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. 2019 Nov 25;2019(11):CD013487.
doi: 10.1002/14651858.CD013487.

Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis

Vanessa Piechotta  1 , Tina Jakob  1 , Peter Langer  1 , Ina Monsef  1 , Christof Scheid  2 , Lise J Estcourt  3 , Sunday Ocheni  4 , Sebastian Theurich  5 , Kathrin Kuhr  6 , Benjamin Scheckel  1   7 , Anne Adams  6 , Nicole Skoetz  8
Affiliations

Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis

Vanessa Piechotta et al. Cochrane Database Syst Rev. .

Abstract

Background: Multiple myeloma is a bone marrow-based hematological malignancy accounting for approximately two per cent of cancers. First-line treatment for transplant-ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide.

Objectives: To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant-ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines.

Search methods: We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant-ineligible multiple myeloma.

Selection criteria: We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first-line treatment of adults with transplant-ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second-generation novel agents.

Data collection and analysis: Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta-analysis (NMA) unless stated.

Main results: We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre-specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open-label study design. Overall survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression-free survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA-risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta-analysed. However, all studies reported an improvement of QoL after initiation of anti-myeloma treatment for all assessed treatment regimens.

Authors' conclusions: Based on our four pre-selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head-to-head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment-combinations.

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Conflict of interest statement

NS: none known.

VP: none known.

PL: none known.

TJ: none known.

IM: none known.

CS: The author has received honoraria and travel support from Janssen, Celgene, Novartis, Bristol Myers Squibb and Takeda

SO: none known.

LE: none known.

ST: none known.

KK: none known.

BS: none known.

AA: none known.

Figures

1
1
Study flow diagram.
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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Network graph for outcome overall survival. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for the outcome OS. (a) OS‐ Subnetwork 1. Reference treatment: MP. (b) OS‐ Subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending)
5
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in OS‐Subnetwork 1
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Network graph for the outcome PFS. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for the outcome PFS. (a) PFS‐subnetwork 1. Reference treatment: MP. (b) PFS‐subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending)
8
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in PFS‐subnetwork 1
9
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Pairwise comparisons for the outcome grade 3 or 4 adverse events. The first‐named interventions are referred to as "intervention I". The last‐named interventions are referred to as "intervention II". A RR < 1 indicates an advantage for the experimental intervention and correspondingly a smaller risk for AEs grade 3 or 4.
10
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Network graph for the outcome polyneuropathy. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome polyneuropathy. (a) polyneuropathy‐ sSubnetwork 1. Reference treatment: MP. (b) polyneuropathy‐subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending).
12
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in polyneuropathy‐subnetwork 1
13
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Network graph for the outcome neutropenia. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome neutropenia. (a) neutropenia‐subnetwork 1. Reference treatment: MP. (b) neutropenia‐subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending).
15
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in neutropenia‐subnetwork 1
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Network graph for the outcome anaemia. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome anaemia. (a) anaemia‐subnetwork 1. Reference treatment: MP. (b) anaemia‐subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending).
18
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in anaemia‐subnetwork 1
19
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Network graph for the outcome thrombocytopenia. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome thrombocytopenia. (a) thrombocytopenia‐subnetwork 1. Reference treatment: MP. (b) thrombocytopenia‐subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending).
21
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in thrombocytopenia‐subnetwork 1
22
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Network graph for the outcome thromboembolism. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome thromboembolism. thromboembolism‐subnetwork 1. Reference treatment: MP. Treatments are ordered by P‐Score (descending).
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Network graph for the outcome infections. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome infections. (a) infections‐subnetwork 1. Reference treatment: MP. (b) infections‐subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending).
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in infections‐subnetwork 1
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Network graph for the outcome SAEs. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome serious adverse events. (a) SAE‐subnetwork 1. Reference treatment: RD. (b) SAE‐subnetwork 2. Reference treatment: VMPc. SAE‐subnetwork 3. Reference treatment: MP. Treatments are ordered by P‐Score (descending).
29
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Network graph for the outcome withdrawals due to adverse events. A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients
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Forest plot for outcome withdrawals due to adverse events. (a) withdrawals due to AEs‐subnetwork 1. Reference treatment: MP. (b) withdrawals due to AEs‐subnetwork 2. Reference treatment: VMPc. Treatments are ordered by P‐Score (descending).
31
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Local approach to check inconsistency ‐ comparison of direct and indirect estimate for closed loops in withdrawals due to AEs‐subnetwork 1
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Palumbo 2012 {published data only}
    1. Cavo M, Dimopoulos M, Palumbo A, Weisel K, Delforge M, Blade J, et al. Impact of renal impairment on the efficacy and safety of melphalan-prednisone-lenalidomide (LEN) induction followed by LEN maintenance in newly diagnosed multiple myeloma: mM-015 post-hoc analysis. In: Haematologica. Vol. 98. 2013:330-1.
    1. Dimopoulos MA, Delforge M, Hájek R, Kropff M, Petrucci MT, Lewis P, et al. Lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older: results of a randomized phase III trial. Haematologica 2013;98(5):784-8. - PMC - PubMed
    1. Dimopoulos MA, Palumbo A, Hajek R, Kropff M, Petrucci MT, Lewis P, et al. Factors that influence health-related quality of life in newly diagnosed patients with multiple myeloma aged? 65 years treated with melphalan, prednisone and lenalidomide followed by lenalidomide maintenance: results of a randomized trial. Leukemia and Lymphoma 2014;55(7):1489-97. - PMC - PubMed
    1. Gay F, Cavallo F, Raimondo F, Hardan I, Nagler A, Petrucci MT, et al. Impact of continuous treatment vs fixed duration of therapy in newly diagnosed myeloma patients: pFS1, PFS2, OS endpoints. In: Haematologica. Vol. 99. 2014:519.
    1. Palumbo A, Adam Z, Kropff M, Foa R, Catalano J, Gisslinger H. A phase 3 study evaluating the efficacy and safety of lenalidomide (len) combined with melphalan and prednisone followed by continuous lenalidomide maintenance (MPR-R) in patients (pts) = 65 Years (yrs) with newly diagnosed multiple myeloma (NDMM): updated results for pts aged 65-75 yrs enrolled in MM-015. In: Blood. Vol. 118. 2011.
Palumbo 2014 {published data only}
    1. Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 2010;116(23):4745-53. - PubMed
    1. Bringhen S, Larocca A, Rossi D, Romano A, Genuardi M, Ria R, et al. Efficacy and safety of once weekly bortezomib in multiple myeloma patients. In: Blood. Vol. 116. 2010. - PubMed
    1. Bringhen S, Magarotto V, Rossi D, Ria R, Offidani M, Patriarca F, et al. Bortezomib, melphalan, prednisone and thalidomide followed by maintenance with bortezomib and thalidomide (VMPT-VT) vs bortezomib, melphalan, prednisone (VMP) alone as first line treatment of multiple myeloma: updated follow-up and impact of prognostic factors. In: Haematologica. Vol. 96. 2011:67-8.
    1. Corso A, Raimondo F, Mangiacavalli S, Ria R, Offidani M, Pascutto C, et al. Bortezomib-based therapy overcomes the prognostic role of ISS score in multiple myeloma patients not eligible for transplant. In: Haematologica. Vol. 96. 2011:128.
    1. Gay F, Cavallo F, Raimondo F, Hardan I, Nagler A, Petrucci MT, et al. Impact of continuous treatment vs fixed duration of therapy in newly diagnosed myeloma patients: pFS1, PFS2, OS endpoints. In: Haematologica. Vol. 99. 2014:519.
Pawlyn 2017 {published data only}
    1. Brioli A, Davies F, Gregory W, Hinsley S, Marshall S, Pawlyn C, et al. Low rate of secondary primary malignancies (SPMs) in newly diagnosed multiple myeloma (MM) patients treated with lenalidomide: first results from the MRC MM XI trial. In: Haematologica. Vol. 98. 2013:104.
    1. Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; Results of the phase III myeloma XI study. In: Blood. Vol. 128. 2016.
    1. Jones JR, Cairns D, Gregory W, Sigsworth R, Collett C, Pawlyn C, et al. The NCRI Myeloma XI trial for newly diagnosed symptomatic multiple myeloma (NDMM); second primary malignancy (SPM) incidence when lenalidomide is used as an induction and maintenance treatment option. In: British Journal of Haematology. Vol. 173. 2016:86.
    1. Jones JR, Cairns DA, Gregory WM, Collett C, Pawlyn C, Sigsworth R, et al. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer Journal 2016;6(12):e506. - PMC - PubMed
    1. Jones JR, Cairns DA, Sigsworth R, Collett C, Pawlyn C, Striha A, et al. Myeloma XI trial for newly diagnosed multiple myeloma (NDMM); a report of second primary malignancy (SPM) rates and the importance of review of reported cases. In: Blood. Vol. 126. 2015:1847.
Sacchi 2011 {published data only}
    1. Sacchi S, Marcheselli R, Lazzaro A, Morabito F, Fragasso A, Di Renzo N, et al. A randomized trial with melphalan and prednisone versus melphalan and prednisone plus thalidomide in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplant. Leukemia and Lymphoma 2011;52(10):1942-8. - PubMed
San Miguel 2008 {published data only}
    1. Delforge M, Terpos E, Richardson PG, Shpilberg O, Khuageva NK, Schlag R, et al. Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma. European Journal of Haematology 2011;86(5):372-84. - PubMed
    1. Dimopoulos MA, Mateos MV, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, et al. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. European Journal of Haematology 2011;86(1):23-31. - PubMed
    1. Dimopoulos MA, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, Kastritis E, et al. VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. Journal of Clinical Oncology 2009;27(36):6086-93. - PubMed
    1. Harousseau JL, Palumbo A, Richardson PG, Schlag R, Dimopoulos MA, Shpilberg O, et al. Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood 2010;116(19):3743-3750. - PubMed
    1. Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. Journal of Clinical Oncology 2010;28(13):2259-66. - PubMed
Stewart 2015 {published data only}
    1. Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan Khan AA, et al. E1A06: a phase III trial comparing melphalan, prednisone, and thalidomide (MPT) versus melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed multiple myeloma MM). In: Haematologica. Vol. 99. 2014:220.
    1. Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, et al. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood 2015;126(11):1294-301. - PMC - PubMed
Waage 2010 {published data only}
    1. Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 2010;116(9):1405-12. - PubMed
    1. Waage A, Gimsing P, Juliusson G, Turesson I, Fayers P. Melphalan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo controlled randomised phase 3 trial. In: Blood. Vol. 110. 2007:32a.
Wijermans 2010 {published data only}
    1. Beurden-Tan C, Blommestein H, Zweegman S, Sonneveld P. The relationship of response on time to next treatment based on evidence from two RCTs in newly diagnosed stem cell transplantation ineligible multiple myeloma patients. In: Blood. Vol. 128. 2016:(no pagination).
    1. Verelst S, Termorshuizen F, Uyl-De Groot C, Sonneveld P, Wijermans P. Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQOL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial (HOVON 49). In: Haematologica. Vol. 96. 2011:S135. - PubMed
    1. Verelst S, Termorshuizen F, Uyl-de Groot C, Schaafsma MR, Ammerlaan R, Wittebol S. Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQOL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial. In: Blood. Vol. 116. 2010. - PubMed
    1. Verelst SG, Termorshuizen F, Uyl-de Groot CA, Schaafsma MR, Ammerlaan AH, Wittebol S, et al. Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial. Annals of Hematology 2011;90(12):1427-39. - PubMed
    1. Wijermans P, Schaafsma M, Norden Y, Ammerlaan R, Sonneveld P, Wittebol S, et al. Melphalan + prednisone vs melphalan + prednisone + thalidomide in induction therapy for multiple myeloma in elderly patients: first interim results of the Dutch cooperative group HOVON. In: Haematologica. Vol. 93. 2008:177.
Zweegman 2016 {published data only}
    1. Beurden-Tan C, Blommestein H, Zweegman S, Sonneveld P. The relationship of response on time to next treatment based on evidence from two RCTs in newly diagnosed stem cell transplantation ineligible multiple myeloma patients. In: Blood. Vol. 128. 2016:(no pagination).
    1. Kongsgaard Nielsen L, Stege C, Witte B, Holt B, Mellqvist UH, Salomo M, et al. Health-related quality of life in non-transplant eligible newly diagnosed multiple myeloma patients treated with melphalan/prednisolone plus either thalidomide or lenalidomide; results of the HOVON87/NMSG18 study. In: Quality of Life Research. Vol. 26. 2017:56-7.
    1. Stege C, Holt B, Mellqvist UH, Levin MD, Salomo M, Abildgaard N, et al. Frailty predicts survival and toxicity in newly diagnosed multiple myeloma patients ineligible for autologous stem cell transplantation; report of the HOVON-87/NMSG-18 study group. In: Blood. Vol. 130. 2017:(no pagination).
    1. Stege C, Kongsgaard Nielsen L, Witte B, Holt B, Mellqvist UH, Salomo M, et al. Quality of life with melphalan/prednisone plus either thalidomide (MPT-T) or lenalidomide (MPR-R) in non-transplant eligible newly diagnosed multiple myeloma; Results of the Hovon87/NMSG18 study. In: Haematologica. Vol. 102. 2017:190.
    1. Zweegman S, Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, et al. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood 2016;127(9):1109-16. - PubMed

References to studies excluded from this review

Anonymous 2003 {published data only}
    1. Anonymous. A multicenter parallel-group, placebo controlled, randomized, double-blind study of combination thalidomide plus glucocorticoid therapy versus glucocorticoid therapy alone as induction therapy for previously untreated subjects with multiple myeloma. available at: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-00500364/... (accessed 06 May 2019).
Barlogie 2004 {published data only}
    1. Anonymous. Study of bortezomib and Revlimid ™ for patients relapsing or progressing on total therapy II. available at: https://clinicaltrials.gov/show/nct00093028 (Accessed 28 May 2019).
    1. Barlogie B, Rasmussen E, Tricot G, Crowley J. Management of patients with multiple myeloma (MM) failing total therapy 2 (TT 2) according to thalidomide (THAL) randomization. In: Blood. Vol. 104. 2004:414a.
Brioli 2014 {published data only}
    1. Brioli A, Galli M, Tacchetti P, Crippa C, Spadano T, Pezzi A, et al. A combination therapy with bortezomib (BOR) and thalidomide in newly diagnosed myeloma patients is associated with a low incidence of second primary malignancies (SPMS). In: Haematologica. Vol. 99. 2014:373.
Facon 2006 {published data only}
    1. Facon T, Mary JY, Attal M, Pegourie B, Harousseau JL, Sadoun A. Melphalan-prednisone versus dexamethasone-based regimens for newly diagnosed myeloma patients aged 65-75 years. Final analysis of the IFM 95-01 trial on 489 patients. In: Blood. Vol. 102. 2003:147a.
    1. Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 2006;107(4):1292-8. - PubMed
Facon 2017 {published data only}
    1. Anonymous. Phase 3 study of carfilzomib, melphalan, prednisone vs bortezomib, melphalan, prednisone in newly diagnosed multiple myeloma. available at: ttps://clinicaltrials.gov/show/nct01818752 (accessed 03 July 2019).
    1. Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos MA, Hajek R, et al. Phase 3 Study (CLARION) of carfilzomib, melphalan, prednisone (KMP) v bortezomib, melphalan, prednisone (VMP) in newly diagnosed multiple myeloma (NDMM). Clinical Lymphoma, Myeloma and Leukemia 2017;17(1):e26-7.
Facon 2018 {published data only}
    1. Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. LBA-2 phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). In: Blood. Vol. 132. 2018:LBA-2.
Foa 2007 {published data only}
    1. Foa R, Weber D, Dimopoulos M, Olesnyckyj M, Yu Z, Zeldis J, et al. Lenalidomide/dexamethasone improves response and prolongs time to progression, even in patients with IgA multiple myeloma: a sub-analysis of the MM-009/010 studies. In: Blood. Vol. 110. 2007:284b.
Harousseau 2003 {published data only}
    1. Harousseau JL, Attal M. The IFM-90 trial. In: Hematology Journal. Vol. 4. 2003:S55.
Hejlova 2000 {published data only}
    1. Hejlova N, Hajek R, Adam Z, Scudla Z, Bacovsky J, Koza V, et al. Report of the "4W" trial of the Czech myeloma group. In: Hematology Journal. Vol. 1. 2000:168-9.
Hernández 2004 {published data only}
    1. Hernández JM, García-Sanz R, Golvano E, Bladé J, Fernandez-Calvo J, Trujillo J, et al. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. British Journal of Heamatology 2004;127(2):159-64. - PubMed
Kumar 2012 {published data only}
    1. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119(19):4375-82. - PubMed
Ludwig 2017a {published data only}
    1. Anonymous. Patients with newly diagnosed multiple myeloma comparing KTd vs. KRd induction therapy and investigating a K-mono maintenance strategy. Available at: https://clinicaltrials.gov/show/nct02891811 (accessed 03 July 2019).
    1. Ludwig H. AGMT-MM2 A randomized phase II study in transplant ineligible patients with newly diagnosed multiple myeloma (NDMM) comparing Carfilzomib + Thalidomide + Dexamethasone(KTd) with Carfilzomib + Lenalidomide + Dexamethasone (KRd) induction therapy followed by Carfilzomib (K) maintenance or control. In: Magazine of European Medical Oncology. Vol. 10. 2017:S44-s45.
Mateos 2016 {published data only}
    1. Mateos MV, Gutierrez NC, Martin ML, Martinez-Lopez J, Hernandez MT, Martinez R, et al. Bortezomib plus melphalan and prednisone (VMP) followed by lenalidomide and dexamethasone (RD) in newly diagnosed elderly myeloma patients overcome the poor prognosis of high-risk cytogenetic abnormalities (CA) detected by fluorescence in situ hibridization (FISH). In: Blood. Vol. 126. 2015:4243.
    1. Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, et al. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood 2016;127(4):420-5. - PubMed
    1. Mateos MV, Martinez-Lopez J, Hernandez M, Martinez R, Rosinol L, Ocio EM, et al. Depth of response as surrogate marker for progression-free survival and overall survival in elderly newly diagnosed myeloma patients treated with VMP and Rd: gEM2010MAS65. In: Haematologica. Vol. 102. 2017:143.
    1. Mateos MV, Martinez-Lopez J, Hernandez MT, Ocio EM, Rosinol L, Martinez R, et al. Bortezomib, melphalan, prednisone (VMP) and lenalidomide plus dexamethasone (RD) is the optimal combination for patients with newly diagnosed multiple myeloma (MM) patients between 65 and 80 years. In: Blood. Vol. 126. 2015:1848.
Mateos 2018 {published data only}
    1. Facon T, Cavo M, Jakubowiak A, San Miguel J, Kumar S, Orlowski RZ, et al. Two randomized open-label studies of daratumumab (DARA) plus standard of care treatment versus standard of care alone in patients with previously untreated multiple myeloma (MM) ineligible for high-dose therapy: 54767414MMY3007 (Alcyone) and 54767414MMY3008 (Maia). In: Clinical Lymphoma, Myeloma and Leukemia. Vol. 15. 2015:e294-5.
    1. Mateos MV, Cavo M, Jakubowiak AJ, Carson RL, Qi M, Bandekar R, et al. A randomized open-label study of bortezomib, melphalan, and prednisone (VMP) versus daratumumab (DARA) plus VMP in patients with previously untreated multiple myeloma (MM) who are ineligible for high-dose therapy: 54767414MMY3007 (Alcyone). In: Journal of Clinical Oncology. Vol. 33. 2015:supplement 1 (no pagination).
    1. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients (PTS) ineligible for transplant: a phase 3 ran-domized study (alcyone). In: Haematologica. Vol. 103. 2018:22.
    1. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. New England Journal of Medicine 2018;378(6):518-28. - PubMed
    1. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak AJ, Knop S, et al. Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for transplant (ALCYONE). In: Blood. Vol. 130. 2017:Supplement 1 (no pagination).
Merz 2015 {published data only}
    1. Merz M, Salwender HJ, Haenel M, Bertsch U, Kunz C, Hielscher T, et al. Clinical risk factors for peripheral neuropathy in patients treated with subcutaneous or intravenous bortezomib for newly diagnosed multiple myeloma. In: BLood. Vol. 126. 2015:4233.
Montefusco 2013 {published data only}
    1. Montefusco V. First-line treatment in elderly patients. In: European journal of cancer. Vol. 49. 2013:S19.
Morgan 2002 {published data only}
    1. Morgan G, Davies FE, Hawkins K, Brown J, Drayson MT. The MRC Myeloma VII Trial of standard versus intensive treatment in patients <65 years of age with multiple myeloma. In: Blood. Vol. 100. 2002:178a.
NCT00522392 {published data only}
    1. Anonymous. Bortezomib and dexamethasone with or without lenalidomide in treating patients with multiple myeloma previously treated with dexamethasone. available at: https://clinicaltrials.gov/show/nct00522392 (accessed 06 May 2019).
NCT00734877 {published data only}
    1. Anonymous. UARK 2013-13, Total Therapy 4B - Formerly 2008-01 - A phase III trial for low risk myeloma. available at: https://clinicaltrials.gov/show/nct00734877 (accessed 06 May 2019).
NCT01850524 {published data only}
    1. Anonymous. IXAZOMIB plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in adult patients with newly diagnosed multiple myeloma. available at: https://clinicaltrials.gov/show/nct01850524 (accessed 03 July 2019).
NCT01863550 {published data only}
    1. Anonymous. Bortezomib or carfilzomib With lenalidomide and dexamethasone in treating patients with newly diagnosed multiple myeloma. available at: https://clinicaltrials.gov/show/nct01863550 (accessed 03 July 2019).
NCT02586038 {published data only}
    1. Anonymous. Study that compares 3 arm: MLN9708 dexamethasone, MLN9708 cyclophosphamide and dexamethasone, MLN9708 thalidomide and dexamethasone followed by maintenance with MLN9708 in newly diagnosed elderly multiple myeloma patients. available at: https://clinicaltrials.gov/show/nct02586038 (accessed 03 July 2019).
NCT03710603 {published data only}
    1. Anonymous. A study comparing daratumumab, VELCADE (bortezomib), lenalidomide, and dexamethasone (D-VRd) with VELCADE, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. available at: https://clinicaltrials.gov/show/nct03652064 (accessed 03 July 2019).
    1. Anonymous. Daratumumab, VELCADE (bortezomib), lenalidomide and dexamethasone compared to VELCADE, lenalidomide and dexamethasone in subjects with previously untreated multiple myeloma. available at: https://clinicaltrials.gov/show/nct03710603 (accessed 03 July 2019).
Niesvizky 2003 {published data only}
    1. Niesvizky R, Pekle K, Lyons L, Pearse RN, Bergsagel PL, Schuster MW. Dexamethsone alone, or in combination with low-dose thalidomide as induction therapy for advanced multiple myeloma, and the effect of the addition of clarithromycin (Biaxin?) on response rate. Interim results of a prospective, sequential, randomized trial. In: Blood. Vol. 102. 2003:237a.
Offidani 2004 {published data only}
    1. Offidani M, Corvatta L, Marconi M, Olivieri A, Catarini M, Mele A, et al. Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma. Hematology Journal 2004;5(4):312-7. - PubMed
Palumbo 2016 {published data only}
    1. Lonial S, Ribeiro De Oliveira M, Yimer H, Mateos MV, Rifkin R, Schjesvold F, et al. KEYNOTE-185: a randomized, open-label phase 3 study of pembrolizumab in combination with lenalidomide and lowdose dexamethasone in newly diagnosed and treatmentnaive multiple myeloma (MM). In: Annals of Oncology. Vol. 27. 2016:viii16.
    1. Palumbo A, Mateos MV, San Miguel J, Shah J, Thompson S, Marinello P, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone in newly diagnosed and treatment-naive multiple myeloma (MM): randomized, phase 3 KEYNOTE-185 study. In: Annals of Oncology. Vol. 27. 2016:(no pagination).
    1. Shah J, Lonial S, Oliveira MR, Yimer H, Mateos MV, Rifkin R, et al. KEYNOTE-185: randomized, open-label, phase III study of pembrolizumab in combination with lenalidomide and low-dose dexamethasone in patients with newly diagnosed and treatment-naive multiple myeloma (MM). In: Journal for Immunotherapy of Cancer. Vol. 4. 2016.
Rajkumar 2006b {published data only}
    1. Greipp PR. Eastern Cooperative Oncology Group E1A00: phase III randomized study of dexamethasone with or without thalidomide in patients with newly diagnosed multiple myeloma. Clinical Advances in Hematology & Ooncology 2003;1(3):188-9. - PubMed
    1. Rajkumar SV, Blood E , Vesole D, Fonseca R, Greipp PR, Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. Journal of Clinical Oncology 2006;24(3):431-6. - PubMed
    1. Rajkumar SV, Vesole DH, Shepard PR, Greipp PR. A randomised phase III trial of thalidomide plus dexamethasone versus dexamethasone in newly diagnosed multiple myeloma (E1A00): a trial coordinated by the Eastern Cooperative Oncology Group. In: Journal of Clinical Oncology. Vol. 22. 2004:558. - PubMed
    1. Rajkumar SV, Vesole DH, Shepard R, Greipp PR. Thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed multiplemMyeloma (E1A00): results of a phase III trial coordinated by the Eastern Cooperative Oncology Group. In: Blood. Vol. 104. 2004:63.
Rajkumar 2008 {published data only}
    1. Rajkumar SV, Hussein M, Catalano J, Jedrzejcak W, Sirkovich S, Olesnyckyj M, et al. A multicenter, randomized, double-blind, placebo-controlled trial of thalidomide plus dexamethasone versus dexamethasone alone as initial therapy for newly diagnosed multiple myeloma. In: Journal of Clinical Oncology. Vol. 24. 2006:426. - PMC - PubMed
    1. Rajkumar SV, Hussein M, Catalano J, Jedrzejczak W, Sirkovich S, Olesnyckyj M, et al. A randomized, double-blind, placebo-controlled trial of thalidomide plus dexamethasone versus dexamethasone alone as primary therapy for newly diagnosed multiple myeloma. In: Blood. Vol. 108. 2006:238.
    1. Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. Journal of Clinical Oncology 2008;26(13):2171-7. - PMC - PubMed
San Miguel 2014 {published data only}
    1. San Miguel J, Blade J, Samoilova O, Shpilberg O, Grosicki S, Maloisel F, et al. Randomized, open-label, phase 2 study of siltuximab (an anti-il-6 mab) and bortezomib-melphalan-prednisone versus bortezomib-melphalan-prednisone in patients with previously untreated multiple myeloma. In: Haematologica. Vol. 98. 2013:97.
    1. San Miguel J, Blade J, Shpilberg O, Grosicki S, Maloisel F, Min CK, et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 2014;123(26):4136-42. - PMC - PubMed
Takezako 2017 {published data only}
    1. Anonymous. PH III study of lenalidomide and dexamethasone with or without elotuzumab to treat peviously untreated multiple myeloma (ELO 1 substudy). available at: https://clinicaltrials.gov/show/nct01891643 (accessed 03 July 2019).
    1. Anonymous. Phase III study of lenalidomide and dexamethasone with or without elotuzumab to treat newly diagnosed, previously untreated multiple myeloma. available at: https://clinicaltrials.gov/show/nct01335399 (accessed 03 July 2019).
    1. Takezako N, Ohta K, Handa H, Hori M, Kinoshita G, Shelat S, et al. Elotuzumab plus lenalidomide/dexamethasone (ELD) vs LD in patients with newly diagnosed multiple myeloma: phase 2, randomized, open-label study in Japan. In: Blood. Vol. 130. 2017:supplement 1 (no pagination).
Usmani 2014 {published data only}
    1. Anonymous. S1211 Bortezomib, Dexamethasone, and Lenalidomide With or Without Elotuzumab in Treating Patients With Newly Diagnosed High-Risk Multiple Myeloma. available at: https://clinicaltrials.gov/show/nct01668719 (accessed 03 July 2019).
    1. Usmani SZ, Hoering A, Sexton R, Ailawadhi S, Shah JJ, Fredette S, et al. SWOG 1211: a randomized phase I/II study of optimal induction therapy for newly diagnosed high-risk multiple myeloma (HRMM). In: Journal of Clinical Oncology. Vol. 32. 2014:15 suppl.1 (no pagination).
White 2007 {published data only}
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References to other published versions of this review

Piechotta 2018
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