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Many patients with multiple myeloma (MM) are ineligible for stem cell transplant (SCT) due to older age (typically >65 years) or other existing comorbidities.1 Multiple clinical trials have focused on finding the optimal combination of treatments as a therapeutic alternative to SCT; with the addition of daratumumab (dara) to existing therapies like bortezomib (V), melphalan (M) and prednisone (P) or lenalidomide (R) and dexamethasone (d) leading the most promising developments.2 However, this rapid innovation in the field has made it difficult for physicians to determine the optimal strategy for patients. Additionally, there is a lack of clinical trials directly comparing the efficacy of these therapies.
In an attempt to uncover whether there is an optimal first-line treatment regimen for patients with transplant-ineligible MM, Manuel David Gil-Sierra and colleagues conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) selected via systematic review, using progression-free survival (PFS) data to assess efficacy.
The MM Hub is currently focussing on the improvement of frontline therapies as part of a monthly educational theme; click here to find out more.
A vast bibliographic search was performed using the MEDLINE® and EMBASE® databases to identify phase II and III RCTs for analysis. Population, intervention, comparator, outcome and study design (PICOS criteria) were used to identify RCTs as per the criteria below:
Of the 593 studies identified in the MEDLINE® and EMBASE® search, 10 RCTs met the inclusion criteria. The remaining studies were excluded, predominantly due to a different trial design or indication.
A primary analysis of all studies was conducted, followed by a sensitivity analysis omitting one study, the SWOG S077, to determine its potential influence on the rest of the network. SWOG S0777 included patients who were both eligible and ineligible for SCT, thus causing heterogeneity where data separation was not possible.
Details of the 10 RCTs used for the NMA are shown in Table 1.
Table 1. RCTs used for NMA
CrI, credibility interval; CRP, cyclophosphamide, lenalidomide and prednisone; Dara, daratumumab; HR, hazard ratio; MPT, melphalan, prednisone and thalidomide; MRP, melphalan, lenalidomide and prednisone; R, lenalidomide; Rd, lenalidomide and dexamethasone; Rd18, lenalidomide for up to 18 cycles; T, thalidomide; VMP, bortezomib, melphalan and prednisone; VRd, bortezomib, lenalidomide and dexamethasone |
|||||
Trial name or publication |
Intervention arm |
N |
Control arm |
N |
HR (95% CrI) |
---|---|---|---|---|---|
MAIA |
Dara-Rd with dara maintenance |
368 |
Rd |
369 |
0.56 (0.43–0.73) |
ALCYONE |
Dara-VMP with dara maintenance |
350 |
VMP |
356 |
0.50 (0.38–0.65) |
Zweegman et al., 2016 |
MPT with R maintenance |
319 |
MPT with T maintenance |
318 |
0.87 (0.72–1.04) |
Magarotto et al., 2016 |
CRP with R maintenance |
220 |
Rd |
217 |
1.005 (0.895–1.127) |
MRP with R maintenance |
217 |
0.805 (0.631–1.027) |
|||
Hungria et al., 2016 |
MPT |
32 |
CTd |
32 |
0.89 (0.48–1.64) |
ECOG E1A06 |
MPT with T maintenance |
154 |
MPR with R maintenance |
152 |
0.84 (0.64–1.09) |
FIRST |
Rd18 |
541 |
Rd |
535 |
1.429 (1.220–1.667) |
MPT |
547 |
1.389 (1.176–1.639) |
|||
VISTA |
VMP |
344 |
MP |
338 |
0.56 (0.43–0.72) |
Palumbo et al., 2006 |
MPT with T maintenance |
129 |
MP |
126 |
0.51 (0.35–0.75) |
SWOG S0777 |
VRd with Rd maintenance |
242 |
Rd |
229 |
0.71 (0.56–0.90) |
Table 2. Fixed-effects analysis of treatment regimen compared to dara-VMP plus dara maintenance
CrI, credibility interval; CRP, cyclophosphamide, lenalidomide and prednisone; Dara, daratumumab; HR, hazard ratio; MPT, melphalan, prednisone and thalidomide; MRP, melphalan, lenalidomide and prednisone; R, lenalidomide; Rd, lenalidomide and dexamethasone; Rd18, lenalidomide for up to 18 cycles; T, thalidomide; VMP, bortezomib, melphalan and prednisone; VRd, bortezomib, lenalidomide and dexamethasone |
||
Dara-VMP plus dara maintenance vs |
Primary analysis HR (95% CrI) |
Sensitivity analysis HR (95% CrI) |
---|---|---|
CRP with R maintenance |
2.2 (1.2–3.9) |
2.2 (1.2–3.9) |
CTD |
3.4 (1.4–8.2) |
3.4 (1.4–8.2) |
Dara-Rd with dara maintenance |
1.2 (0.6–2.4) |
1.2 (0.6–2.4) |
MP |
3.6 (2.5–5.1) |
3.6 (2.5–5.1) |
MPT |
3.0 (1.6–5.7) |
3.0 (1.6–5.6) |
MPT with T maintenance |
1.8 (1.1–3.1) |
1.8 (1.1–3.1) |
MRP with R maintenance |
1.8 (1.0–3.0) |
1.7 (1.0–3.0) |
Rd |
2.2 (1.2–4.0) |
2.2 (1.2–4.0) |
RD18 |
3.1 (1.7–5.8) |
3.1 (1.7–5.8) |
VMP |
2.0 (1.5–2.6) |
2.0 (1.5–2.6) |
VRd with Rd maintenance |
1.6 (0.8–3.0) |
Excluded* |
* The SWOG S0777 trial (VRd with Rd maintenance) was excluded from the sensitivity analysis
These results show that treatments based on daratumumab present the best PFS results. Bortezomib combination treatments, particularly VRD, have similar efficacy to daratumumab treatments. Nevertheless, the limitations of the SWOG heterogenous population should be taken into account.
The main limitation to this study is the lack of uniformity in the trials. One particular challenge is being able to distinguish between study populations since heterogenous populations were included in some of them. Given this NMA aimed to study transplant-ineligible patients, the inclusion of data from transplant eligible patients has the potential to affect the results significantly. Likewise, many of the trials’ treatment schemes differed for VMP, MRP with R maintenance, MPT with T maintenance and Rd. These limitations should be considered when interpreting results for clinical decision making.
In this NMA of frontline treatment regimens for patients with transplant ineligible MM, dara-VMP followed by dara maintenance provided the best efficacy in relation to PFS, while dara-Rd followed by dara maintenance and VRd regimens showed some promising activity. To further elucidate the efficacy of these treatments, patient safety, suitability and efficiency should be assessed.
Medical Masterclass contributors and Firth J. Haematology: multiple myeloma. Clin Med (Lond). 2019 Jan;19(1):1-58. DOI: 7861/clinmedicine.19-1-58
Gil-Sierra M.D. et al. Network meta-analysis of first line treatments in transplant-ineligible multiple myeloma patients. Eur J Haematol. 2020 March 2;00:1-10. DOI: 1111/ejh.13407
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