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

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.

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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 (PICOS criteria) 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 2 below
• 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.