Multiple drug combinations of bortezomib, lenalidomide and thalidomide for initial treatment of adults with transplant-ineligible multiple myeloma

Background

Multiple myeloma is a type of blood cancer. It accounts for approximately 2% of all cancers and is still considered incurable. For people with newly diagnosed multiple myeloma (NDMM), who are unsuitable for a procedure where damaged blood cells are replaced with healthy ones (stem-cell transplant), treatment is usually a multiple drug combination of bortezomib, lenalidomide, or thalidomide, plus melphalan and prednisolone (MP) or dexamethasone (D). Multiple drug combinations are approved for initial anti-myeloma therapy, however, access to these medicines is restricted in many countries worldwide.

Aim of the review

To compare the benefits and harms of selected anti-myeloma drugs (bortezomib (V), lenalidomide (R), thalidomide (T)) for transplant-unsuitable NDMM.

Study characteristics

We searched selected medical databases and trial registries until 14th February 2019. We included studies comparing multiple drug combinations of V, R, and T for the treatment of people with NDMM who were unsuitable for a stem-cell transplant. We differentiated between fixed treatment duration and continuous therapy. Fixed therapy is a pre-specified number of cycles, while a continuous therapy is given until the disease gets worse, the person finds the drug hard to tolerate, or when the treatment is given for a prolonged period. Continuous therapies are indicated with a "c".

Key results

We identified 25 studies involving 11,403 transplant-unsuitable adults with NDMM, and comparing 21 different treatment regimens.

Survival

People who had the standard treatment, MP, lived for an average of 35 months. People treated with RD, TMP, and VRDc probably live for much longer (moderate certainty). Treatment with VMP may also lead to much longer survival, compared to MP (low certainty). People treated with RD lived for an additional 20.4 months; with TMP an additional 11.6 months; with VRDc an additional 36.2 months, and with VMP an additional 14.9 months.

Harms

On average, 0.9% (9 out of 1000) of people treated with MP experienced peripheral nerve damage (polyneuropathies).The evidence was inconclusive whether treatment with RD decreases the risk of developing a polyneuropathy, compared to MP. The estimated risk of polyneuropathies with RD was 0.5%. Treatment with TMP and VMP probably increases the risk of experiencing polyneuropathies compared to MP (moderate certainty). The estimated risk with TMP was 4.0%, and with VMP 79.4%. No VRDc treatment study reported the number of participants with severe polyneuropathies.

On average, 36.1% (361 out of 1000) of people on MP-treatment experienced at least one serious adverse event (SAE). VMP probably increases the proportion of participants with SAEs compared to MP to 46.2% (moderate certainty).

On average, 9.2% (92 out of 1000) of people treated with MP stop the treatment because of adverse events (AEs). Treatment with RD, TMP, and VRDc leads to a much higher proportion of people stopping treatment because of AEs than MP (high certainty). The risk of stopping treatment with RD is 38.5%; with TMP 37.7%, with VRDc 82.1%. Treatment with VMP probably increases the risk of stopping treatment because of AEs compared to MP (9.75%, moderate certainty).

Quality of life

Quality of life (QoL) was reported in four studies for seven different treatments 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 in QoL after anti-myeloma treatment was started for all assessed treatments.

Conclusions

VRDc showed the highest overall survival benefits, compared to MP. RD and TMP also improved OS compared to MP. However, these combinations of drugs also led to more adverse events compared to MP, and led to more people stopping treatment. More trials are needed that look carefully at both harms and QoL.

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.

Read the full 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 strategy: 

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 with RD (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.

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