Effectiveness of targeted therapy as monotherapy or combined therapy in patients with relapsed or refractory multiple myeloma: A systematic review and meta-analysis Sylwia Łopuch 1, Paweł Kawalec 2 , Natalia Wis´niewska1 1

Independent researcher, 2Jagiellonian University Medical College, Faculty of Health Sciences, Institute of Public Health, Kraków, Poland Objectives: The aim of this systematic review was to evaluate the efficacy and safety of targeted agents used as monotherapy or combined therapy in patients with relapsed/refractory multiple myeloma (MM). Methods: The systematic literature search was conducted in PubMed, Embase, Cochrane Library till 27 May 2013. Results: Four randomized controlled trials were included. The meta-analysis showed that combined therapy significantly improved progression-free survival compared with monotherapy (P < 0.05). However, there was not a significant difference between monotherapy and combined therapy in overall survival (P > 0.05). The combined therapy also significantly increased the risk of serious adverse events and grade 3/4 AEs compared to monotherapy (P < 0.05). Overall, the results of comparisons between monotherapy and combined therapy in individual trials were differentiated, and some combinations were not more effective than monotherapy (bortezomib plub bevacizumab vs. bortezomib and thalidomide plus INFα vs. thalidomide) which emphasizes the role of individualized therapy in relapsed/refractory MM especially in the elderly or patients with significant comorbidities. Conclusions: The results of this meta-analysis showed that combined therapy is superior to monotherapy only in some end points and it is less tolerated in patients with relapsed/refractory MM. Thus, the overall superiority of complex therapy to monotherapy depends on the combination of the targeted agents. Keywords: Relapsed/refractory multiple myeloma, Systematic review and meta-analysis, Targeted therapy

Introduction Multiple myeloma (MM) is the second most common lymphoid malignancy in adults. Worldwide, 102 826 new cases of MM were diagnosed in 2008 accounting for about 0.8% of total cases of cancer, and MM was responsible for 72 463 deaths (1% of all cancer deaths per year).1,2 MM is a chronic, malignant monoclonal plasma cell neoplasm characterized by an accumulation of malignant plasma cells in bone morrow, bone morrow insufficiency, osteolytic bone lesions, anaemia, hypercalcaemia, renal insufficiency, and increased risk of infections.3–6 Thus, MM results in considerable morbidity and mortality among affected patients.1,2,7 The median age of patients at the time of diagnosis is about 65–72 years, based on particular studies.8,9 MM consists of at least six cytogenetic Correspondence to: Paweł Kawalec, Drug Management Department, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, 20 Grzegorzecka St, 31-531 Kraków, Poland. Email: [email protected]

© W. S. Maney & Son Ltd 2015 DOI 10.1179/1607845414Y.0000000159

subtypes.3 There is consensus that detection of any cytogenetic abnormality suggests higher-risk disease;10 however, the t(4;14), t(14;16) translocations the del(17p) are the most important for outcome prediction, and all of them predicting a short overall survival (OS).11 Survival for patients with MM depends on the basic variables including: cytogenetic type, age, performance status, renal function, and disease stage.3 Thus, MM is a heterogeneous disease with variable disease courses, response to therapy, and survival outcome that ranges from less than 1 year in patients with aggressive disease to more than 10 years in patients with indolent disease presentation.10 The median length of survival after diagnosis is approximately five years.3 The introduction of new targeted agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors improved treatment outcomes; however, MM remains incurable and patients eventually relapse.3,12 The duration of response (DR) decreases

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consistently with each successive regimen, probably reflecting acquired drug resistance and an increasing proliferative rate of the myeloma cells.7,12 Targeted agents approved by the European Medicine Agency (EMA) and the US Food and Drug Administration (FDA) in MM include thalidomide, lenalidomide, pomalidomide, and bortezomib.13,14 Recently, the FDA has also approved carfilzomib in this indication.14 Thalidomide, lenalidomide, and pomalidomide are IMiDs, while bortezomib and carfilzomib are proteasome inhibitors. Thalidomide and its analogues: lenalidomide and pomalidomide, are considered to have anti-inflammatory, immunomodulatory, anti-proliferative, and anti-angiogenic effects against myeloma cells.15–18 Next, bortezomib and carfilzomib target the proteaseome’s chymotrypsin-like activity.19,20 Nowadays, the targeted agents such as thalidomide, lenalidomide, and bortezomib are widely used at relapse of MM.21,22 Moreover, the guidelines prepared by the National Comprehensive Cancer Network (NCCN),23 the International Myeloma Working Group (IMWG),24 and the European Society for Medical Oncology (ESMO)25 recommend thalidomide, lenalidomide, or bortezomib as single agents or in combination with other types of agents (e.g. dexamethasone, liposomal doxorubicin, cyclophosfamide, etoposide, or cisplatin) in relapsed or refractory patients with MM. New therapies significantly improved treatment outcomes in patients with MM; however, because the disease is still incurable the newer agents and new combinations of the existing agents are needed. The optimal sequence or combination of the existing agents remains unclear, and therefore, the information is needed on the efficacy and safety of each therapeutic option. Certain combined therapies demonstrate synergistic anti-tumour effects, however, there are also some data indicating the combined regimens are not much more effective and are less tolerated than monotherapy by patients with relapsed or refractory MM.26,27 It is especially important in face of emerging resistance to drugs and limited number of drugs efficient in MM. Therefore, we performed a systematic review with meta-analysis to assess the balance between benefits and harms resulting from monotherapy and combined therapy in patients with relapsed or refractory MM treated with targeted agents approved in this indication by the FDA and/or the EMA.

Materials and methods This systematic review was performed according to the methods and recommendations from the Cochrane handbook,28 and the meta-analysis was conducted according to the Preferred Reporting Items for

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Systematic Reviews and Meta-analysis (PRISMA) Statement protocol, as described elsewhere.29

Search strategy and data sources Searches for primary trials were based on MeSH and EMTREE terms including: medical condition – MM and the interventions – thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib (monotherapy or combined therapy), combined with Boole’s logical operators (see supplementary material available at http://www.maneyonline.com/doi/suppl/10. 1179/1607845414Y.0000000159). Primary trials were identified by searching the main electronic databases (Medline/PubMed, Embase, the Cochrane Central Register of Controlled Trials), and others such as American Society of Clinical Oncology (ASCO), ESMO, as well as clinical trials register (http://www. clinicaltrials.gov) for unpublished or ongoing trials. The search was conducted till 27 May 2013. We also hand searched reference lists of all included trials and related review articles to identify additional relevant trials missed in the initial search.

Eligibility criteria Randomized controlled trials (RCTs) evaluating the use of targeted agents alone (monotherapy) vs. their combinations with other types of agents (combined therapy) for the treatment of patients with relapsed or refractory MM were included in this review. The full-text articles were preferable because of opportunity to verify reliability of potentially useful trials (availability of the full-text articles of primary trials allows accurate assessment of their quality and provide essential information about study population, applied treatment regimen and specific data to extract), but non-published ones were also taken into consideration.

Study selection and data extraction The search and eligibility assessments using predefined inclusion and exclusion criteria were performed independently by two reviewers (S.Ł. and P.K.). Disagreements were resolved by consensus, and when needed, a third reviewer acted as an adjudicator (N.W.). Two authors (P.K. and S.Ł.) read the titles, abstracts, and if necessary, full-text articles to identify potentially relevant ones, resolving any uncertainties with a third author (N.W.). Two authors (P.K. and S.Ł.) read in full all articles selected as potentially relevant. Trials fulfilling the eligibility criteria were included in the systematic review. Data were extracted from the included trials independently by two reviewers (S.Ł. and P.K.) using a standard data extraction form, and then, they were checked by a third reviewer (N.W.). Essential information from each eligible trial was collected: study design, regimen details, line of treatment, characteristics of

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participants and sample size, clinical outcomes, follow-up period. The efficacy and safety outcomes were also extracted and they include data on: overall response rate (ORR), complete response (CR), partial response (PR), progressive disease (PD), progression-free survival (PFS), event-free survival (EFS), time to progression (TTP), time to response (TTR) or OS, incidents of death (overall and caused by adverse events, AEs), and discontinuation of the intervention from any cause, any AEs, any serious adverse events (SAEs), grade 3/4 AEs, AEs leading to death or incidents of discontinuation the intervention due to AEs. Meta-analysis was conducted only when the end points were identically or very similarly defined. All trials included were scored by three independent reviewers in accordance to the Jadad scale.30

Statistical analysis The meta-analysis and all statistical tests or forest plots were conducted using StatsDirect (version 2.7.8, StatsDirect Ltd, UK). Data were analyzed using intention-to-treat results from the included trials. For dichotomous data, the influence of interventions was expressed as relative benefit (RB) to analyse the positive outcomes (ORR, CR, PR) or relative risk (RR) to analyse the negative outcomes (PD, deaths, AEs, SAEs) with 95% confidence intervals (CIs). All HR values for time to event outcomes (PFS, EFS, TTP, TTR, OS) were extracted from the trials or calculated by the authors with 95% CIs. Results for similar clinical outcomes and homogenous data (determined by degree of clinical and statistical heterogeneity) of the included trials were aggregated using appropriate statistical methods of meta-analysis. Based on data input

Figure 1

Targeted therapy in multiple myeloma

and heterogeneity of the results, the inverse variance in Mantel-Haenszel or Der Simonian-Laird effects model was used. The clinical heterogeneity was evaluated on the basis of the characteristics of the eligible trials, while the statistical heterogeneity of the trial results was evaluated by Cochran Q statistics and I 2 test. RB or RR were calculated using the fixed effects model when the statistical heterogeneity was at P ≥ 0.10, and the random effects model was applied when heterogeneity was at P < 0.10.28 Statistical significance was defined at P < 0.05 for other calculations.

Results Search results The initial search yielded 3708 records, of which 3687 were excluded on the basis of the titles and abstracts. After this exclusion, 21 potentially eligible full-text articles were left. Four RCTs fulfilled the inclusion criteria for this systematic review and meta-analysis, the other articles were excluded for various reasons specified in Fig. 1. The characteristics of all included studies are summarized in Table 1. All study participants were diagnosed with relapsed or refractory MM. The included trials compared: pomalidomide vs. pomalidomide plus dexamethasone,31 bortezomib vs. bortezomib plus pegylated liposomal doxorubicin (PLD),32 bortezomib vs. bortezomib plus bevacizumab33 and thalidomide vs. thalidomide plus interferon alfa (IFNα).26 No published or unpublished RCTs of carfilzomib and lenalidomide in monotherapy compared with combined therapy in relapsed or refractory patients with MM were identified. The methodological quality of the included RCTs was evaluated as

Preferred reporting items for systematic reviews and meta-analysis flow diagram – study selection and exclusion. Hematology

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Table 1

Characteristics of the included randomized controlled trials

References

Type of study

NCT0083383331

RCT, open

Orlowski (2007)32

RCT, open

White (2013)33

RCT, DB

Chiou (2007)26

RCT, open

Median follow-up

Treatment regimen

Population

Trial endpoints

Pomalidomide vs. pomalidomide plus dexamethasone 4 mg pomalidomide was given once per day on days 1–21 of each 28-day cycle, dexamethasone was given on days 1, 8, 15, and 2 of each 28-day cycle (20 mg dexamethasone for participants who were ≥75 years and 40 mg dexamethasone for participants who were ≤75 years) Bortezomib vs. bortezomib plus PLD 1.3 mg/m2 bortezomib was given on days 1, 4, 8, and 11 of each 21-day cycle, 30 mg/m2 PLD was given on day 4 of each 21-day cycle

Patients with relapsed or refractory multiple myeloma who received prior treatment that includes lenalidomide and bortezomib, N = 221

Primary: PFS; secondary: AEs, CR, PR, MR, SD, PD, DR, TTR, OS

70 weeks

Patients with multiple myeloma who progressed after a response to ≥1 line of therapy or refractory to initial therapy (lenalidomide or thalidomide), N = 646 Patients with relapsed or refractory multiple myeloma who progressed after 1–3 prior treatment regimens, N = 102

Primary: TTP; secondary: PFS, OS, CR, PR, AEs

7.2 months

Primary: PFS; secondary: ORR, CR, PR, VGPR, DR, OS, AEs

13.3 months

Patients with relapsed or refractory multiple myeloma who relapsed or failed initial therapy, N = 28

Primary: ORR; secondary: TTR, DR, TTP, EFS, OS, CR, PR, MR, PD, AEs

Not reported

Bortezomib vs. bortezomib plus bevacizumab 1.3 mg/m2 bortezomib was given on days 1, 4, 8, and 11 of each 21-day cycle, 15 mg/kg bevacizumab was given on day 1 of each 21-day Thalidomide vs. thalidomide plus INFɑ, thalidomide was given at a dose of 200 mg per day, a dose increased by 200 mg each 2 weeks to the maximal daily dose of 800 mg, 3 MIU/m2 of INFɑ-2b was given 3 times weekly

AEs, adverse events; CR, complete response; DB, double blind; EFS, event-free survival; INFα, interferon alfa; DR, duration of response; MIU, million international units; MR, minimal response; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PR, partial response; RCT, randomised controlled trial; SD, stable disease; TTP, time to progression; TTR, time to response; VGPR, very good partial response.

moderate (two trials31,32 scored two points and two trials26,33 scored three points). All eligible trials were randomized,26,31–33 but only one trial33 was double blind and only one trial26 included description of the randomization method. All included trials were published in English as peer-reviewed articles. The results of the comparison of monotherapy with combined therapy in patients with relapsed or refractory MM are shown in Table 2.

Efficacy of monotherapy compared with combined therapy The meta-analysis of four RCTs comparing monotherapy to combined therapy showed that the risk of discontinuation of the intervention was similar in both groups (P = 0.27). However, significant between-study heterogeneity was observed (P = 0.06, I 2 = 58.5%). There were not statistically significant differences between monotherapy and combined

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therapy in each individual trial (P > 0.05, data not shown).26,31–33 The median PFS was significantly prolonged in combined therapy group compared to monotherapy group; HR was reduced by 27% (P < 0.0001, Fig. 2). There was not between-study heterogeneity (P = 0.97).31,33 Similar result was achieved in the trial of Orlowski et al.,32 where the median PFS was also significantly longer in combined therapy group compared with monotherapy group; HR was reduced by 69% (P = 0.0003). On the contrary, in the trial of Chiou et al. 26 the median EFS was significantly improved in monotherapy group compared to combined therapy group (P = 0.0193). In combined therapy group the median TTP was also significantly prolonged when compared to monotherapy group; HR was reduced by 82% (P = 0.000004).32 The meta-analysis of two RCTs demonstrated that the risk of disease progression (PD) was significantly higher in monotherapy group than

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Table 2 Summary of the efficacy and safety outcomes of the included studies

End points

No. of trials

Group of patients Monotherapy

Combined therapy

2

N 161

N 162

1

322

324

EFS TTP

1 1

12 322

16 324

TTR

2

143

178

OS

3

161

162

1

322

324

Discontinuation

4

n/N 354/495

n/N 330/502

ORR

3

158/387

175/389

CR

4

9/495

16/502

PR

4

155/495

179/502

PD

2

23/120

10/129

Death

4

62/495

44/502

Discontinuation due to AEs

4

94/491

226/496

AEs

3

457/475

472/480

SAEs

2

148/425

184/430

Grade 3/4 AEs

3

328/475

393/480

AEs leading to death

2

14/368

14/368

PFS

RB/RR/HR (95% CI), P

Test of heterogeneity Cochran Q, df, P, I2

HR = 0.73 [0.53–0.93], P < 0.0001 HR = 1.69 [1.32–2.16], P = 0.0003 P = 0.0193 HR = 1.82 [1.41–2.35], P = 0.000004 HR = 1,04 [0.46–1.62], P > 0.05 HR = 0.80 [0.48–1.11] P > 0.05 HR = 1,41 [1.002–1.97], P = 0.0476

Cochran Q = 0.002, df = 1, P = 0.97

RR = 1.06 [0.96–1.17], P = 0.27 RB = 0.90 [0.77–1.06], P = 0.22 RB = 0.58 [0.27–1.27], P = 0.17 RB = 0.78 [0.42–1.45], P = 0.44 RR = 2.58 [1.29–5.12], P = 0.007 RR = 1.38 [0.96–1.99], P = 0.08 RR = 0.74 [0.28–1.94], P = 0.54 RR = 0.98 [0.96–1.001], P = 0.58 RR = 0.82 [0.69–0.97], P = 0.02 RR = 0.87 [0.76–0.98], P = 0.03 RR = 1.00 [0.48–2.07], P = 0.999

References

31,33

32

26 32

Cochran Q = 16.32, df = 1, P = 0.003, I 2 = 87.7%

31,32

Cochran Q = 0.34, df = 1, P = 0.84, I 2 = 0%

26,31,33

Cochran Q = 7.23, df = 3, P = 0.06, I 2 = 58,5%

26,31,32,33

Cochran Q = 1.15, df = 2, P = 0.56, I 2 = 0%

26,32,33

Cochran Q = 0.24, df = 3, P = 0.97, I 2 = 0%

26,31,32,33

Cochran Q = 12.45, df = 3, P = 0.01, I 2 = 75,9%

26,31,32,33

Cochran Q = 0.004, df = 1, P = 0.95

26,31

Cochran Q = 0.16, df = 3, P = 0.98, I 2 = 0%

26,31,32,33

Cochran Q = 14.00, df = 3, P = 0.0029, I2 = 78,6%

26,31,32,33

Cochran Q = 0.80, df = 2, P = 0.67, I 2 = 0%

31,32,33

Cochran Q = 0.48, df = 1, P = 0.49

31,32

Cochran Q = 5.70, df = 2, P = 0.06, I 2 = 64.9%

31,32,33

Cochran Q = 1.11, df = 1, P = 0.29

32,33

32

AEs, adverse events; EFS, event-free survival; CR, complete response; HR, hazard ratio; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RB, relative benefit; RR, relative risk; SAEs, serious adverse events; TTP, time to progression; TTR, time to response. There was not possibility to perform meta-analysis of HRs for PFS and OS reported in three trials31–33 because in two trials31,33 HR was calculated relative to monotherapy and in the third trial32 HR was calculated relative to combined therapy.

combined therapy group (P = 0.007). No betweenstudy heterogeneity was seen (P = 0.95).26,31 There was not statistically significant difference in the median OS between monotherapy group and combined therapy group; HR was reduced by 20% (P > 0.05, Fig. 3). No between-study heterogeneity was seen (P = 0.84, I 2 = 0%).26,31,33

Only in one trial32 the median OS was significantly prolonged in combined therapy group compared with monotherapy group; HR was reduced by 41% (P = 0.0476). The lack of statistically significant differences between monotherapy and combined therapy in terms of OS was confirmed by the similar risk of death in both groups (P = 0.08). There was not between-study Hematology

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Figure 2 Meta-analysis of progression-free survival (PFS) for targeted agents used as monotherapy or combined therapy in patients with relapsed or refractory MM.

Figure 4 Meta-analysis of any adverse events (AEs) for targeted agents used as monotherapy or combined therapy in patients with relapsed or refractory MM.

heterogeneity in the meta-analysis of four RCTs (P = 0.98, I 2 = 0%). Moreover, there were not statistically significant differences between monotherapy and combined therapy in each single trial, either (P > 0.05, data not shown).26,31–33 The median TTR was similar in monotherapy and combined therapy groups (P > 0.05). However, there was significant between-study heterogeneity (P = 0.003, I 2 = 87.7%).26,31,32 The RB of CR or PR was similar in monotherapy group and combined therapy group (P = 0.17 and P = 0.44, respectively). No between-study heterogeneity was seen in the metaanalysis of four RCTs concerning CR (P = 0.97, I 2 = 0%), while significant between-study heterogeneity was observed in the meta-analysis of the results concerning PR (P = 0.01, I 2 = 75.9%). There were not statistically significant differences in CR between monotherapy and combined therapy in each individual trial, either (P > 0.05, data not shown).26,31–33 However, the combined therapy significantly increased PR by 68% compared with monotherapy (P < 0.05) in one trial.31 Regarding ORR, the RB was similar in monotherapy group and combined therapy group (P = 0.22). No between-study heterogeneity was seen

in three RCTs included in the meta-analysis (P = 0.56, I 2 = 0%). There were not statistically significant differences in ORR between monotherapy and combined therapy in the individual trials, either (P > 0.05, data not shown).26,32,33

Figure 3 Meta-analysis of overall survival (OS) for targeted agents used as monotherapy or combined therapy in patients with relapsed or refractory MM.

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Safety of monotherapy compared with combined therapy Regarding the risk of discontinuation of intervention due to AEs, the meta-analysis of four RCTs showed no significant difference between monotherapy and combined therapy groups (P = 0.54). However, there was significant between-study heterogeneity (P = 0.0029, I 2 = 78.6%).26,31–33 Only in one trial32 the risk of discontinuation of intervention due to AEs was significantly decreased by 64% (P < 0.05) in the monotherapy group compared with combined therapy group. The overall risk of any AEs was higher in combined therapy group compared to monotherapy group, however, the difference was marginally insignificant (P = 0.058, Fig. 4). No between-study heterogeneity was seen (P = 0.67, I 2 = 0%).31–33 There were not

Figure 5 Meta-analysis of grade 3/4 AEs for targeted agents used as monotherapy or combined therapy in patients with relapsed or refractory MM.

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statistically significant differences in the risk of any AEs between monotherapy and combined therapy in each single trial, either (P > 0.05, data not shown).26,31–33 It is noteworthy that the risk of serious adverse events (SAEs) and the risk of grade 3/4 grade AEs were significantly decreased by 18% and 13% respectively, in monotherapy group compared to combined therapy group (P = 0.0231,32 and P = 0.03,31–33 respectively; Fig. 5). There was no between-study heterogeneity when the incidence of SAEs was compared (P = 0.49), whereas, in case of the risk of grade 3/4 AEs there was between-study heterogeneity (P = 0.06, I 2 = 64.9%). However, only in one trial31 the risk of SAEs and in one trial32 the risk of grade 3/4 AEs was significantly smaller (P < 0.05) in the monotherapy group than in combined therapy group. The risk of AEs leading to death was insignificant between monotherapy and combined therapy (P = 0.999). No between-study heterogeneity was observed (P = 0.29).32,33 There were not statistically significant differences between monotherapy and combined therapy in each single trial, either (P > 0.05, data not shown).32,33

Discussion This systematic review with meta-analysis took into account four RCTs fulfilling the inclusion criteria which enabled comparing monotherapy with combined therapy ( pomalidomide vs. pomalidomide plus dexamethasone,31 bortezomib vs. bortezomib plus PLD,32 bortezomib vs. bortezomib plus bevacizumab33 and thalidomide vs. thalidomide plus interferon alfa (IFNα)26) in patients with relapsed or refractory MM. The eligible trials made possible to compare the efficacy and safety of distinctive therapeutic options, as well as aggregate their results. The main results of the meta-analyses showed that combined therapy significantly increased the risk of SAEs and grade 3/4 AEs. On the contrary, combined therapy significantly improved the efficacy outcomes such as PFS and decreased the risk of PD. However, there was not a significant difference in OS between monotherapy and combined therapy. The above results indicate that combined therapy is superior to monotherapy only in limited range, improving only some of the end points, but it is also less tolerated. The higher incidence of AEs may lead to discontinuation of the therapy as it took place in one included trial,32 where significantly more patients discontinued treatment in the combined therapy group compared to monotherapy group. Non-compliance with drug treatment due to AEs also reduces the efficacy outcomes. In order to avoid or decrease the treatmentrelated toxicity, the dose of used medicine is often reduced what might be responsible for worse treatment

Targeted therapy in multiple myeloma

outcomes in one included trial.26 The next problem results from drug interactions, especially in case of complex regimens. Overall, the risk of drug interactions in patients with MM is high due to agerelated organ dysfunction and concomitant drug therapy for comorbid conditions.34 Thus, there are important limitations of the administration of combined therapy compared to monotherapy, especially in elderly patients who usually use many other medications due to comorbid conditions or in younger patients with significant comorbidities. Therefore, one- or two-drug regimens or more complex regimens with reduced doses are recommended by IMWG for such patients.24 It should be noted that the efficacy outcomes of particular trials are differentiated. The combination of bortezomib and PLD compared to bortezomib monotherapy seems to be the most effective in terms of significantly prolonged TTP, PFS, DR, and even OS.32 However, the combined therapy caused significantly more drug-related AEs, grade 3/4 AEs and significantly more patients discontinued the intervention because of AEs.32 Slightly less effective seems to be the combination of pomalidomide and dexamethaseone compared with pomalidomide alone, because the combined therapy significantly prolonged only PFS and significantly more patients achieved PR, as well as significantly less patients experienced PD. No other significant differences were demonstrated (OS, TTR, and DR).31 The combined therapy again occurred to be less tolerated than monotherapy causing significantly more SAEs.31 Lack of any significant differences in terms of the efficacy outcomes (PFS, OS, DR, ORR) and the safety outcomes (AEs, SAEs) were demonstrated in the trial comparing the combination of bortezomib and bevacizumab vs. bortezomib alone.33 Similar results were showed in the trial comparing the combination of thalidomide and INFα vs. thalidomide monotherapy; there were not any significant differences in TTR, DR, OS, and AEs.26 Only EFS was significantly prolonged in monotherapy group compared with combined therapy group.26 However, lack of statistically significant differences between monotherapy and combined therapy in the two trials26,33 might be the result of too small number of patients which decreased the possibility to demonstrate such a difference even if it existed. Moreover, in the trial of Chiou et al. 26 the mean duration of therapy was significantly longer in thalidomide alone group than in combination therapy group (236 vs. 101 days, P = 0.029) and the total dose of thalidomide was also significantly higher in monotherapy group (116.10 vs. 40.36 g, P = 0.030). It may explain the inferior results of patients treated with the combined therapy compared to monotherapy.26 Next, in the trial White et al. 33 Hematology

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about 18% patients were previously treated with bortezomib what might also influence the efficacy outcomes. Another possible explanation why bortezomib alone was similarly effective to bortezomib plus bevacizumab is that the angiogenesis inhibition is the main mechanism of action of bevacizumab and one of multiple anticancer mechanisms proposed for bortezomib. Because of that further inhibition of this pathway (the angiogenesis inhibition) may not add further clinical benefit.33 Bevacizumab alone or in combination with other agents may be more effective only in patients whose myeloma cells are enriched for VEGF expression.27,33 There were not any significant differences between comparison of bevacizumab and bevacizumab with thalidomide27 that would confirm this explanation because thalidomide also inhibits VEGF-associated angiogenesis.35 The above results indicate that not all combinations of anticancer agents are effective or are effective only in some patient subgroups. The advantage of combined therapy often results from administration of agents which differs from each other their mechanisms of action and specific molecular targets, because of that they may better control disease course and are less vulnerable to develop potential drug resistance.36 This systematic review also demonstrated that there are a very limited number of RCTs comparing monotherapy with combined therapy what limits possibility to precisely assess the efficacy and safety of these regimens, and differences among the trials make difficult to draw general conclusions from the obtained results. Moreover, there is also limited possibility to compare head-to-head particular agents. The results of RCTs included in this review indicate that bortezomib is more effective than pomalidomide and thalidomide (IMiDs) in terms of efficacy outcomes (OS, PFS, ORR) as well as safety outcomes (≥1 AEs, ≥1 SAEs, grade 3/4 AEs).31–34 However, good qualities RCTs are needed to draw specific conclusions. Additional trials are necessary to identify patient subgroups that benefit most from one of these options. Moreover, there is a necessity to investigate new combinations of the existing agents because some of them better control disease in combination than as single agents.31,32 Individualized therapy is especially needed for patients with relapsed or refractory MM who are vulnerable due to age, comorbid conditions, life expectancy, resistance to drugs previously used, drug interactions which complicate the management of MM. The comorbid conditions such as heart disease may limit the usability of the effective combination of bortezomib plus PLD due to anthracycline cardiotoxicity.37,38 Moreover, patients with MM are at high risk of thromboembolic events and therapy with thalidomide or lenalidomide increases the risk of venous thromboembolism (VTE) even more.39,40

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However, data indicate the low risk of VTE associated with bortezomib,41 which may be a useful therapeutic option for patients at high risk of thromboembolism. Bortezomib alone or in combination with PLD may be also helpful for steroid-intolerant patients. Bortezomib also seems to be more effective than thalidomide in terms of response rate what can be helpful especially in patients with aggressive relapse.42 Next, pomalidomide alone or with dexamethasone may be effective for patients with double-refractory MM relapsing after therapy with IMiDs and bortezomib whose prognosis is poor with the median OS of 9 months and PFS of 5 months.43 The important problem in therapy of patients with relapsed or refractory MM is also increasing resistance to drugs applied previously. The efficacy outcomes are worse in patients with relapsed or refractory MM previously exposed to thalidomide,44,45 and DR decreases consistently with each successive regimen.7,12 Therefore, it is so important for patients with relapsed or refractory MM to have the possibility of exchanging drugs which will be potentially able to overcome the existing drug resistance. There are encouraging results regarding lenalidomide and carfilzomib in relapsed or refractory MM;46–48 however, more therapeutic options are needed. Thus, one of the valid aims of the therapy of relapsed or refractory MM is to optimize the efficacy and safety of the novel agents alone and their combinations in order to establish the best sequences of the effective treatment. Individualized therapy for patients with relapsed or refractory MM should support new findings concerning the identification of biomarkers potentially useful for predicting sensitivity or resistance of MM cells to treatment. One of the most interesting findings is cerebion (CRBN), which is crucial for IMiD activity and low levels of CRBN correlate with poor drug response as well as marked IMiD resistance in human MM cells.49 Because of that CRBN expression in MM cells may be a useful biomarker for the clinical efficacy of IMiD-based therapy,49 but not bortezomibbased therapy.50 Another potentially useful biomarker is XBP1 (X-box binding protein 1) which is highly expressed in human MM cells.51,52 Patients with low XBP1s/u (XBP1spliced/unspliced) ratios have a significantly better OS and achieve better treatment outcomes using thalidomide.52 New findings also indicate that suppression of XBP1s in MM cells induces bortezomib resistance and may be responsible for therapeutic failure.53 Thus, XBP1s may be a useful biomarker for the clinical efficacy of IMiD- and bortezomib-based therapy.52,53 There are a few limitations to this systematic review with meta-analysis. First of all, we did not identify any published or unpublished RCTs comparing carfilzomib and lenalidomide monotherapy with combined therapy in relapsed or refractory patients with MM;

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however, both agents are relatively new what may explain a lack of such trials. Moreover, to assess the effectiveness of pomalidomide we used data coming from the clinical trials register which reliability is limited in comparison with data published in goodquality peer-reviewed journals. Another important limitation is the fact that the calculations in the metaanalysis were based on the published study results instead of individual patient data what may generate mistakes. The lack of required data in the included trials (e.g. HR values with CIs were not reported or survival data were not mature at the time of data cut-off ) caused that performing a meta-analysis of some end points all eligible trials was impossible and the narrative synthesis was conducted. The patients populations were differentiated (after one to three prior therapies) in the included trials which additionally differed in follow-up periods (in one trial follow-up period was not reported26); this differentiation limits the possibility to draw conclusions about the efficacy and safety of the analyzed interventions in case of specific patient subgroups. Other important limitations of this review include a small number of trials concerning therapeutic effects of the targeted therapies in relapsed or refractory MM and small number of patients included in two trials what might influence the results.26,33

Conclusion Despite the limitations, this systematic review gives the chance to compare the efficacy and safety of the approved targeted agents used as monotherapy or combined therapy in patients with relapsed or refractory MM. According to our knowledge, this is the first meta-analysis and the most up-to-date systematic review of literature performing such an assessment. The results of this comparison should be useful especially for the elderly or young patients with significant comorbidities for whom one- or two-drug regimens are recommended. This paper also demonstrated that there is very limited number of RCTs conducted on large patient populations and assessing different therapeutic options for relapsed or refractory MM.

Disclaimer statements Contributors All listed authors approved the final version of the manuscript. Funding The manuscript was self-financed by the authors. Conflicts of interest None. Ethics approval None.

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