Lenalidomide/bortezomib/dexamethasone (RVd) induction followed by continuous lenalidomide/dexamethasone (Rd) was demonstrated to be superior to continuous Rd in patients with newly diagnosed multiple myeloma (MM), without an intent for immediate autologous stem cell transplant (ASCT), prolonging both progression-free survival (PFS) and overall survival (OS) in SWOG S0777.r However, the patient population in SWOG S0777 were significantly younger than the typical transplant-ineligible population in Australia, with 57% of patients aged less than 65 years.
Induction therapy was discontinued in 23% of patients receiving RVd in SWOG S0777 due to adverse events.r Older patients are at higher risk of discontinuationr and attenuated RVd regimens have been proposed to reduce toxicity and to optimise continuation of therapy. There are no phase III studies evaluating these dose attenuated schedules. The expert reference panel supported publication of this protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II O’Donnell study evaluating RVd-lite.r
RVd-lite was evaluated in a single-arm phase II study of 50 patients.r It was administered over a 35 day cycle with lenalidomide 15 mg orally on days 1-21, bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15 and 22 and dexamethasone 20 mg orally on the day of and day after bortezomib for 9 cycles (for patients >75 years old, dexamethasone dose was administered weekly on day 1, 8, 15 and 22). This was followed by six 28-day cycles of consolidation with lenalidomide 15 mg orally on days 1-21 and bortezomib 1.3 mg/m2 subcutaneously on days 1 and 15. Maintenance lenalidomide was not mandated, but was given to 66% of patients. Only the induction part of this protocol is currently available through the PBS.
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trial |
O'Donnell et al. 2018r |
Yes |
Yes |
Followed by 6 cycles of consolidation with lenalidomide and bortezomib. |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
V.3.2023 |
Yes |
Yes |
|
BCCA |
N/A |
N/A |
N/A |
|
CCO |
2019 |
Yes |
Yes |
|
MSAG |
2022 |
Yes |
Yes |
|
Efficacy
The primary endpoint of the RVd-lite study was overall response rate (ORR) after 4 cycles of therapy. The ORR was 86% for the 50 patients, 66% of whom achieved a very good partial response (VGPR) or better. At a follow-up of 61 months, median PFS was 41.9 months (95% CI, 31.2 – not reached) and median OS not reached. The 5-year OS was 61.3%.r
Within the limits of cross-trial comparisons, this was comparable to the results obtained in SWOG S0777 which reported a median PFS of 41 months in those receiving RVd induction and the median OS was not reached, but was longer than 84 months.r
Figure 1: Progression free survival and overall survival graphsr
© British Journal of Haematology 2018
Toxicity
The toxicity profile can be seen in the table below. Fatigue was the most common toxicity, reported by 37 (74%) of patients. Peripheral neuropathy was reported in 31 (62%). 27 experienced sensory peripheral neuropathy: 17 grade 1; 9 grade 2 and 1 grade 3. Six patients reported peripheral motor neuropathy: 3 grade 1 and 3 grade 2.r
39 patients had dose modifications: 19 patients (38%) for bortezomib, 27 (54%) for lenalidomide and 32 (64%) for dexamethasone. Two patients discontinued treatment because of toxicity: retinal artery thrombosis (attributable to lenalidomide) and grade 3 peripheral neuropathy (attributable to bortezomib).
Table 1: Treatment-related adverse events with overall incidence greater than 15%r
© British Journal of Haematology 2018
Patient Reported Outcomes
At the end of treatment there were statistically significant improvements in scores of physical functioning, future perspective and disease symptoms. Patients reported fewer symptoms across all symptom domains with the exception of diarrhoea.rr