Lenalidomide/bortezomib/dexamethasone (RVd) has not been compared to other triplet induction regimens (cyclophosphamide, bortezomib, dexamethasone [CyBorD or VCD] and bortezomib, thalidomide, dexamethasone [VTD]) in phase III randomised studies. However, on the basis of cross-trial comparisons of response rates and toxicity, the expert reference panel supports the use of RVd as induction treatment for transplant eligible patients with multiple myeloma (MM). The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II GRIFFIN study.r
The dosing schedule in this eviQ protocol is based on the GRIFFIN study.r 207 newly diagnosed transplant eligible patients with MM were randomised to receive 4 cycles of RVd +/- daratumumab induction, autologous stem cell transplant (ASCT) and then 2 cycles of RVd +/- daratumumab consolidation (followed by lenalidomide maintenance). This schedule was preferred by the committee over other published regimens as it utilised subcutaneous bortezomib (which is associated with significantly lower peripheral neuropathy rates than intravenous administration) and could be administered within the PBS restrictions.
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase III trials |
Attal et al. 2017 (IFM-2009)r |
Yes |
No |
3 induction, 2 consolidation cycles
IV bortezomib 1.3 mg/m2 Day 1,4,8,11
Lenalidomide 25 mg Day 1-14
Dexamethasone 20 mg Day 1,2,4,5,8,9,11,12
|
Rosinol et al. 2019 (PETHEMA)r |
Yes |
No |
28 day cycles. 6 induction, 2 consolidation cycles.
SC bortezomib 1.3 mg/m2 Day 1,4,8,11
Lenalidomide 25 mg Day 1-21
Dexamethasone 40 mg Day 1-4, 9-12
|
Phase II trials |
Voorhees et al. 2020 (GRIFFIN)r |
Yes |
Yes |
- |
Roussel et al. 2014r |
Yes |
No |
3 induction, 2 consolidation cycles
IV bortezomib 1.3 mg/m2 Day 1,4,8,11
Lenalidomide 25 mg Day 1-14
Dexamethasone 40 mg Day 1,8,15
|
Retrospective studies |
Okazuka et al. 2020r |
Yes |
No |
28 day cycles. 4 induction cycles.
SC bortezomib 1.3 mg/m2 Day 1,8,15,22
Lenalidomide 15 mg Day 2-21 (not on Day 1,8,15)
Dexamethasone 40 mg weekly
|
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
V.3.2020 - 2021 |
Yes |
No |
IV/SC bortezomib 1.3 mg/m2 Day 1,4,8,11
Lenalidomide 25 mg Day 1-14
Dexamethasone 20 mg Day 1,2,4,5,8,9,11,12 or Dexamethasone 40 mg Day 1,8,15
|
BCCA |
01/02/2021 Revised: 01/06/2022 |
N/A |
No |
Published protocol for non-transplant candidates only. |
CCO |
2019 |
N/A |
No |
Published protocol for non-transplant candidates only. |
Efficacy
Table 1 - GRIFFIN studyr
© Blood 2020
In the RVd arm of the GRIFFIN study, the stringent complete response (sCR) rate by the end of post-ASCT consolidation was 32%. A final analysis of the GRIFFIN trial was presented in 2022, which showed sCR rates for RVd (48.0%) and minimal residual disease (MRD) negativity (next generation sequencing 10-5 threshold) reached 30.1%. The estimated 48-month PFS was 70%.r
Toxicity
A summary of the toxicities associated with this protocol are included in the table below. The most clinically significant toxicities for this treatment are peripheral neuropathy and haematological adverse events (AEs) (namely neutropenia and lymphopenia). Peripheral neuropathy was reported in 72.5% of patients and was grade 3/4 in 7.8% of patients using RVd in the GRIFFIN study. Haematological grade 3/4 events were common in patients including neutropenia (21.6%), thrombocytopenia (8.8%) and anaemia (5.9%).
Serious adverse events (AEs) were reported in 51% of patients in the RVd arm. The most common were pyrexia (7.8%) and pneumonia (10.8%). 20.6% of patients in the RVd arm discontinued therapy, most commonly due to peripheral neuropathy (3.9%).r
Table 2 - GRIFFIN study adverse eventsr
© Blood 2020