ABSTRACT
Background
Lenalidomide, bortezomib, and dexamethasone (RVD) remains a standard of care regimen for newly diagnosed multiple myeloma in centers without access to upfront anti‐CD38 therapy within the Asia‐Pacific. However, regimens proven efficacious in clinical trials utilize twice‐weekly bortezomib, which is now thought to confer unacceptable toxicity, particularly in transplant‐ineligible patients. There is a paucity of prospective data on RVD treatment schedules utilizing weekly bortezomib, which has implications for health care systems implementing standardized treatment based on clinical trial evidence.
Methods
Eighty‐three patients with newly diagnosed transplant‐ineligible multiple myeloma from six hospitals in Australia, received one of two RVD regimens utilizing weekly subcutaneous bortezomib (Modified SWOG and Modified RVD Lite) pragmatically adapted from their corresponding clinical trials. Baseline characteristics, response rates, toxicities, and survival were assessed.
Results
At a median follow‐up of 27.4 months, Modified SWOG achieved an ORR 91.4%, ≥ VGPR 71.4%, and 24‐month progression‐free survival (PFS) of 63.1% (95% CI: 47.6–83.5). Modified RVD Lite achieved an ORR 93.9%, ≥ VGPR 64.7%, and 24‐month PFS of 53.6% (95% CI: 39.1–73.4). Despite dose attenuation, significant toxicity was still seen overall with hospitalizations in 48.2% and premature cessation due to toxicity in 31.3%. Peripheral sensory neuropathy was lower than in published clinical trials, reported in 32 (38.6%) patients, with Grade 3 events in only 2 patients.
Conclusion
This study demonstrates that real‐world outcomes of weekly RVD regimens have comparable efficacy to published twice‐weekly regimens; however, toxicity remains a significant challenge in this patient population.
Keywords: frailty, myeloma, RVD, transplant‐ineligible, VRD
RVD with weekly bortezomib dosing in real‐world newly diagnosed transplant‐ineligible myeloma shows comparable efficacy and reduced toxicity compared to twice‐weekly trial protocols.
1. Introduction
Lenalidomide, bortezomib, and dexamethasone (RVD) remains a standard of care induction regimen for newly diagnosed multiple myeloma within the Asia‐Pacific [1, 2, 3, 4], particularly in resource‐limited centers without access to frontline anti‐CD38 therapy [3]. However, there are no standardized approaches to RVD with numerous published variations of the regimen in clinical trials and varying adaptations in real‐world practice [5, 6, 7, 8].
Evidence for RVD in transplant‐ineligible patients has largely been derived from the landmark SWOG S0777 Phase 3 trial, which demonstrated improved progression‐free survival (PFS) and overall survival (OS) when compared to lenalidomide/dexamethasone (Rd) [9, 10]. However, its outcomes are difficult to generalize to the real‐world transplant‐ineligible population, where patients are typically older and frailer. Notably, 69% of participants in the SWOG S0777 study were intended for deferred transplant, 38% were ≥ 65 years, and only 12% Eastern Cooperative Oncology Group (ECOG) > 1. Post hoc analyses of SWOG S0777 outcomes stratified by age suggested PFS and OS benefits were not statistically significant in those > 65 years, potentially attributed to higher treatment discontinuation rates due to increased toxicity (47% vs. 26% in those < 65 years receiving RVD) [11]. This treatment schedule with its use of twice‐weekly bortezomib is widely considered to confer unacceptable toxicity in a survey of contemporary prescribing practices, particularly for transplant‐ineligible patients [12].
A subsequent Phase 2 trial of dose‐attenuated RVD (RVD Lite) in elderly/frail patients demonstrated comparable response rates and PFS with less toxicity [13]. There are other published dose‐attenuated protocols, such as RVD Premium Lite and RVD Ultra Lite, which have not been formally assessed in trials but commonly utilized in clinical practice [6, 7]. Of note, there are no randomized trial data for weekly RVD regimens and limited registry data on real‐world outcomes and toxicities of RVD in transplant‐ineligible patients [14].
For real‐world implementation of RVD as standard of care, myeloma centers globally have navigated decisions around which variations of RVD to employ in practice. In routine hematology practice, there is often a tendency to preserve dose intensity in an effort to maximize response, which may lead to the use of more intensive regimens in older or frail patients. Divergence from published regimens in jurisdictions with centralized health care can present challenges to governance. Within the Australian context, there is a strong reliance on consensus RVD protocols derived from treatment schedules used in clinical trials, which predominantly used twice‐weekly bortezomib. In addition, not all published regimens (including RVD Lite) can be delivered as per protocol under the funding limitations of the Australian Pharmaceutical Benefits Scheme (PBS). To address these concerns, several centers opted to “harmonize” RVD administration with two pragmatic consensus regimens incorporating weekly bortezomib based on RVD Lite or SWOG0777. The intent of protocol harmonization was to support clinicians in adopting evidence‐based dose attenuation, including once‐weekly bortezomib, while maintaining acceptable efficacy.
The aim of this study is to prospectively evaluate toxicity, response rates, and survival outcomes utilizing these harmonized consensus RVD regimens incorporating weekly bortezomib in transplant‐ineligible, newly diagnosed multiple myeloma.
2. Methods
2.1. Study Design and Patients
Patients were prospectively included from six participating hospitals in Australia, from the PBS listing of RVD on June 1, 2020 until January 1, 2023. All patients ≥ 18 years of age with newly diagnosed transplant‐ineligible multiple myeloma receiving harmonized RVD were included in this study. Those who underwent alternative induction therapy were excluded. The harmonized RVD protocols utilized in this study were consensus‐based protocols that were developed to provide a safe and consistent approach to treatment delivery for transplant‐ineligible patients across participating centers within the available reimbursement restrictions for RVD under the Australian PBS. This study was approved by the St Vincent's Hospital Sydney Human Research Ethics Committee.
2.2. Treatment Regimens
Patients received one of two harmonized RVD protocols as decided by their treating physician, which were named Modified SWOG S0777 or Modified RVD Lite.
Modified SWOG S0777 is a consensus‐derived adaptation of the SWOG S0777 study protocol [9] to a 28‐day cycle with weekly bortezomib and subcutaneous administration to minimize neurotoxicity. Induction consists of eight cycles with subcutaneous bortezomib 1.3 mg/m2 on Days 1, 8, 15, and 22, combined with oral lenalidomide 25 mg on Days 1–14 and oral dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23. Induction is followed by 28‐day cycles of oral lenalidomide 25 mg maintenance on Days 1–21 with oral dexamethasone 40 mg weekly until disease progression.
Modified RVD Lite is a consensus‐derived adaptation of the RVD Lite study [13], administered in eight 35‐day cycles to comply with Australian reimbursement restrictions as triplet therapy (RVD) cannot be prescribed beyond 6 cycles. Bortezomib is given at 1.3 mg/m2 subcutaneously weekly on Days 1, 8, 15, and 22, combined with oral lenalidomide 15 mg on Days 1–21 and dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23. Lenalidomide is omitted in Cycles 7–8. Completion of induction is followed by maintenance with oral lenalidomide, with dosing at investigators’ discretion (10–25 mg) on Days 1–21 ± dexamethasone 20 mg on Days 1, 8, 15, and 22 of a 28‐day cycle continuously until disease progression.
Differences in induction duration between regimens in this study reflect pragmatic adaptations to the Australian reimbursement environment at the time rather than biological considerations. Dose reductions and treatment modifications were implemented in response to protocol‐defined toxicity criteria rather than at prespecified treatment cycles, with adjustments made at the time toxicity emerged to maintain treatment continuity while minimizing cumulative toxicity (Appendices 1 and 2).
For bortezomib, dose modification was driven by peripheral neuropathy, hematological toxicity, and hepatic dysfunction, with protocol guidance for stepwise dose reduction from 1.3 to 1.0 mg/m2 and 0.7 mg/m2 or schedule modification to once‐weekly dosing.
For dexamethasone, upfront dose attenuation was recommended in older patients, with further reductions guided by tolerability rather than fixed cycle numbers. In patients aged ≥ 75 years, dexamethasone 20 mg weekly was recommended from treatment initiation, with subsequent dose reduction or omission at the clinician's discretion in response to cumulative steroid‐related toxicity.
2.3. Assessments
Baseline data were collected from the electronic medical record, including demographics and disease characteristics (myeloma type, cytogenetics, beta‐2 microglobulin, albumin, lactate dehydrogenase, and the Revised International Staging System for multiple myeloma [R‐ISS]), and frailty assessments based on ECOG, International Myeloma Working Group (IMWG), and Mayo Frailty Scores. High‐risk myeloma was defined by the presence of t(14;14), t(14;16), t(14;20), or del (17p) by fluorescence in situ hybridization (FISH) as per IMWG [15].
2.4. Outcomes
Patients were assessed post‐induction for treatment response based on IMWG consensus criteria [16], and tolerability based on dose adjustments required and toxicities encountered. Outcome data were collected by retrospective chart review; however, documentation of reasons for dose adjustments and grading of sensory and motor neuropathy at the time of clinic visits was mandated by the study. Toxicities were graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Patients were followed up 6‐monthly for response status.
2.5. Statistical Analysis
Baseline characteristics were described using proportions for categorical variables and medians for continuous variables. Comparisons between treatment groups were conducted using Pearson chi‐square, Fisher's exact, and Mann–Whitney U tests as appropriate. Time‐to‐event outcomes were estimated using the Kaplan–Meier method and compared between groups using the stratified log‐rank tests. Two‐sided p‐values < 0.05 were considered statistically significant. Statistical analyses were performed using IBM SPSS version 27 (IBM, Armonk, NY, USA).
3. Results
3.1. Patient Characteristics
From June 1, 2020 until data cutoff on September 1, 2023, 83 eligible patients were identified at six sites, of whom 35 (42.2%) received Modified SWOG and 48 (57.8%) received Modified RVD Lite. Seven patients receiving Modified RVD Lite had a single deviation from the harmonized protocol (6 received a higher lenalidomide dose of 25 mg on Days 1–21, and 1 received Modified RVD Lite in 28‐day cycles); however, they were included as part of this real‐world study.
Median age at study entry was 74 years. Fifty‐seven patients (68.7%) were male. The majority of patients had ECOG 0–1 (Table 1). Among patients with available data, 11 (13.3%) were R‐ISS III, 16 (19.3%) had high‐risk cytogenetics and 13 (15.6%) deemed frail by IMWG frailty Score. There were no statistically significant differences in baseline characteristics between the two regimens; however, there was a trend toward poorer functional status by ECOG and IMWG frailty Score in those receiving Modified RVD Lite.
TABLE 1.
Baseline characteristics.
| Patient characteristics | N |
All patients (N = 83) |
Modified SWOG (N = 35) |
Modified RVD Lite (N = 48) |
p‐value |
|---|---|---|---|---|---|
| Median age (range) | 83 | 74 (55–86) | 74 (55–83) | 76 (65–86) | 0.426 |
| Gender, n (%) | 83 | 0.092 | |||
| Male | 57 (68.7%) | 28 (80.0%) | 29 (60.4%) | ||
| Female | 26 (31.3%) | 7 (20.0%) | 19 (39.6%) | ||
| Paraprotein | 81 | 0.555 | |||
| IgG | 44 (53.1%) | 20 (57.1%) | 24 (50.0%) | ||
| IgA | 17 (20.4%) | 6 (17.2%) | 11 (22.9%) | ||
| Other heavy chain | 2 (2.4%) | 2 (5.7%) | 0 (0.0%) | ||
| Light chain only | 16 (19.2%) | 6 (17.2%) | 10 (20.8%) | ||
| Non‐secretory | 2 (2.4%) | 1 (2.9%) | 1 (2.1%) | ||
| Missing | 2 (2.4%) | 0 (0.0%) | 2 (4.2%) | ||
| R‐ISS, n (%) | 73 | ||||
| I | 12 (14.5%) | 6 (17.1%) | 6 (12.5%) | 0.774 | |
| II | 50 (60.2%) | 24 (68.6%) | 26 (54.2%) | ||
| III | 11 (13.3%) | 4 (11.4%) | 7 (14.6%) | ||
| Not assessed | 10 (12.0%) | 1 (2.9%) | 9 (18.8%) | ||
| Cytogenetics | 78 | 0.525 | |||
| Standard risk | 62 (74.7%) | 27 (77.1%) | 35 (72.9%) | ||
| High risk | 16 (19.3%) | 6 (17.1%) | 10 (20.8%) | ||
| Not assessed | 5 (6.0%) | 2 (5.7%) | 3 (6.3%) | ||
| ECOG | 83 | 0.079 | |||
| 0 | 43 (51.8%) | 23 (65.7%) | 20 (41.7%) | ||
| 1 | 28 (33.7%) | 10 (28.6%) | 18 (37.5%) | ||
| 2 | 7 (8.4%) | 2 (5.7%) | 5 (10.4%) | ||
| 3 | 5 (6.0%) | 0 (0.0%) | 5 (10.4%) | ||
| Mayo Frailty Score | 31 | 0.413 | |||
| 0 | 1 (1.2%) | 0 (0.0%) | 1 (2.1%) | ||
| 1 | 16 (19.3%) | 9 (25.7%) | 7 (14.6%) | ||
| 2 | 11 (13.3%) | 5 (14.3%) | 6 (12.5%) | ||
| 3 | 3 (3.6%) | 0 (0.0%) | 3 (6.3%) | ||
| Not assessed | 52 (62.7%) | 21 (60.0%) | 31 (64.6%) | ||
| IMWG Frailty Score | 40 | 0.063 | |||
| Fit (0) | 10 (12.0%) | 4 (11.4%) | 6 (12.5%) | ||
| Intermediate (1) | 17 (20.5%) | 12 (34.3%) | 5 (10.4%) | ||
| Frail (≥2) | 13 (15.6%) | 2 (5.7%) | 11 (23.0%) | ||
| Not assessed | 43 (51.8%) | 17 (48.6%) | 26 (54.2%) |
3.2. Efficacy
Overall response rate (ORR) was 92.7% with 67.4% achieving a VGPR or better (Table 2). ORR was 91.4% in those receiving Modified SWOG and 93.9% in those receiving Modified RVD Lite. VGPR or better was achieved in 71.4% receiving Modified SWOG and 64.7% in those receiving Modified RVD Lite. There was no statistically significant difference in ORR or ≥ VGPR between the two groups.
TABLE 2.
Response rates to Modified SWOG and RVD Lite regimens.
| IMWG defined response |
All patients (N = 83) |
Modified SWOG (N = 35) |
Modified RVD Lite (N = 48) |
p‐value |
|---|---|---|---|---|
| Overall response | ||||
| sCR | 3 (3.6%) | 1 (2.9%) | 2 (4.2%) | 0.693 |
| CR | 4 (4.8%) | 2 (5.7%) | 2 (4.2%) | 0.674 |
| VGPR | 49 (59.0%) | 22 (62.9%) | 27 (56.3%) | |
| PR | 21 (25.3%) | 7 (20.0%) | 14 (29.2%) | |
| SD | 1 (1.2%) | 1 (2.9%) | 0 (0.0%) | |
| PD | 5 (6.0%) | 2 (5.7%) | 3 (6.3%) | |
| Overall response rate (≥PR) | 77 (92.7%) | 32 (91.4%) | 45 (93.9%) | |
| ≥VGPR | 56 (67.4%) | 25 (71.4%) | 31 (64.7%) |
At a median follow‐up of 27.5 months (range: 0.6–45.6), disease progression or death had occurred in 14 of 35 patients (40%) in the Modified SWOG group and 23 of 48 patients (47.9%) in the Modified RVD Lite group. Estimated PFS at 24 months was 63.1% (95% confidence interval [CI], 47.6–83.5) in the Modified SWOG group and 53.6% (95% CI, 39.1–73.4) in the Modified RVD Lite group (Figure 1A). Estimated OS at 24 months was 94.0% (95% CI, 86.3–100) for Modified SWOG and 82.9% (95% CI, 71.0–96.9) for Modified RVD Lite (Figure 1B). There was no statistically significant difference in OS or PFS between the two groups.
FIGURE 1.
(A) Progression‐free survival by RVD protocol. (B) Overall survival by RVD protocol.
3.3. Safety
The majority of patients completed eight cycles of induction with premature discontinuation of RVD occurring in 10 patients (28.5%) receiving Modified SWOG and 16 patients (33.4%) receiving Modified RVD Lite (Table 3). Toxicity was the most common cause of premature RVD cessation, occurring in 6 patients (17.1%) with Modified SWOG compared to 12 patients (25%) with Modified RVD Lite. Rates of peripheral neuropathy were similar in both groups (37.1% vs. 39.6%), with rare grade ≥ 3 events seen in those receiving Modified SWOG (5.7%). The number of patients hospitalized was similar in both groups (48.6% vs. 47.9%), of which infection was the most common cause (31.4% vs. 22.9%). Dose modifications were common, with more patients requiring adjustments in bortezomib dosing with Modified RVD Lite (37.5% vs. 20%) and more changes to dexamethasone dosing with Modified SWOG (45.7% vs. 35.4%).
TABLE 3.
Summary of toxicities and protocol adjustments.
|
All patients (N = 83) |
Modified SWOG (N = 35) |
Modified RVD Lite (N = 48) |
p‐value | |
|---|---|---|---|---|
| Median number of cycles completed (range) | 8 (1–8) | 8 (1–8) | 8 (1–8) | 0.078 |
| Premature cessation, n (%) | 26 (31.3%) | 10 (28.5%) | 16 (33.4%) | 0.777 |
| Toxicity | 18 (21.7%) | 6 (17.1%) | 12 (25.0%) | |
| Progressive disease | 5 (6.0%) | 2 (5.7%) | 3 (6.3%) | |
| Other | 3 (3.6%) | 2 (5.7%) | 1 (2.1%) | |
| Dose modifications, n (%) | ||||
| Bortezomib | 25 (30.1%) | 7 (20.0%) | 18 (37.5%) | 0.229 |
| Lenalidomide | 30 (36.1%) | 13 (37.1%) | 17 (35.4%) | 0.794 |
| Dexamethasone | 33 (39.8%) | 16 (45.7%) | 17 (35.4%) | 0.372 |
| Peripheral sensory neuropathy | ||||
| Any grade | 32 (38.6%) | 13 (37.1%) | 19 (39.6%) | 0.048 |
| Grade ≥ 3 | 2 (2.4%) | 2 (5.7%) | 0 (0.0%) | |
| Peripheral motor neuropathy | 0.569 | |||
| Any grade | 5 (6.0%) | 2 (5.8%) | 3 (6.3%) | |
| Grade ≥ 3 | 3 (3.6%) | 2 (5.8%) | 1 (2.1%) | |
| Hospitalizations, n (%) | 40 (48.2%) | 17 (48.6%) | ||
| Multiple hospitalizations, n (%) | 19 (22.9%) | 11 (31.4%) | 23 (47.9%) | |
| Reasons for hospitalization | 22 (26.5%) | 11 (31.4%) | 8 (16.7%) | 0.953 |
| Infection | 1 (1.2%) | 0 (0.0%) | 11 (22.9%) | 0.114 |
| Venous thromboembolism | 7 (8.4%) | 4 (11.4%) | 1 (2.1%) | |
| Cardiac | 4 (4.8%) | 2 (5.7%) | 3 (6.3%) | |
| Pain | 2 (2.4%) | 0 (0.0%) | 2 (4.2%) | |
| Rash | 2 (2.4%) | 2 (5.7%) | 2 (4.2%) | |
| Renal failure | 3 (3.6%) | 2 (5.7%) | 0 (0.0%) | |
| Postural hypotension | 3 (3.6%) | 1 (2.9%) | 1 (2.1%) | |
| Functional decline | 2 (2.4%) | 2 (5.7%) | 2 (4.2%) | |
| Bleeding | 8 (9.6%) | 1 (17.1%) | 0 (0.0%) | |
| Other a | 40 (48.2%) | 17 (48.6%) | 7 (20.8%) |
Other causes of hospitalizations include: post‐vaccine Guillain‐Barré syndrome, pneumonitis, diverticulitis, pneumothorax, non–small cell lung cancer, constipation, and adrenal insufficiency.
4. Discussion
Our study demonstrated that real‐world outcomes with harmonized weekly RVD regimens were comparable to the corresponding trials they were adapted from. Despite its use of weekly bortezomib, Modified SWOG achieved similar efficacy to that seen in the SWOG S0777 trial [9] with ORR 91.4% and ≥ VGPR 71.4% (vs. ORR 90.2%, ≥ VGPR 74.9%). Moreover, this was achieved with significant improvements in tolerability with lower rates of trial discontinuation due to adverse effects (17% vs. 23% in SWOG S0777). Comparing survival curves, 24‐month PFS was approximately 65% in the SWOG S0777 trial, similar to our 24‐month PFS of 63.1% in those receiving Modified SWOG in our study.
Modified RVD Lite also demonstrated similar efficacy to the Phase 2 RVD Lite trial [13] with an ORR 93.9% and ≥ VGPR 64.7% (vs. ORR 86%, ≥ VGPR 66%). However, 24‐month PFS was notably higher at approximately 80% in the RVD Lite trial, compared to our 24‐month PFS 53.6% with Modified RVD Lite. This may be accounted for by differences in our study population, which was comparably older (median age 76 vs. 73 years), frailer (inclusion of ECOG 3 patients) with a greater proportion of patients with high‐risk cytogenetics (20.8% vs. 12%). Our outcomes with Modified RVD Lite are otherwise comparable to real‐world data from the Flatiron MM Core Registry [14] on newly diagnosed non‐transplanted myeloma patients, where an approximately 55% 24‐month PFS was reached in a similarly older, frailer cohort (25% ≥ 75 years, 47.9% frail), although the Flatiron study was limited in its exploration of dosing modifications utilized in this population.
At the outset of this study, we sought to explore frailty and whether frailty influenced the choice of regimen or predicted toxicity. Despite this focus, frailty remained poorly documented overall with only 37.3% having an assessable Mayo Frailty Score and 48.2% having an assessable IMWG Frailty Score. In fact, a large proportion of these were not calculated by the physician (and hence not utilized to make treatment decisions) and were calculated at the time of data entry. This may highlight that clinicians are not using validated frailty scores in making treatment decisions, and clinical trials utilizing frailty‐adapted approaches are needed, such as the FRAIL‐M [17] and the UKMRA Myeloma XIV FiTNEss trials [18].
Comparing between the two regimens in our study, although there was a trend toward frailer patients receiving Modified RVD Lite over Modified SWOG, patients were able to achieve similar efficacy by ORR with no significant differences in survival outcomes. Both regimens were similarly well‐tolerated except for a slight difference in rates of peripheral sensory neuropathy in those receiving Modified RVD Lite (39.6% vs. 37.1%, p = 0.048), which may be reflective of increased vulnerability to neurotoxicity in this cohort, given that bortezomib dosing was identical in both regimens. Nonetheless, both regimens had considerably reduced rates of peripheral neuropathy compared to the trials they were adapted from. The rates of peripheral neuropathy were 37% with Modified SWOG compared with 78% in SWOG S0777. Lower rates of peripheral neuropathy were also seen with Modified RVD Lite (39.6% vs. 60%), most likely attributed to reduced exposure to bortezomib, which had additionally been used in consolidation in RVD Lite.
As anticipated, dexamethasone was associated with significant toxicities in older and frail patients in this study. Despite the use of dose‐attenuated dexamethasone (20 mg weekly) in patients aged > 75 years, further dose reductions were required in 33 patients (39.8%) due to toxicity, highlighting the limited tolerability of corticosteroids in this population. Importantly, accumulating evidence supports a proactive and liberal approach to dexamethasone dose reduction. A secondary analysis of the SWOG S0777 and S1211 trials demonstrated no detriment in PFS or OS among patients requiring dexamethasone dose reductions for grade ≥ 3 toxicity [19]. The Rd‐R strategy has also shown that planned dexamethasone dose reduction and cessation after an induction period can be safely implemented and may improve outcomes in elderly, intermediate‐fit patients [20]. Taken together, these data support careful early attenuation of dexamethasone as a key principle of treatment delivery in transplant‐ineligible patients. Clinicians should actively target dexamethasone minimization, including low‐dose weekly schedules and, where appropriate, cessation after a defined induction period, without concern for compromising disease control.
Although toxicity was comparatively improved utilizing our dose‐attenuated protocols, there were still significant rates of dose modification and discontinuation due to toxicity. In particular, hospitalization rates during induction were high in both cohorts. While rates of toxicity and hospital admission were relatively high, we believe this reflects the real‐world nature of the cohort. Patients included in this study were older and more comorbid than those enrolled in pivotal clinical trials such as SWOG S0777 [9]. In addition, this study specifically focused on the systematic capture of treatment‐related toxicities and hospitalizations, which may result in higher reported rates compared with other real‐world series. Nevertheless, our data emphasize the importance of close monitoring of these patients, and by detailing a toxicity‐driven, protocolized approach to dose modification, these data also support clinicians in proactively adjusting treatment intensity rather than reacting late to severe toxicity. This approach reflects routine clinical practice and may be particularly relevant in older or frail patients, where rigid adherence to trial‐based dose intensity may compromise tolerability and treatment continuity.
Overall, the objective of this study was to support a pragmatic approach to treatment intensity and treatment delivery in transplant‐ineligible patients. Our study has shown that using dose‐attenuated RVD regimens with weekly bortezomib dosing compared to twice‐weekly dosing used in trials (Modified SWOG vs. SWOG S0777 [9]) had substantial improvements in tolerability with reduced rates of peripheral neuropathy and fewer trial discontinuations, while maintaining efficacy given similar response rates and PFS to the published studies. These data provide reassurance that dose‐attenuated strategies can be both effective and appropriate for transplant‐ineligible patients, thereby discouraging unnecessary escalation of treatment intensity in pursuit of marginal gains in response.
A central principle emerging from this work is the use of once‐weekly bortezomib as a time‐limited induction component, which may be paired with either 14‐day or 21‐day lenalidomide schedules depending on local funding constraints. Readers may use these data to inform locally appropriate protocols, particularly recognizing that reduced bortezomib frequency and liberal dexamethasone dose attenuation are feasible and effective strategies in routine clinical practice.
Limitations of this study include those inherent in real‐world studies, such as incomplete data, which may limit conclusions drawn, particularly with regard to missing data on frailty scores. Progress bone marrow biopsies are not performed routinely for response assessments in our real‐world practice, which may underestimate assessments of stringent and complete responses. The demographics of this study were male predominant with no ethnicity data available, which may limit generalizability. We included 7 patients with minor protocol deviations (higher lenalidomide dose or shorter dosing interval) in the Modified RVD Lite group, which may affect outcomes and toxicities seen. We also recognize that daratumumab, lenalidomide, dexamethasone (DRd) is increasingly a favored regimen for newly diagnosed transplant‐ineligible patients based on the MAIA trial [21], which demonstrated a median PFS 61.9 months (vs. 34.4 months with Rd) with median OS not reached at median follow‐up of 64.5 months. Other emerging approaches in transplant‐ineligible patients include quadruplet regimens with the addition of isatuximab (IMROZ [22]) or daratumumab (CEPHEUS [23]) to RVD, which have been demonstrated to have improved MRD negativity rates and PFS compared to triplet therapy. However, our data remain highly relevant in jurisdictions where upfront anti‐CD38 therapy is not accessible in first line.
5. Conclusion
Our multicenter real‐world study of once‐weekly RVD‐harmonized regimens in newly diagnosed transplant‐ineligible myeloma demonstrated comparable efficacy to twice‐weekly clinical trial regimens with an improved toxicity profile and contributes further evidence that weekly dosing of bortezomib should be the standard of care. Future studies should explore frailty‐adapted dosing and integration with novel agents to further optimize outcomes.
Author Contributions
Samantha Kurniawan: data curation, formal analysis, writing – original draft. Angela Hwang: data curation, writing – review and editing. Nicole Wong Doo: data curation, writing – review and editing. Tracy King: data curation, writing – review and editing. Christian Bryant: writing – review and editing. Jennifer Zhang: data curation. Kristina Whelan: data curation. Parisa Fani‐Molky: data curation. Giselle Kidson‐Gerber: writing – review and editing. Annmarie Bosco: writing – review and editing. Nada Hamad: writing – review and editing. Gurdeep Parmar: writing – review and editing. Fiona Kwok: writing – review and editing. Sam Lai: data curation. Silvia Ling: writing – review and editing. P. Joy Ho: writing – review and editing. Georgia McCaughan: conceptualization, data curation, methodology, writing – review and editing, supervision. Adam Bryant: conceptualization, data curation, methodology, writing – review and editing, supervision.
Funding
The authors have nothing to report.
Ethics Statement
This study was reviewed and approved by the St Vincent's Hospital Sydney Human Research Ethics Committee.
Consent
A waiver of consent was approved on review by the St Vincent's Hospital Human Research Ethics Committee (2020/ETH02281) as this research study was low risk and involved the collection of de‐identified data with no additional testing or burden on patients. All possible means were undertaken to maintain patient privacy and confidentiality during the collation, analysis, and publication of the data.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
Open access publishing facilitated by University of New South Wales, as part of the Wiley ‐ University of New South Wales agreement via the Council of Australasian University Librarians
Appendix 1. Modified SWOG Protocol Treatment Schedule
1.1.
Induction
Cycle 1–8
| Drug | Dose | Route | Day |
|---|---|---|---|
| Lenalidomide | 25 mg | Oral | 1–14 |
| Bortezomib | 1.3 mg/m2 | Subcutaneous | 1, 8, 15, and 22 |
| Dexamethasone | 20 mg | Oral | 1, 2, 8, 9, 15, 16, 22, and 23 * |
Consider reduction of dexamethasone to 20 mg weekly in patients ≥ 75 years of age.
Cycle length: 28 days
Cycle 9 onward
| Drug | Dose | Route | Day |
|---|---|---|---|
| Lenalidomide | 25 mg | Oral | 1–14 |
| Dexamethasone | 40 mg * | Oral | 1, 8, 15, and 22 |
*Consider reduction of dexamethasone to 20 mg weekly in patients ≥ 75 years of age.
Cycle length: 28 days
Dose modifications
Dose reduction steps for lenalidomide
| Starting dose | 25 mg |
| Dose level 1 | 15 mg |
| Dose level 2 | 10 mg |
| Dose level 3 | 5 mg |
Dose reduction steps for bortezomib
| Starting dose | 1.3 mg/m2 |
| Dose level 1 | 1 mg/m2 |
| Dose level 2 | 0.7 mg/m2 |
Hematological toxicity
| Neutropenia | |
| First episode < 0.5 × 109/L |
Withhold lenalidomide and bortezomib Recommence at same dose once ANC > 0.5 × 109/L Granulocyte colony‐stimulating factor can be started at discretion of treating hematologist |
| Subsequent episodes < 0.5 × 109/L |
Withhold lenalidomide and bortezomib Recommence with a dose reduction of lenalidomide by one dose level once ANC > 0.5 × 109/L Granulocyte colony‐stimulating factor can be started at discretion of treating hematologist |
| Thrombocytopenia | |
| 25–50 × 109/L | Reduce lenalidomide by one dose level for the remainder of cycle |
| ≤ 25 × 109/L or 25–50 × 109/L with bleeding |
Withhold lenalidomide and bortezomib until recovery of platelet count > 50 × 109/L Upon recovery, reduce bortezomib and lenalidomide by one dose level |
Renal impairment
| CrCl 30–50 mL/min |
Reduce lenalidomide to 10 mg once daily Can increase to 15 mg after 2 cycles depending on tolerability |
| CrCl < 30, not requiring dialysis | Reduce lenalidomide to 15 mg on alternate days |
| CrCl < 30, requiring dialysis |
Reduce lenalidomide to 5 mg once daily Dose should be administered after dialysis |
Rash
| <10% body surface area | Continue lenalidomide |
| 10%–30% body surface area | Consider interruption of lenalidomide therapy |
| > 30% body surface area | Consider interruption of lenalidomide therapy |
| Steven Johnson syndrome or toxic epidermal necrolysis | Permanent discontinuation of lenalidomide therapy |
Hepatic dysfunction
| Moderate or severe | Reduce bortezomib to 0.7 mg/m2 per dose for the first cycle, then consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 for subsequent cycles depending on tolerability |
Peripheral neuropathy
| Grade 1 | No action required |
| Grade 1 with pain or Grade 2 | Dose reduce by one dose level |
| Grade 2 with pain or Grade 3 |
Withhold bortezomib until toxicity resolves Reinitiate with a reduced dose of bortezomib by one dose level |
| Grade 4 | Discontinue bortezomib |
Appendix 2. RVD Lite Protocol Treatment Schedule
2.1.
Induction
Cycle 1–6
| Drug | Dose | Route | Day |
|---|---|---|---|
| Lenalidomide | 15 mg | Oral | 1–21 |
| Bortezomib | 1.3 mg/m2 | Subcutaneous | 1, 8, 15, and 22 |
| Dexamethasone | 20 mg | Oral | 1, 2, 8, 9, 15, 16, 22, and 23* |
*Reduce dexamethasone to 20 mg weekly in patients ≥ 75 years of age.
Cycle length: 35 days
Cycle 7–8
| Drug | Dose | Route | Day |
|---|---|---|---|
| Bortezomib | 1.3 mg/m2 | Subcutaneous | 1, 8, 15, and 22 |
| Dexamethasone | 20 mg | Oral | 1, 2, 8, 9, 15, 16, 22, and 23* |
*Reduce dexamethasone to 20 mg weekly in patients ≥ 75 years of age.
Cycle length: 35 days
Cycle 9 onward
| Drug | Dose | Route | Day |
|---|---|---|---|
| Lenalidomide | 10 mg* | Oral | Continuously |
*Increased to 15 mg after 3 cycles if tolerating.
Or
| Drug | Dose | Route | Day |
|---|---|---|---|
| Lenalidomide | 25 mg | Oral | 1–21 |
| Dexamethasone | 20 mg | Oral | 1, 8, 15, and 22 |
Cycle length: 28 days
Dose modifications
Dose reduction steps for lenalidomide
| Starting dose | 15 mg |
| Dose level 1 | 10 mg |
| Dose level 2 | 5 mg |
Dose reduction steps for bortezomib
| Starting dose | 1.3 mg/m2 |
| Dose level 1 | 1 mg/m2 |
| Dose level 2 | 0.7 mg/m2 |
Hematological toxicity
| Neutropenia | |
| First episode < 0.5 × 109/L |
Withhold lenalidomide and bortezomib Recommence at same dose once ANC > 0.5 × 109/L Granulocyte colony‐stimulating factor can be started at discretion of treating hematologist |
| Subsequent episodes < 0.5 × 109/L |
Withhold lenalidomide and bortezomib Recommence with a dose reduction of lenalidomide by one dose level once ANC > 0.5 × 109/L Granulocyte colony‐stimulating factor can be started at discretion of treating hematologist |
| Thrombocytopenia | |
| 25–50 × 109/L | Reduce lenalidomide by one dose level for the remainder of cycle |
| ≤ 25 × 109/L or 25–50 × 109/L with bleeding |
Withhold lenalidomide and bortezomib until recovery of platelet count > 50 × 109/L Upon recovery, reduce bortezomib and lenalidomide by one dose level |
Renal impairment
| CrCl 30–50 mL/min |
Reduce lenalidomide to 10 mg once daily Can increase to 15 mg after 2 cycles depending on tolerability |
| CrCl < 30, not requiring dialysis | Reduce lenalidomide to 15 mg on alternate days |
| CrCl < 30, requiring dialysis |
Reduce lenalidomide to 5 mg once daily Dose should be administered after dialysis |
Rash
| < 10% body surface area | Continue lenalidomide |
| 10%–30% body surface area | Consider interruption of lenalidomide therapy |
| > 30% body surface area | Consider interruption of lenalidomide therapy |
| Steven Johnson syndrome or toxic epidermal necrolysis | Permanent discontinuation of lenalidomide therapy |
Hepatic dysfunction
| Moderate or severe | Reduce bortezomib to 0.7 mg/m2 per dose for the first cycle, then consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 for subsequent cycles depending on tolerability |
Peripheral neuropathy
| Grade 1 | No action required |
| Grade 1 with pain or Grade 2 | Dose reduce by one dose level |
| Grade 2 with pain or Grade 3 |
Withhold bortezomib until toxicity resolves Reinitiate with a reduced dose of bortezomib by one dose level |
| Grade 4 | Discontinue bortezomib |
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.