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Network meta-analysis of first-line treatments in transplant-ineligible multiple myeloma patients

Apr 9, 2020

Many patients with multiple myeloma (MM) are ineligible for stem cell transplant (SCT) due to older age (typically >65 years) or other existing comorbidities. 1Multiple 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. 2However, 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-Sierraand 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.

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Study design  

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 ( PICOScriteria) were used to identify RCTs as per the criteria below:

  • Population: patients with newly diagnosed MM (NDMM) not eligible for SCT
  • Intervention: treatments with R, thalidomide (T), V or dara and any combination of these
  • Comparator: any
  • Outcome: PFS
  • Study design: phase II/III RCTs

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.

Results

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)

Primary analysis

  • Dara-VMP with dara maintenance showed the best HR value and was further used as the reference to compare the HRs of different therapies, which are shown in Table 2below
  • Dara-Rd with dara maintenance and VRd with Rd maintenance showed the next best HR values compared to the reference (dara-VMP dara)
    • However, since the 95% credibility intervals (CrI) covered 1, there were no statistically significant differences between the three regimens

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

Sensitivity analysis

  • Sensitivity analysis included all studies in the network except SWOG S0777, again using dara-VMP with dara maintenance as the reference treatment
  • The optimal combinations, using HRs, were found to be dara-Rd with dara maintenance and MRP with R maintenance ( Table 2)
    • However, these combinations had 95% CrI values crossing 1 indicating non-significant differences
  • Only dara-VMP with dara maintenance provided a statistically significant difference in HR (p<0.05) compared to alternative therapies

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.

Limitations

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.

Conclusion

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.

  1. Medical Masterclass contributors and Firth J. Haematology: multiple myeloma. Clin Med (Lond). 2019 Jan;19(1):1-58. DOI: 7861/clinmedicine.19-1-58

  2. 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