| Coverage Policy Manual | |
| Policy #: | 2022029 |
| Category: | Pharmacy |
| Initiated: | October 2022 |
| Last Review: | July 2024 |
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| Bortezomib (e.g., Velcade) | |
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| Description: |
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vitro in nonclinical tumor models, including multiple myeloma. (FDA, 2021)
Regulatory Status
On May 13, 2003, the Food and Drug Administration approved the use of bortezomib (e.g., Velcade) for Injection for the treatment of multiple myeloma individuals who have received at least two prior therapies and have demonstrated disease progression on the last therapy.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective October 15, 2022, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service when rendered for oncologic indications and is managed through the oncology benefits management program.
Effective July 17, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Bortezomib meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following:
FDA Labeled Indications:
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
INITIAL STANDARD REVIEW for up to 12 months:
ADULTS:
CONTINUED APPROVAL for up to 12 months:
Off-label Indications:
For off-label indications, authorizations will not exceed 1.6 mg/ square meters unless medical literature supports a higher dose.
INITIAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
FDA dosing for Mantle Cell Lymphoma and Multiple Myeloma:
The recommended starting dose of bortezomib is 1.3 mg/ square meters administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection.
Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose.
Hepatic Impairment: Use a lower starting dose for individuals with moderate or severe hepatic impairment.
Dose must be individualized to prevent overdose.
Bortezomib is available in a single-dose vial containing of 3.5 mg lyophilized powder for reconstitution.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Bortezomib, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, Bortezomib, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective July 12, 2023 to July 16, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Bortezomib meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following:
ADULTS:
Pediatrics:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
FDA dosing for Mantle Cell Lymphoma and Multiple Myeloma:
Bortezomib is available in a single-dose vial containing of 3.5 mg lyophilized powder for reconstitution.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Bortezomib does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above.
For members with contracts without primary coverage criteria, Bortezomib is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective October 15, 2022 to July 11, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Bortezomib meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:
ADULTS:
1. Acute Lymphoblastic Leukemia (NCCN 2A)
2. Mantle Cell Lymphoma (FDA 2021) (NCCN 2A)
3. Castleman Disease (NCCN 2A)
4. Kaposi Sarcoma (NCCN 2A)
5. Multiple Myeloma (FDA 2021) (NCCN 1 and 2A)
6. Systemic Light Chain Amyloidosis (NCCN 1 and 2A)
7. Adult T-Cell Leukemia/Lymphoma (NCCN 2A)
8. Lymphoplasmacytic Lymphoma – Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma (NCCN 2A)
Pediatrics:
9. Pediatric Acute Lymphoblastic Leukemia (NCCN 2A)
10. Pediatric Hodgkin Lymphoma (NCCN 2A)
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
FDA dosing for Mantle Cell Lymphoma and Multiple Myeloma:
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Bortezomib does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any circumstance other than those outlined above .
For members with contracts without primary coverage criteria, Bortezomib is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance) were compared. A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in a retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m2); median dose intensity was lower (2.0 vs 5.1 mg/m2/month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen. (Mateos MV, Oriol A, Martínez-López J, et.al., 2016)
Bortezomib-dexamethasone is widely used for relapsed myeloma in routine clinical practice, but comparative data versus single-agent bortezomib are lacking. A retrospective analysis compared second-line treatment with bortezomib-dexamethasone and bortezomib using 109 propensity score-matched pairs of patients treated in three clinical trials: MMY-2045, APEX, and DOXIL-MMY-3001. Propensity scores were estimated using logistic regression analyses incorporating 13 clinical variables related to drug exposure or clinical outcome. Patients received intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, in 21-day cycles, alone or with oral dexamethasone 20 mg on the days of/after bortezomib dosing. Median bortezomib cumulative dose (27.02 and 28.60 mg/m(2)) and treatment duration (19.6 and 17.6 weeks) were similar with bortezomib-dexamethasone and bortezomib, respectively. The overall response rate was higher (75% vs. 41%; odds ratio=3.467; P<0.001), and median time-to-progression (13.6 vs. 7.0 months; hazard ratio [HR]=0.394; P=0.003) and progression-free survival (11.9 vs. 6.4 months; HR=0.595; P=0.051) were longer with bortezomib-dexamethasone versus bortezomib, respectively. Rates of any-grade adverse events, most common grade 3 or higher adverse events, and discontinuations due to adverse events appeared similar between the groups. Two patients per group died of treatment-related adverse events. These data indicate the potential benefit of bortezomib-dexamethasone compared with single-agent bortezomib at first relapse in myeloma. (Dimopoulos MA, Orlowski RZ, Facon T, et.al., 2015)
Bortezomib is approved for both subcutaneous (SC) and IV administration. Approval of SC administration was based on the phase III MMY-3021 study in 222 patients with relapsed MM, which demonstrated non-inferiority of SC versus IV bortezomib in terms of response rates after four cycles, similar efficacy, and an improved systemic safety profile. To confirm these findings in the setting of renal impairment, a post hoc subanalysis was conducted to compare activity, response kinetics, long-term outcomes, and safety with SC versus IV bortezomib in patients with moderate-to-severe (CrCl 20–50 mL/min) or mild/no renal impairment (baseline CrCl >50 mL/min).
Patients were randomized 2:1 to receive up to eight 21-day cycles of SC or IV bortezomib 1.3 mg/m2 on days 1, 4, 8, and 21. Two additional cycles were permitted for patients with evolving response. Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 could be added from cycle 5 onwards. All patients required adequate hematologic, hepatic, and renal function (baseline CrCl ≥20 mL/min).
Response rates were generally similar between SC and IV bortezomib in patients with CrCl more than 50 mL/min; the relative risk of response was 0.92 (95%CI: 0.69, 1.22; unstratified Mantel-Haenszel estimate). Overall response rate also appeared to be similar with SC bortezomib in patients with CrCl 20–50 mL/min and CrCl more than 50 mL/min (53% and 52%, respectively). In the patient population with CrCl 20–50 mL/min, time to response was rapid via both routes of bortezomib administration; a finding also seen in the subgroups of patients with CrCl more than 50 mL/min. In addition, among patients with baseline CrCl 20–50 mL/min, clinical benefit in terms of renal impairment reversal (to CrCl >60 mL/min) was reported in 10 (30%) SC bortezomib patients and 2 (15%) IV bortezomib patients.
Overall median follow up was 17.3 months in the SC arm and 17.8 months in IV arm. In the subgroups of patients with CrCl more than 50 mL/min, long-term outcomes including time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were generally similar between SC and IV bortezomib (Table 2). Median TTP (10.5 and 9.7 months) and median PFS (8.6 and 9.5 months) also appeared to be similar between patients with CrCl 20–50 mL/min and CrCl more than 50 mL/min who received SC bortezomib. However, OS with SC bortezomib appeared somewhat shorter in patients with CrCl 20–50 mL/min compared with patients with CrCl more than 50 mL/min (1-year OS: 69.7% and 78.3%, respectively). These data suggest that SC bortezomib may possibly partly overcome the negative prognostic impact of renal impairment, while the apparent trend to shorter OS may be influenced by the use of subsequent therapies that do not sustain the effect of SC bortezomib in renally impaired patients.
Findings showed an improved systemic safety profile with SC versus IV bortezomib in patients with CrCl more than 50 mL/min, with the most common AEs including PN not elsewhere classified (NEC; high-level term) (36% vs. 57%), anemia (33% vs. 38%), and thrombocytopenia (33% vs. 41%). Overall, 54% versus 69% of patients with CrCl more than 50 mL/min receiving SC versus IV bortezomib reported grade 3 or more AEs, which included 5% versus 18% PN NEC. Serious AEs were reported in 35% versus 33% of patients, 22% versus 28% of patients discontinued due to AEs, and 3% versus 7% of patients died due to AEs with SC versus IV bortezomib. In patients with CrCl 20–50 mL/min, comparisons of the safety profiles of SC and IV bortezomib are confounded; the relative safety profiles differed compared with in the overall study population, likely associated with the difference in treatment exposure.
The findings of the subanalysis indicate that SC bortezomib appears effective in patients with renal impairment, resulting in a beneficial impact in terms of response rates and long-term outcomes, including TTP, PFS, and OS. Of clinical importance, SC bortezomib resulted in a 30% rate of renal impairment reversal in this patient population. Moreover, across renal subgroups, SC bortezomib resulted in a rapid onset of response. Notably, the activity and safety of SC bortezomib in MM patients with renal impairment demonstrated in these analyses appear to reflect previously reported data on IV bortezomib-based therapy in this setting. Furthermore, the findings from this post hoc subgroup analysis of the MMY-3021 study add to the increasing level of recent data on SC bortezomib in previously untreated and relapsed/refractory MM that support the feasibility and utility of this route of administration. For example, similar efficacy and a substantially lower rate of PN were seen with SC compared with IV bortezomib in the bortezomib-thalidomide-dexamethasone regimen when used as pre-transplant induction therapy in previously untreated patients.
In conclusion, the findings from the subgroup analysis, combined with data from other recent studies, support the use of SC bortezomib across the MM treatment algorithm in settings in which bortezomib use is established, including as a feasible and effective treatment that can enable renal function reversal in relapsed MM patients with moderate-to-severe renal impairment. (Moreau P, Pylypenko H, Grosicki S, et.al., 2015)
An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive VELCADE 1 mg/m2 or 1.3 mg/m2 intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten-day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of VELCADE on this trial was two years, and patients had received a median of one prior line of treatment (median of three prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1 mg/m2 and 38% (10/26) at 1.3 mg/m2. (FDA 2021)
Patients from the two Phase 2 studies, who in the investigators’ opinion would experience additional clinical benefit, continued to receive VELCADE beyond 8 cycles on an extension study. Sixty-three (63) patients from the Phase 2 multiple myeloma studies were enrolled and received a median of seven additional cycles of VELCADE therapy for a total median of 14 cycles (range: 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty-seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard three-week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged VELCADE treatment. (FDA 2021)
A single-arm, open-label trial (NCT00431769) was conducted to determine the efficacy and safety of retreatment with VELCADE. One hundred and thirty patients (≥18 years of age) with multiple myeloma who previously had at least partial response on a VELCADE-containing regimen (median of two prior lines of therapy [range: 1 to 7]) were retreated upon progression with VELCADE administered intravenously. Patients were excluded from trial participation if they had peripheral neuropathy or neuropathic pain of Grade ≥2. At least six months after prior VELCADE therapy, VELCADE was restarted at the last tolerated dose of 1.3 mg/m2 (n=93) or ≤1 mg/m2 (n=37) and given on Days 1, 4, 8 and 11 every three weeks for maximum of eight cycles either as single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with VELCADE to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of VELCADE retreatment cycles. The primary endpoint was best confirmed response to retreatment as assessed by European Group for Blood and Marrow Transplantation (EBMT) criteria. Fifty of the 130 patients achieved a best confirmed response of Partial Response or better for an overall response rate of 38.5% (95% CI: 30.1, 47.4). One patient achieved a Complete Response and 49 achieved Partial Response. In the 50 responding patients, the median duration of response was 6.5 months, and the range was 0.6 to 19.3 months. (FDA 2021)
In a randomized, open-label, phase 3 study done at 128 clinical centers in 28 countries in Asia, Europe, North America, and South America. adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomization was done according to a computer-generated randomization schedule prepared by the sponsor; permuted blocks central randomization was used (block size of 4) and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analyzed in the intention-to-treat population.
Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease.
Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. ( Robak T, Jin J, Pylypenko H, et. al., 2018)
The safety and efficacy of VELCADE in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study (NCT00063713) of 155 patients with progressive disease who had received at least one prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were Caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were Stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty-seven percent (37%) of patients were refractory to their last prior therapy. An intravenous bolus injection of VELCADE 1.3 mg/m2/dose was administered twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles. Patients achieving a CR or CRu were treated for four cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity [see Dosage and Administration (2.6, 2.7)]. Responses to VELCADE are shown in Table 19. Response rates to VELCADE were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was four; in responding patients the median number of cycles was eight. The median time to response was 40 days (range: 31 to 204 days). The median duration of follow-up was more than 13 months. (FDA 2021)
2023 Update
Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients.
AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS (P = .412) and OS (P = .600).
Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse. (Teachey DT, Devidas M, Wood BL, et.al., 2022)
July 2024 Update
GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022.
Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy.
Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies. (Voorhees PM, Sborov DW, Laubach J, 2023)
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