eli-
(CRD42020165055). This study followed the Preferred gible studies was reviewed independently by 2 of us (S.G. and
Reporting Items for Systematic Reviews and Meta-analyses P.K.) to confirm final eligibility for qualitative and quantita-
(PRISMA) reporting guideline.20 tive synthesis using the following selection criteria: (1) all phase
3 randomized clinical trials comparing the effectiveness of 2
Search Strategy and Selection Criteria or more systemic treatment regimens (comparator may in-
The search strategy was designed and conducted by a medi- clude placebo) for the treatment of patients with newly diag-
cal librarian (A.G.) with input from study investigators using nosed or relapsed or refractory MM; (2) phase 3 trials compar-
the following databases: Ovid MEDLINE, Ovid Embase, ing backbone MM regimens with the same regimen plus
PubMed, Scopus, Web of Science Core Collection, and the daratumumab, such that the comparative effectiveness be-
Cochrane Library from inception of each database to January tween the 2 groups was primarily caused by the addition of
2, 2020. We used a combination of controlled vocabulary daratumumab, and (3) phase 3 studies reporting comparative
(MeSH [Medical Subject Headings] and Emtree terms) and effectiveness data stratified by cytogenetic risk status in the
key words with various synonyms that reflect the following primary or subgroup analysis. Cytogenetically defined HRMM
concepts: “multiple myeloma OR plasmacytoma” combined was defined as the presence of t(4;14), t(14;16), or del(17p)

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Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors Original Investigation Research

irrespective of the method used in the study and the propor-


Figure 1. PRISMA Flow Diagram
tion of cells exhibiting the cytogenetic abnormality.
5193 Records identified through 1 Additional record identified through
Data Extraction database searching hand-searching conference abstracts
Data extracted included study characteristics (first author, year
of publication, journal, country of origin, study design, sample
size, treatment regimens, and duration of follow-up), base- 3057 Records after duplicates removed
line characteristics of the participants (age, sex, race/
ethnicity, and distribution by stage and performance status), 3057 Records screened

and outcome data (effectiveness data). Quality assessment was


done using the Cochran risk of bias assessment tool.23 2978 Records excluded

Definition of Outcomes 79 Full-text articles assessed for eligibility


The primary outcome was PFS, defined as the time from ran-
domization to the date of first confirmed progression or date 73 Full-text articles excluded
36 Duplicates
of death, whichever occurred earlier. We quantified associa- 12 Trial in progress
tions in terms of hazard ratios (HRs) and 95% CIs. If multiple 11 Wrong study design
5 Wrong outcomes
publications were available from the same study, the publi-
4 Wrong patient population
cation with the longest available follow-up results was used 3 Wrong setting
to extract the summary effect. 2 Wrong intervention

6 Studies included in qualitative synthesis


Statistical Analysis
We conducted statistical analyses according to the prepublished
protocol. After extracting the PFS HRs and 95% CI for each cy- 6 Studies included in quantitative synthesis
(meta-analysis)
togenetic subgroup (HRMM vs standard-risk MM [SRMM]), we
pooled relative log-HRs using a DerSimonian-Laird random-
effects model. We chose to pool effect size using a random effects
model a priori because we anticipated that eligible studies would tative and quantitative analysis (Figure 1 and eTable 2 in the
involve varying backbone regimens. We conducted separate Supplement). This included 3 trials of patients with newly di-
analyses for cytogenetic SRMM vs HRMM and for newly diag- agnosed MM (ALCYONE,11 MAIA,10 and CASSIOPEIA12) (2528
nosed and relapsed or refractory disease. Given the small num- patients; 358 with HRMM) and 3 trials of patients with re-
ber of studies included in this analysis and concerns for impre- lapsed or refractory MM (CASTOR,14 POLLUX,15 and CANDOR16)
cision or biased estimates using the DerSimonian-Laird (1533 patients; 222 with HRMM). The proportion of patients
estimator,24,25 we conducted a sensitivity analysis using alter- with HRMM in these trials ranged from 15% to 33%. The over-
native approaches to random-effects modeling including the all summary characteristics of these 6 studies are shown in
Knapp-Hartung method and small sample profile likelihood eTable 1 in the Supplement.
estimator, as suggested by Cornell et al,24 and a robust inverse
variance heterogeneity model, as suggested by Doi et al.25 Definitions of High-risk MM
We assessed study-level heterogeneity using the Cochran Q The methods for the assessment of HRMM varied across the
and the I2 statistic and planned to explore evidence of any sub- included trials. The CASSIOPEIA trial12 defined HRMM as either
stantial heterogeneity with appropriate sensitivity and subgroup the presence of del(17p) (≥50% abnormal cells) or t(4;14) (≥30%
analyses. We evaluated for the presence of publication bias using abnormal cells) using fluorescence in situ hybridization (FISH),
funnel plots and the Egger regression intercept. Statistical analy- which was confirmed by centralized analysis. Patients for
ses were performed using the admetan package on Stata, version whom cytogenetic testing failed (ie, the test did not provide a
13.0 (StataCorp LLC) and Review Manager, version 5.3 result) were considered to have SRMM. The ALCYONE11 and
(The Nordic Cochrane Centre, The Cochrane Collaboration). MAIA10 studies similarly defined HRMM by the finding of t(4;
All P values were 2 sided, and results were deemed statistically 14), t(14;16), or del(17p) on results of FISH or karyotype test-
significant at P < .05. ing irrespective of the proportion of abnormal cells, but no cen-
tralized confirmation was mandated in the protocol. The
CASTOR14 and POLLUX15 studies defined HRMM based on the
presence of 1 or more of t(4;14), t(14;16), or del(17p) (using a
Results >50% deletion cutoff) using next-generation sequencing con-
The bibliographic search resulted in 5193 citations; 1 addi- ducted in a centralized laboratory. These analyses were done
tional conference abstract was found through hand searching.26 during the screening period for the study at the time of dis-
After removing duplicates, 3057 articles were screened in the ease relapse and additionally involved FISH or karyotype test-
title and abstract review. Of these, 78 articles met the criteria ing at the local laboratory. The details of HRMM testing in the
and were reviewed in full text, of which 6 randomized phase CANDOR study16 were not available. Although all trials in-
3 clinical trials including 4061 patients were selected for quali- cluded a preplanned subgroup analysis based on cytogenetic

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Research Original Investigation Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors

Figure 2. Outcomes Associated With the Addition of Daratumumab to Backbone Multiple Myeloma Regimens for Patients
With High-risk Multiple Myeloma

Log Hazard ratio


(hazard Daratumumab Control (95% CI) IV, Favors Favors Weight,
Source ratio) SE total total random daratumumab control %
Newly diagnosed high-risk multiple myeloma
ALCYONE,11 2018 –0.2485 0.3038 53 45 0.78 (0.43-1.42) 35.0
CASSIOPEIA,12 2019 –0.4005 0.3313 82 86 0.67 (0.35-1.28) 29.4
MAIA,13 2019 –0.5621 0.301 48 44 0.57 (0.32-1.03) 35.6
Subtotal 183 175 0.67 (0.47-0.95) 100
Heterogeneity: τ2 = 0.00; χ22 = 0.54; P = .76; I2 = 0%
Overall effect: z = 2.25; P =.02
Relapsed or refractory high-risk multiple myeloma
CANDOR,16 2019 –0.5447 0.3364 48 26 0.58 (0.30-1.12) 35.6
CASTOR,19 2019 –0.8916 0.3414 41 37 0.41 (0.21-0.80) 34.6
POLLUX,18 2019 –0.9943 0.3676 35 35 0.37 (0.18-0.76) 29.8
Subtotal 124 98 0.45 (0.30-0.67) 100
Heterogeneity: τ2 = 0.00; χ22 = 0.93; P = .63; I2 = 0%
Overall effect: z = 3.98; P <.001

0.1 1 10
Hazard ratio (95% CI) IV, random

Significant improvement in progression-free survival was seen among patients with first-line and relapsed or refractory disease. Squares represent mean values,
with the size of the squares representing the weight, and horizonal lines represent 95% CIs. Diamonds are pooled means with the points representing 95% CIs.
IV indicates inverse variance.

group, the latter was used as a stratification variable during ran- ated with the addition of daratumumab. In the CANDOR
domization only in the CASSIOPEIA study12; the distribution study,16 the association of daratumumab with PFS did not reach
of patients with high-risk disease was well balanced between statistical significance (HR, 0.58; 95% CI, 0.3-1.12).
the 2 groups in all the other trials. In our meta-analysis, the addition of daratumumab to first-
line backbone regimens among patients with HRMM was as-
Risk of Bias sociated with improved PFS (pooled HR, 0.67; 95% CI, 0.47-
Five of 6 studies had a low risk for bias in random sequence 0.95; P = .02), with little heterogeneity (Cochran Q, P = .76;
generation (selection bias, 83%) and allocation concealment I2 = 0%). Consistent results were obtained by using alterna-
(selection bias, 83%). For the CANDOR study,16 the risk of bias tive models for pooling effect sizes, including the Knapp-
could not be evaluated owing to the availability of limited pub- Hartung method (pooled HR, 0.67; 95% CI, 0.45-0.99; P = .04),
lished data in abstract form only.16 All included studies were the partial likelihood method (pooled HR, 0.67; 95% CI, 0.46-
open-label studies and none reported blinding of outcome as- 0.97; P = .04), and the inverse variance heterogeneity model
sessment, potentially indicating the presence of detection bias, (pooled HR, 0.67; 95% CI, 0.47-0.95; P = .03).
although 3 studies (MAIA,10 CASTOR,14 and POLLUX15) re- Similar results were seen for relapsed or refractory dis-
ported using a validated computer algorithm to evaluate treat- ease, again with no significant heterogeneity (pooled HR, 0.45;
ment response and progression. All included studies had a low 95% CI, 0.30-0.67; P < .001; Cochran Q, P = .63; I2 = 0%).
risk for bias of incomplete outcome data (attrition bias) or se- (Figure 2). Similar results were obtained using alternative pool-
lective reporting (reporting bias) (eFigure in the Supple- ing methods.
ment). All studies reported survival analysis using intention-
to-treat analysis and response rates and toxic effect results with Meta-analysis for the Association of Daratumumab
per-protocol analysis. With PFS in SRMM
Among patients with newly diagnosed SRMM, all 3 trials
Meta-analysis for the Association of Daratumumab showed significant improvement in PFS in the daratumumab-
With PFS in HRMM containing groups (ALCYONE: HR, 0.39 [95% CI, 0.28-0.55]11;
Among the 3 trials studying the addition of daratumumab to MAIA: HR, 0.50 [95% CI, 0.38-0.65]13; and CASSIOPEIA: HR,
backbone regimens among patients with newly diagnosed 0.41 [95% CI, 0.26-0.62]12). Similar results were seen among
HRMM, the HRs for PFS using the most recent follow-up data patients with relapsed or refractory SRMM, with significant PFS
were 0.57 (95% CI, 0.32-1.04) in the MAIA study, 13 0.78 benefit in the daratumumab group reported in the CASTOR
(95% CI, 0.43-1.43) in the ALCYONE study,11 and 0.67 (95% CI, (HR, 0.26; 95% CI, 0.18-0.36),19 POLLUX (HR, 0.42; 95% CI,
0.35-1.30) in the CASSIOPEIA study12; none of the findings were 0.32-0.56), 18 and CANDOR (HR, 0.55; 95% CI, 0.31-0.97)
statistically significant. Among patients with relapsed or re- studies.16
fractory MM, analysis of the most recent data from both the In the meta-analysis, the addition of daratumumab to back-
CASTOR19 (HR, 0.41; 95% CI, 0.21-0.83) and POLLUX18 stud- bone regimens in newly diagnosed MM among patients with
ies (HR, 0.37; 95% CI, 0.18-0.76) showed that PFS was associ- SRMM was associated with improved PFS (pooled HR, 0.45;

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Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors Original Investigation Research

Figure 3. Outcomes Associated With the Addition of Daratumumab to Backbone Multiple Myeloma Regimens for Patients
With Standard-Risk Multiple Myeloma

Log Hazard ratio


(hazard Daratumumab Control (95% CI) IV, Favors Favors Weight,
Source ratio) SE total total random daratumumab control %
Newly diagnosed standard-risk multiple myeloma
ALCYONE,11 2018 –0.9416 0.1691 261 257 0.39 (0.28-0.54) 32.8
CASSIOPEIA,12 2019 –0.8916 0.2324 460 454 0.41 (0.26-0.65) 17.4
MAIA,13 2019 –0.6931 0.1373 271 279 0.50 (0.38-0.65) 49.8
Subtotal 992 990 0.45 (0.37-0.54) 100
Heterogeneity: τ2 = 0.00; χ22 = 1.45; P =.48; I2 = 0%
Overall effect: z = 8.35; P <.001
Relapsed or refractory standard-risk multiple myeloma
CANDOR,16 2019 –0.5978 0.2925 104 52 0.55 (0.31-0.98) 24.4
CASTOR,19 2019 –1.3471 0.1876 140 137 0.26 (0.18-0.38) 35.0
POLLUX,18 2019 –0.8675 0.1387 193 176 0.42 (0.32-0.55) 40.6
Subtotal 437 365 0.38 (0.26-0.56) 100
Heterogeneity: τ2 = 0.08; χ22 = 6.19; P =.05; I2 = 68%
Overall effect: z = 4.83; P <.001

0.1 1 10
Hazard ratio (95% CI) IV, random

Significant improvement in progression-free survival was seen among patients with first-line and relapsed or refractory disease. Squares represent mean values,
with the size of the squares representing the weight, and horizonal lines represent 95% CIs. Diamonds are pooled means with the points representing 95% CIs.
IV indicates inverse variance.

95% CI, 0.37-0.54; P < .001), with little evidence of heteroge- need for novel treatments and improvements in outcomes.32
neity (Cochran Q, P = .48; I2 = 0%). Similar results were seen Daratumumab is changing the management of MM. Several
for relapsed or refractory disease (pooled HR, 0.38; 95% CI, phase 3 trials have shown that adding daratumumab to a pro-
0.26-0.56; P < .001) albeit there was some evidence of hetero- teasome inhibitor, immunomodulatory agent, or proteasome
geneity (Cochran Q, P = .05; I2 = 68%) (Figure 3). Similar re- inhibitor plus immunomodulatory agent backbone regimen im-
sults were obtained using alternative pooling methods. proves the rate and depth of responses and PFS.12,14,16,18 More
recently, daratumumab has also been shown to improve over-
Overall Survival all survival in non–transplant-eligible patients with newly di-
Among the included studies, mature overall survival data agnosed MM based on updated results of the ALCYONE trial.9
stratified by cytogenetic group were only available for the The benefit (or lack thereof) of a given MM agent is modu-
ALCYONE study,9 with less-pronounced benefits associated lated by many patient and disease characteristics, including
with daratumumab among patients with HRMM (HR, 0.91; cytogenetic risk. It is therefore important to examine the per-
95% CI, 0.50-1.65) than in patients with SRMM (HR, 0.49; formance of a new drug across cytogenetic subsets. Among pa-
95% CI, 0.35-0.69). Therefore, we were unable to report tients with relapsed or refractory disease, the most recent
pooled overall survival data. follow-up of the CASTOR trial showed improved PFS with the
addition of daratumumab to bortezomib plus dexametha-
sone for HRMM (HR, 0.41; 95% CI, 0.21-0.83) and SRMM (HR,
0.26; 95% CI, 0.18-0.36).19 Similar findings were seen in the
Discussion POLLUX trial, in which the HR for PFS among patients with
The findings from this systematic review and meta-analysis HRMM was 0.37 (95% CI, 0.18-0.76) and among those with
suggest that incorporating daratumumab into backbone my- SRMM was 0.42 (95% CI, 0.32-0.56)18 when daratumumab was
eloma regimens is associated with significantly improved PFS added to lenalidomide plus dexamethasone. More recently, the
for patients with newly diagnosed HRMM or relapsed or re- CANDOR trial compared daratumumab plus carfilzomib and
fractory HRMM. Furthermore, the benefit appears to be con- dexamethasone vs carfilzomib and dexamethasone.16 The ad-
sistent irrespective of the backbone anti-myeloma regimen. dition of daratumumab led to improved PFS for patients with
These findings are of direct clinical relevance and may help cli- SRMM (HR, 0.55; 95% CI, 0.31-0.97); however, no significant
nicians choose an optimal anti-myeloma regimen for pa- improvement was noted among patients with HRMM (HR,
tients with high-risk cytogenetic factors. 0.58; 95% CI, 0.30-1.12).
The presence of t(4;14), t(14;16), or del(17p) is associated In contrast to the above studies, all 3 randomized clinical
with double the risk of death in patients with newly diag- trials of daratumumab for newly diagnosed MM (ALCYONE,9
nosed MM.2 These patients are less likely to achieve deep re- MAIA,13 and CASSIOPEIA12) showed improvement in PFS
sponses to therapy27-30 and are at increased risk for early pro- among patients with SRMM, but the benefit for HRMM was not
gression, even w ith autologous hematopoietic cell statistically significant. It is possible that the benefit of dara-
transplantation.31 Therefore, this subset of patients has greater tumumab for HRMM was not identified in those trials owing

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Research Original Investigation Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors

to relatively small sample sizes. Patients with HRMM consti- additional end points, including response rate, time to sec-
tuted only 15.9% of patients in the ALCYONE trial, 14.3% ond objective disease progression, and overall survival. Some
of patients in the MAIA trial, and 15.5% of patients in the of these limitations could be overcome with an individual pa-
CASSIOPEIA trial. Another possibility is that the effect of dara- tient data meta-analysis, but some of these subsets may have
tumumab on HRMM compared with SRMM was a smaller and too few participants to reach a satisfactory answer.
nonsignificant. Although it appears contradictory that dara- Although the HR was numerically lower for SRMM com-
tumumab would benefit patients with HRMM in the context pared with HRMM in the context of both newly diagnosed and
of relapsed disease but not in the context of newly diagnosed relapsed or refractory disease, such comparison could not be
disease, these are distinct populations. Patients with more ag- formally done and has limited clinical utility because the
gressive high-risk disease may not be candidates for subse- therapy given to a patient can be modulated but the biologi-
quent lines of therapy owing to early mortality and high attri- cal characteristics of the disease cannot be modulated. How-
tion rates.33,34 ever, no prior MM agent has been shown to have an associa-
The current meta-analysis combined multiple studies with tion with PFS in patients with newly diagnosed HRMM. Few
similar design to increase the power to answer a scientifically other agents, namely carfilzomib,27,28 pomalidomide26 and
and clinically relevant question. The method used to select stud- ixazomib,30 have been associated with PFS among patients
ies for the meta-analysis ensured a consistent design in which with relapsed or refractory HRMM, often with less impact than
the only difference between the control and experimental seen among patients with SRMM. This meta-analysis also did
groups was the use of daratumumab. The findings suggest that not find that daratumumab completely abrogated the prog-
daratumumab is associated with improved PFS among pa- nostic impact of t(4;14), t(14;16), or del(17p), a high accom-
tients with newly diagnosed HRMM and SRMM. This finding was plishment that has not been reached by any MM agent to date.
not weakened by the 3 trials entering the analysis having dif- The present analysis provided evidence that, when com-
ferent backbone MM regimens and different age groups, as sup- bined with backbone proteasome inhibitor and immunomodu-
ported by the lack of significant heterogeneity in effect size. latory agent–based regimens, daratumumab was associated
with improved PFS among patients with HRMM and SRMM in
Limitations the context of newly diagnosed and relapsed or refractory dis-
This study has limitations. There may have been imbalances ease. However, it did not provide a comparison between dara-
in patient characteristics between the groups, potentially af- tumumab-based and non–daratumumab-based regimens. The
fecting the study outcome. This imbalance was minimized by identification of the best regimen and therapeutic strategy for
all trials having been randomized and including stratification patients with HRMM may be achieved by network meta-
for other variables (such as disease stage) that affect risk of pro- analysis, preferentially using individual patient data and by fu-
gression or death. Our analysis did not address the benefit as- ture well-designed randomized clinical trials.
sociated with daratumumab in other subsets recognized as high
risk, such as patients with extramedullary disease, high lac-
tate dehydrogenase levels at diagnosis, stage 3 disease, and in-
ferior performance status at enrollment. It also did not ap-
Conclusions
praise the association of daratumumab with PFS among The present study suggests that daratumumab-based regi-
patients with a specific high-risk cytogenetic abnormality, such mens are associated with improved PFS among patients with
as del(17p). Different studies had varying cutoffs to identify HRMM and SRMM in the context of newly diagnosed and re-
high-risk chromosome abnormalities on FISH. In addition, lapsed or refractory disease. Furthermore, lack of substantial
there was no information about P53 mutation paired with del heterogeneity suggests that the associated benefit is seen re-
(17p). We did not have data stratified by cytogenetic group on gardless of the underlying backbone myeloma regimen.

ARTICLE INFORMATION Hematology and Medical Oncology, National and Drafting of the manuscript: Giri, Grimshaw, Kharel,
Accepted for Publication: July 9, 2020. Kapodistrian University of Athens School of Dimopoulos, Usmani, Costa.
Medicine, Athens, Greece (Dimopoulos); Critical revision of the manuscript for important
Published Online: September 24, 2020. Department of Hematology, Lille University intellectual content: Grimshaw, Bal, Godby,
doi:10.1001/jamaoncol.2020.4338 Hospital, Lille, France (Facon); Plasma Cell Djulbegovic, Dimopoulos, Facon, Usmani, Mateos,
Author Affiliations: Institute for Cancer Outcomes Disorders Program, Levine Cancer Institute/Atrium Costa.
and Survivorship, Division of Hematology and Health, Charlotte, North Carolina (Usmani); Statistical analysis: Giri, Djulbegovic, Usmani, Costa.
Oncology, University of Alabama at Birmingham Department of Hematology, University Hospital of Administrative, technical, or material support:
(Giri); Division of Hematology and Oncology, Salamanca/IBSAL, Cancer Research Center, Grimshaw, Kharel, Dimopoulos.
Department of Medicine, University of Alabama at Salamanca, Spain (Mateos). Supervision: Godby, Dimopoulos, Facon, Usmani,
Birmingham (Giri, Bal, Godby, Costa); Harvey Author Contributions: Drs Giri and Costa had full Mateos, Costa.
Cushing/John Hay Whitney Medical Library, Yale access to all of the data in the study and take Conflict of Interest Disclosures: Dr Giri reported
University, New Haven, Connecticut (Grimshaw); responsibility for the integrity of the data and the receiving research funding from Carevive Systems
Department of Hospital Medicine, Geisinger Health accuracy of the data analysis. and Pack Health LLC and honoraria from Carevive
System, Geisinger, Danville, Pennsylvania (Kharel); Concept and design: Giri, Bal, Godby, Djulbegovic, Systems. Dr Dimopoulos reported receiving
Evidence-based Analytics and Comparative Dimopoulos, Costa. honoraria from Janssen, Celgene, Takeda, Amgen,
Effectiveness Research, Department of Supportive Acquisition, analysis, or interpretation of data: Giri, and Bristol Myers Squibb and serving as a
Care, City of Hope Comprehensive Cancer Center, Grimshaw, Kharel, Dimopoulos, Facon, Usmani, consultant or in an advisory role for Janssen,
Duarte, California (Djulbegovic); Section of Mateos, Costa. Celgene, Takeda, Amgen, and Bristol Myers Squibb.

E6 JAMA Oncology Published online September 24, 2020 (Reprinted) jamaoncology.com

© 2020 American Medical Association. All rights reserved.

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Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors Original Investigation Research

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Karyopharm, Oncopeptides, and Roche. Dr Usmani untreated myeloma. N Engl J Med. 2018;378(6): 24. Cornell JE, Mulrow CD, Localio R, et al.
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Array Biopharma, BMS, Celgene, GSK, Janssen, effects: a time for change. Ann Intern Med. 2014;
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Sanofi, SkylineDx, and Takeda; and speaking fees stem-cell transplantation for newly diagnosed Williams GM. Advances in the meta-analysis of
from Amgen, Celgene, Janssen, and Takeda. multiple myeloma (CASSIOPEIA): a randomised, heterogeneous clinical trials, I: the inverse variance
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Amgen, Celgene, Janssen, and Takeda and serving (10192):29-38. doi:10.1016/S0140-6736(19)31240-1 (Pt A):130-138. doi:10.1016/j.cct.2015.05.009
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GlaxoSmithKline, Celgene, Janssen, Takeda, and plus lenalidomide and dexamethasone (D-Rd) versus OPTIMISMM trial investigators. Pomalidomide,
AbbVie. Dr Costa reported receiving research lenalidomide and dexamethasone (Rd) in patients bortezomib, and dexamethasone for patients with
funding from Amgen and Janssen and honoraria with newly diagnosed multiple myeloma (NDMM) relapsed or refractory multiple myeloma previously
from Karyopharm, Celgene, Amgen, Janssen, and ineligible for transplant: updated analysis of Maia. treated with lenalidomide (OPTIMISMM):
Sanofi. No other disclosures were reported. Blood. 2019;134(suppl_1):1875. a randomised, open-label, phase 3 trial. Lancet Oncol.
14. PalumboA,Chanan-KhanA,WeiselK,etal;CASTOR 2019;20(6):781-794. doi:10.1016/S1470-2045
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