AbstractThe phase 3 POLLUX and CASTOR studies demonstrated superior benefit of daratumumab plus lenalidomide/dexamethasone or bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Efficacy and safety of daratumumab was analyzed according to age groups of 65 to 74 years and ≥75 years. Patients received ≥1 prior line of therapy. In POLLUX, patients received lenalidomide/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-2; every two weeks, cycles 3-6; monthly until progression). In CASTOR, patients received eight cycles of bortezomib/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-3; every three weeks, cycles 4-8; monthly until progression). Patients aged >75 years received dexamethasone 20 mg weekly. For patients aged ≥75 years in POLLUX (median follow-up: 25.4 months), daratumumab/lenalido-mide/dexamethasone prolonged progression-free survival versus lenalido-mide/dexamethasone (median: 28.9 versus 11.4 months; hazard ratio, 0.27; 95% confidence interval, 0.10-0.69; P=0.0042) and increased overall response rate (93.1% versus 76.5%; P=0.0740). Neutropenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 44.8%; control: 31.4%). Infusion-related reactions occurred in 12 (41.4%) patients. For patients aged ≥75 years in CASTOR (median follow-up: 19.4 months), daratumumab/bortezomib/dexamethasone prolonged progression-free survival versus bortezomib/dexamethasone (median: 17.9 versus 8.1 months; hazard ratio, 0.26; 95% confidence interval, 0.10-0.65; P=0.0022) and increased overall response rate (95.0% versus 78.8%; P=0.1134). Thrombocytopenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 45.0%; control: 37.1%). Infusion-related reactions occurred in 13 (65.0%) patients. Similar findings were reported for patients aged 65 to 74 years in both studies. Taken together, this subgroup analysis of efficacy and safety of daratumumab was largely consistent with the overall populations.
Multiple myeloma (MM) is a disease of the elderly, which is evidenced by an increasing incidence with advancing age and a median onset age of 69 years.21 Treatment regimens including proteasome inhibitors and immunomodulatory drugs have significantly improved survival for patients with MM;3 however, survival benefits are less pronounced in patients aged >60 years.4 Among patients with MM, median survival times were shown to decrease steadily over each decade from age <50 years (5.2 years) to age ≥80 years (2.6 years).5 Aging is associated with organ dysfunction, reduced functional status, poor resilience to physiologic stressors, an increased burden of comorbidities, and an increased risk of frailty, which affects the ability of elderly patients to tolerate MM treatment regimens.6 Furthermore, higher age correlates with more advanced International Staging System (ISS) stage.5 Based on the challenges of treating MM in elderly patients, a need exists for effective treatment regimens that exhibit a favorable benefit/risk profile in this age group.
Daratumumab is a human immunoglobulin G1 (IgG1κ) monoclonal antibody targeting CD38 with a direct on-tumor107 and immunomodulatory1311 mechanism of action. Tumor cell death is induced by daratumumab via several CD38 immune-mediated actions, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis, and modulation of CD38 enzymatic activity.107 Daratumumab exhibits immunomodulatory effects through reduction of CD38 immunosuppressive cellular populations, including myeloid-derived suppressor cells, regulatory B cells and regulatory T cells; induction of helper and cytotoxic T-cell expansion; increased T-cell clonality, and production of interferon in response to viral peptides.11
In two randomized, open-label, active-controlled, phase 3 studies (POLLUX and CASTOR), daratumumab in combination with standard-of-care regimens (lenalido-mide and dexamethasone [RD] or bortezomib and dexamethasone [VD]) demonstrated superior clinical benefit compared with Rd or Vd alone in patients with MM who had received ≥1 prior line of therapy. In POLLUX, daratumumab in combination with Rd (D-Rd) reduced the risk of disease progression or death by 63% compared with Rd after a median follow-up of 13.5 months.14 Similarly, in CASTOR, the risk of the progression or death was reduced by 61% with daratumumab in combination with Vd (D-Vd) versus Vd after a median follow-up of 7.4 months.15 Findings from these pivotal studies led to the approval of daratumumab in combination with Rd or Vd in many countries for the treatment of patients with MM who received ≥1 prior line of therapy.16 This analysis reports the efficacy and safety of daratumumab in patients aged 65 to 74 years or ≥75 years from POLLUX and CAS-TOR after further median follow-up of 25.4 and 19.4 months, respectively.
Study design and patients
POLLUX and CASTOR were multicenter, randomized, open-label, active-controlled, phase 3 studies of patients with relapsed or refractory MM (RRMM). Trials were approved by an institutional review board or independent ethics committee at each site. Study protocols were conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. Detailed study designs were published previously.1514 Briefly, patients received ≥1 prior line of therapy, had at least a partial response to ≥1 prior therapy, and had documented progressive disease, according to the International Myeloma Working Group (IMWG) criteria.18171514 Patients refractory or intolerant to lenalidomide were excluded from POLLUX. Patients refractory or intolerant to bortezomib, or refractory to another proteasome inhibitor were excluded from CASTOR.
Patients were randomized 1:1 to D-Rd or Rd in POLLUX and D-Vd or Vd in CASTOR.1514 Stratification was described previously and did not include age.1514 In POLLUX, all patients received 28-day cycles of lenalidomide (25 mg orally [PO] on days 1-21 of each cycle) and dexamethasone (40 mg PO weekly in patients aged ≤75 years; 20 mg PO weekly in patients aged >75 years) with or without daratumumab (16 mg/kg intravenously [IV] weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression, unacceptable toxicity, or withdrawal of consent). Patients in the D-Rd group received a split dose of dexamethasone during daratumumab dosing weeks (20 mg before infusion; 20 mg the following day). Patients aged >75 years received the entire 20-mg dose prior to infusion.
In CASTOR, patients received eight, 21-day cycles of bortezomib (1.3 mg/m subcutaneously (SC) on days 1, 4, 8, and 11) and dexamethasone (20 mg PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12; for a total dose of 160 mg/cycle during cycles 1-8) with or without daratumumab (16 mg/kg IV weekly in cycles 1-3, every three weeks during cycles 4-8, and every four weeks thereafter until withdrawal of consent, disease progression, or unacceptable toxicity). In patients aged >75 years, dexamethasone could be reduced to 20 mg weekly. In both studies, daratumumab-treated patients received pre- and post-infusion medications to prevent the onset of infusion-related reactions (IRR).1514
Outcomes and statistical analyses
Frailty score was not assessed as these studies were initiated before this metric was adopted.19 The safety analysis set included all patients who received ≥1 administration of study treatment. Efficacy was assessed by progression-free survival (PFS) and response rates,1514 which were based on the intent-to-treat (ITT) and response-evaluable populations, respectively. A stratified log-rank test compared PFS between groups. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using a stratified Cox regression model, with treatment as the sole explanatory variable. Distributions were estimated using the Kaplan-Meier method. A stratified Cochran-Mantel-Haenszel chi-square test measured treatment differences in overall response rate (ORR) and rates of very good partial response (VGPR) or better and complete response (CR) or better.
At the clinical cut-off date of March 7, 2017, the median (range) duration of follow-up was 25.4 (0-32.7) months for POLLUX. Of the 569 patients enrolled, 29/286 (D-Rd) and 35/283 (Rd) were aged ≥75 years, and 124/286 (D-Rd) and 108/283 (Rd) were aged 65 to 74 years. The clinical cut-off date for CASTOR was January 11, 2017, conferring a median (range) duration of follow-up of 19.4 (0-27.7) months. Of the 498 patients enrolled in CASTOR, 23/251 (D-Vd) and 35/247 (Vd) were aged ≥75 years, and 96/251 (D-Vd) and 87/247 (Vd) were aged 65 to 74 years. In both studies, demographic and baseline clinical characteristics were well balanced between treatment groups (Table 1). In POLLUX, among patients aged ≥75 years, 3/13 (23.1%) patients in the D-Rd group and 4/16 (25.0%) patients in the Rd group had high-risk cytogenetic abnormalities. Similarly, among patients aged ≥75 years in CASTOR, 2/11 (18.2%) patients in the D-Vd group and 6/28 (21.4%) patients in the Vd group had high cytogenetic risk. Among patients aged 65 to 74 years in POLLUX, 11 (16.4%) patients in the D-Rd group and 13 (22.8%) of patients in the Rd group had high cytogenetic risk abnormalities. Similarly, among patients aged 65 to 74 years in CASTOR, 12 (16.7%) patients in the D-Vd group and 18 (25.4%) patients in the Vd group had high cytogenetic risk.
The dispositions of patients according to age from POLLUX and CASTOR are summarized in Figure 1. In POLLUX, nine (31.0%) patients aged ≥75 years who were treated with D-Rd and 24 (68.6%) patients who were treated with Rd discontinued treatment. In CASTOR, 11 (55.0%) patients aged ≥75 years who received D-Vd and 15 (42.9%) patients who were treated with Vd discontinued treatment. Among patients aged ≥75 years who were randomized to D-Vd, 3 (13.0%) did not receive treatment. Similar findings were observed in the patients aged 65 to 74 years: in POLLUX, 51 (41.5%) patients who were treated with D-Rd and 76 (70.4%) patients who received Rd discontinued treatment, and in CASTOR, 56 (59.6%) patients who were treated with D-Vd and 44 (51.2%) patients who received Vd discontinued treatment.
In POLLUX, the median dose intensity of lenalidomide was generally lower in both treatment arms for patients aged ≥75 years (D-Rd, 210.00 mg/cycle; Rd, 305.00 mg/cycle) compared with patients aged 65 to 74 years (D-Rd, 333.93 mg/cycle; Rd, 420.00 mg/cycle). In CAS-TOR, the median dose intensity of bortezomib was similar among patients aged ≥75 years (D-Vd, 4.06 mg/m/cycle; Vd, 4.37 mg/m/cycle) and 65 to 74 years (D-Vd, 4.56 mg/m/cycle; Vd, 4.70 mg/m/cycle).
In POLLUX, in the ITT population, the clinical benefit of D-Rd over Rd was maintained after a median follow-up of 25.4 months (Figure 2). PFS was significantly prolonged with D-Rd versus Rd in the ITT population (median: not reached versus 17.5 months; HR, 0.41; 95% CI, 0.31-0.53; P<0.0001; Figure 2A),20 with 18-month PFS rates of 75.3% and 48.5%, respectively. Similarly, PFS was significantly prolonged with D-Rd compared with Rd in patients aged ≥75 years (median: 28.9 versus 11.4 months; HR, 0.27; 95% CI, 0.10-0.69; P=0.0042; Figure 2A), with 18-month PFS rates of 86.2% versus 36.9%, respectively. PFS was also significantly prolonged with D-Rd versus Rd in patients aged 65 to 74 years (median: not reached versus 17.1 months; HR, 0.40; 95% CI, 0.27-0.60; P<0.0001; Figure 2B), with 18-month PFS rates of 72.0% and 48.7%, respectively. At the time of the clinical cut-off, overall survival (OS) data were immature. Survival follow-up for POLLUX will continue until 330 deaths are observed in the ITT population.
In CASTOR, in the ITT population, the clinical benefit of D-Vd over Vd was maintained after a median follow-up of 19.4 months (Figure 2). PFS was significantly prolonged with D-Vd versus Vd in the ITT population (median: 16.7 versus 7.1 months; HR, 0.31; 95% CI, 0.24-0.39; P<0.0001; Figure 2C), with 18-month PFS rates of 48.0% versus 7.9%, respectively.21 Similarly, PFS was significantly prolonged with D-Vd compared with Vd in patients aged ≥75 years (median: 17.9 versus 8.1 months; HR, 0.26; 95% CI, 0.10- 0.65; P=0.0022; Figure 2C), with 18-month PFS rates of 45.8% versus 0%, respectively. PFS was also significantly prolonged for D-Vd versus Vd in patients aged 65 to 74 years (median: 18.9 versus 6.1 months; HR, 0.25; 95% CI, 0.16-0.40; P<0.0001; Figure 2D). Follow-up for OS in CASTOR will continue until 320 deaths are reported in the ITT population, per protocol.
In POLLUX, among patients aged ≥75 years, higher ORR were observed with D-Rd versus Rd (93.1% versus 76.5%; P=0.0740), with significantly higher rates of VGPR or better (75.9% versus 41.2%; P=0.0059) and CR or better (55.2% versus 8.8%; P<0.0001), respectively (Table 2). Similar findings were observed in patients aged 65 to 74 years (ORR: 92.6% versus 80.2%; P=0.0057; VGPR or better: 76.2% versus 49.1%; P<0.0001; CR or better: 50.0% versus 22.6%; P<0.0001). In both age groups, deeper responses with D-Rd versus Rd translated to a significantly higher proportion of patients with minimal residual disease (MRD)-negative status at a sensitivity threshold of 10 (Table 2). Among patients aged ≥75 years, the rates of MRD negativity were 27.6% versus 5.7% (P=0.014464), and in patients aged 65 to 74, the rates were 23.4% versus 8.3% (P=0.001520).
In patients who received one prior line of therapy, a higher proportion of patients who received D-Rd achieved MRD negativity at a sensitivity threshold of 10 (Online Supplementary Table S1). Among patients aged ≥75 years, the rates of MRD negativity were 23.5% versus 12.5% (P=0.407414), and in patients aged 65 to 74 years, the rates were 24.2% versus 8.5% (P=0.017519).
In CASTOR, among patients aged ≥75 years, higher ORR were observed with D-Vd versus Vd (95.0% versus 78.8%; P=0.1134), including higher rates of VGPR or better (70.0% versus 18.2%; P=0.0002) and CR or better (25.0% versus 3.0%; P=0.0154), respectively (Table 2). Similar findings were observed for patients aged 65 to 74 years (ORR: 82.8% versus 62.4%; P=0.0022; VGPR or better: 64.5% versus 27.1%; P<0.0001; CR or better: 33.3% versus 10.6%; P=0.0003). The rates of MRD-negative status (10 sensitivity) were significantly higher with D-Vd versus Vd among patients aged 65 to 74 years (15.6% versus 2.3%; P=0.000959; Table 2). One (4.3%) patient treated with D-Vd in the subgroup of patients aged ≥75 years achieved MRD-negative status (10 sensitivity) compared with no patients in the Vd treatment group. Rates of MRD negativity at sensitivity thresholds of 10 and 10 are presented for both POLLUX and CASTOR in the Online Supplementary Table S2.
In patients who received one prior line of therapy, a higher proportion of patients who received D-Vd achieved MRD negativity at a sensitivity threshold of 10 (Online Supplementary Table S1). Among patients aged ≥75 years, the rates of MRD negativity were 12.5% versus 0% (P=0.123775), and in patients aged 65 to 74, the rates were 19.1% versus 2.6% (P=0.011285).
In POLLUX and CASTOR, all patients aged ≥75 years reported at least 1 treatment-emergent adverse event (TEAE; Table 3). In POLLUX, among patients aged ≥75 years, grade 3/4 TEAE occurred in 25 (86.2%) and 27 (77.1%) patients in the D-Rd and Rd treatment groups, respectively (Table 3). Neutropenia was the most common grade 3/4 TEAE among patients aged ≥75 years (D-Rd: 44.8%; Rd: 31.4%) and among patients aged 65 to 74 years (D-Rd: 55.3%; Rd: 39.8%). Higher rates of pneumonia were observed with daratumumab in both age groups. In CASTOR, among patients aged ≥75 years, grade 3/4 TEAE were reported in 18 (90.0%) and 26 (74.3%) patients in the D-Vd and Vd treatment groups, respectively (Table 3). Thrombocytopenia was the most common grade 3/4 TEAE in both treatment groups among patients aged ≥75 years (D-Vd: 45.0%; Vd: 37.1%) and in patients aged 65 to 74 years (D-Vd: 52.1%; Vd: 32.6%).
In POLLUX, IRR of any grade were reported in 12 (41.4%) patients aged ≥75 years and 57 (46.3%) patients aged 65 to 74 years (Table 4). The most common IRR in both age groups was dyspnea (≥75 years: 13.8%; 65-74 years: 10.6%). The majority of IRR were mild, with grade 3/4 IRR occurring in four (13.8%) patients aged ≥75 years and six (4.9%) patients aged 65 to 74 years. Among patients aged ≥75 years, all IRR occurred with the first infusion, with the exception of one IRR that occurred in a subsequent infusion. Among patients aged 65 to 74 years, two (1.6%) patients reported an IRR in the second infusion, and seven (5.9%) patients reported an IRR in subsequent infusions. In CASTOR, 13 (65.0%) patients aged ≥75 years and 43 (45.7%) patients aged 65 to 74 years reported an IRR of any grade (Table 4). IRR were generally mild, with grade 3/4 IRR occurring in 2 (10.0%) and 8 (8.5%) patients aged ≥75 and 65 to 74 years, respectively. Among patients aged ≥75 years, no IRR in the second or subsequent infusions were reported; only one patient (aged 65-74 years) had an IRR in the second infusion. In both studies, IRR were manageable and did not result in treatment discontinuations in these populations.
MM is a disease of the elderly, and patients are a heterogeneous population with the potential for various comorbidities, reduced functional status, and increased risk of frailty.6 Approximately 35% to 40% of patients with MM are aged >75 years, but conversely this age group is underrepresented in clinical studies.22 To determine if treatment strategies are safe and effective for elderly patients with MM, subgroup analyses of clinical trial data are needed. In the current sub-analysis of POLLUX and CASTOR, the efficacy and safety of daratumumab in combination with standard-of-care regimens were evaluated in patients aged ≥75 years and 65 to 74 years.
Efficacy results were consistent with those observed in the overall study populations, showing significantly prolonged PFS for patients aged ≥75 years and 65 to 74 years. In both studies, ORR were significantly higher with daratumumab versus standard-of-care treatment in patients aged 65 to 74 years and numerically higher in patients aged ≥75 years, with significantly higher rates of CR or better and VGPR or better in both age categories. While responses were considerably deeper among patients treated with daratumumab, the lack of statistical significance observed with ORR between groups may be due in part to the small number of patients aged ≥75 years in POLLUX (D-Rd, n=29; Rd, n=35) and CASTOR (D-Vd, n=23; Vd, n=35). Consistent with the overall study populations, deeper responses with daratumumab translated to a higher proportion of patients who achieved MRD-negative status. In both studies, safety analyses identified that the rates of common grade 3/4 hematologic TEAE were similar to those of the overall study populations.1514 Importantly, IRR were manageable and did not result in treatment discontinuations. While the incidence of grade 3/4 IRR was numerically higher for patients aged ≥75 years versus patients aged 65-74 years (13.8% versus 4.9%) and what was reported for the primary analysis of POL-LUX (grade 3 IRR; 5.3%),14 a larger sample size is needed to appropriately determine if this age group is more susceptible to experiencing an IRR.
There are limited clinical trial data focused on elderly patients with RRMM, a population that is likely to exhibit tolerability and safety concerns with treatment.236 A retrospective, observational study was conducted to assess the efficacy and toxicity of bortezomib-based regimens used in combination with dexamethasone as salvage therapy for elderly patients with RRMM.23 Patients (n=81) who were aged 65 to 89 years (median, 73 years) and received a median of two prior lines of therapy (range 1-3) were included. A median of six cycles (range 1-11) of Vd were administered, and after a median follow-up of 24 months, the median PFS and OS were 8.7 and 22 months, respectively. Partial response or better was achieved in 65.4% of patients, including 11% CR and 12.5% VGPR. The most common adverse events included peripheral neuropathy (47% of patients), gastrointestinal symptoms (22.2%), thrombocytopenia (11.1%), and anemia (7.4%). Overall, these results are comparable with studies of Vd in younger patients.23
Sub-analyses of the phase 3 ASPIRE and ENDEAVOR studies demonstrated a benefit for carfilzomib in elderly patients with MM. The ASPIRE study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus Rd demonstrated prolonged PFS with KRd in patients with relapsed multiple myeloma aged ≥70 years (median: 23.8 versus 16.0 months; HR, 0.75, 95% CI, 0.53-1.08) and an improved ORR (90.3% versus 66.1%, respectively).24 While cardiovascular events occurred more frequently in the elderly population compared with patients aged <70 years, KRd demonstrated a favorable benefit-risk profile in elderly patients.25 The ENDEAVOR study of carfilzomib and dexamethasone (Kd) versus Vd demonstrated prolonged PFS with Kd in patients with RRMM who received 1 to 3 prior lines of therapy and were aged 65 to 74 years (median: 15.6 versus 9.5 months; HR, 0.528, 95% CI, 0.382-0.728) or ≥75 years (median: 18.7 versus 8.9 months; HR, 0.383; 95% CI, 0.227-0.647).26 While hypertension was the most common grade ≥3 TEAE in patients aged 65 to 74 years and ≥75 years who received Kd, the safety results were similar to the overall population in ENDEAV-OR.
Due to the nature of drug development, clinical trials and regulatory approvals usually proceed with patients with more advanced disease. Ideally, moving these regimens into front-line treatment may provide the best opportunity for patients to mount prolonged responses and delay relapse. Newly diagnosed elderly patients are usually excluded from receiving stem cell transplants due to their age. The VISTA phase 3 study of bortezomib, mel-phalan, and prednisone (VMP) established this regimen as a standard of care in transplant-ineligible newly diagnosed MM patients.27 Of interest is whether the benefit of daratumumab-based regimens in RRMM could be extended to these patients. In the phase 3 ALCYONE study, daratumumab in combination with VMP reduced the risk of disease progression or death by 50% compared with VMP alone (HR, 0.50; 95% CI, 0.38-0.65).28 Over 90% of patients were aged ≥65 years, and 30% were aged ≥75 years. In a prespecified subgroup analysis, the HR for the primary endpoint of PFS were similar for patients aged ≥75 years (0.53) and <75 years (0.49). The addition of daratumumab to VMP produced no new safety signals except for a higher rate of infections that resolved with few discontinuations.28 Furthermore, Rd is also a standard treatment regimen for patients with transplant-ineligible newly diagnosed MM. Recently, in the phase 3 MAIA study, D-Rd significantly reduced the risk of disease progression or death and nearly doubled the rate of CR or better.29 MAIA enrolled patients aged ≥65 years, 44% of whom were aged ≥75 years.29
MM is a disease of the elderly with 35 to 40% of patients aged ≥75 years at diagnosis.22 One of the limitations of the current analysis is that the subgroup of patients aged ≥75 years in POLLUX and CASTOR was relatively small (<15% of the overall study population was ≥75 years of age). Comorbidities and other ailments, including frailty, that are often associated with elderly patients may have compro mised eligibility for the study, and it is recognized that this is a limitation of many MM studies.30 However, differences in efficacy were still observed between the treatment groups. An additional limitation is that the study did not assess frailty. The IMWG frailty score system which is based on age, comorbidities, and functional status, can be used to predict survival and toxicity, making it a useful metric for determining feasibility of a treatment regimen and for clinical trial design.19 This metric was adopted after these studies were initiated.
In conclusion, the safety and efficacy of daratumumab in combination with Rd or Vd does not appear to be negatively impacted by age in patients studied in POLLUX and CASTOR, and is consistent with the overall study populations. This subgroup analysis supports the addition of daratumumab to standard-of-care regimens in patients with RRMM, regardless of age.
The authors thank the patients who participated in this study, the staff members at the study sites, the data and safety monitoring committee, and staff members who were involved in data collection and analyses.
- Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/468
- Funding These studies (ClinicalTrials.gov Identifiers: NCT02076009 and NCT02136134) were sponsored by Janssen Research & Development, LLC. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.Editorial and medical writing support were provided by Kristin Runkle, PhD, of MedErgy, and were funded by Janssen Global Services, LLC.
- Received January 23, 2019.
- Accepted June 20, 2019.
- Madan S, Kumar S. Current treatment options for elderly patients with multiple myeloma: clinical impact of novel agents. Therapy. 2011; 8(4):415-429. Google Scholar
- Howlader N, Noone AM, Krapcho M. SEER Cancer Statistics Review, 1975-2014. National Cancer Institute; 2017. Google Scholar
- Kumar SK, Rajkumar SV, Dispenzieri A. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111(5):2516-2520. PubMedhttps://doi.org/10.1182/blood-2007-10-116129Google Scholar
- Palumbo A, Bringhen S, Ludwig H. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011; 118(17):4519-4529. PubMedhttps://doi.org/10.1182/blood-2011-06-358812Google Scholar
- Ludwig H, Bolejack V, Crowley J. Survival and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol. 2010; 28(9):1599-1605. PubMedhttps://doi.org/10.1200/JCO.2009.25.2114Google Scholar
- Willan J, Eyre TA, Sharpley F, Watson C, King AJ, Ramasamy K. Multiple myeloma in the very elderly patient: challenges and solutions. Clin Interv Aging. 2016; 11:423-435. Google Scholar
- de Weers M, Tai YT, van der Veer MS. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011; 186(3):1840-1848. PubMedhttps://doi.org/10.4049/jimmunol.1003032Google Scholar
- Lammerts van Bueren J, Jakobs D, Kaldenhoven N. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014; 124(21):3474. Google Scholar
- Overdijk MB, Verploegen S, Bogels M. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015; 7(2):311-321. PubMedhttps://doi.org/10.1080/19420862.2015.1007813Google Scholar
- Overdijk MB, Jansen JH, Nederend M. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcgamma receptor-mediated cross-linking. J Immunol. 2016; 197(3):807-813. PubMedhttps://doi.org/10.4049/jimmunol.1501351Google Scholar
- Krejcik J, Casneuf T, Nijhof IS. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016; 128(3):384-394. PubMedhttps://doi.org/10.1182/blood-2015-12-687749Google Scholar
- Chiu C, Casneuf T, Axel A. Daratumumab in combination with lenalidomide plus dexamethasone induces clonality increase and T-cell expansion: results from a phase 3 randomized study (POLLUX). Blood. 2016; 128(22):4531. Google Scholar
- Adams HC, Stevenaert F, Krejcik J. High-parameter mass cytometry evaluation of relapsed/refractory multiple myeloma patients treated with daratumumab demonstrates immune modulation as a novel mechanism of action. Cytometry A. 2019; 95(3):279-289. Google Scholar
- Dimopoulos MA, Oriol A, Nahi H. Daratumumab, lenalidomide, and dexam-ethasone for multiple myeloma. N Engl J Med. 2016; 375(14):1319-1331. PubMedhttps://doi.org/10.1056/NEJMoa1607751Google Scholar
- Palumbo A, Chanan-Khan A, Weisel K. Daratumumab, bortezomib, and dexam-ethasone for multiple myeloma. N Engl J Med. 2016; 375(8):754-766. PubMedGoogle Scholar
- Blair HA. Daratumumab: a review in relapsed and/or refractory multiple myeloma. Drugs. 2017; 77(18):2013-2024. Google Scholar
- Durie BGM, Harousseau JL, Miguel JS. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9):1467-1473. PubMedhttps://doi.org/10.1038/sj.leu.2404284Google Scholar
- Rajkumar SV, Harousseau JL, Durie B. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117(18):4691-4695. PubMedhttps://doi.org/10.1182/blood-2010-10-299487Google Scholar
- Palumbo A, Bringhen S, Mateos MV. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015; 125(13):2068-2074. PubMedhttps://doi.org/10.1182/blood-2014-12-615187Google Scholar
- Dimopoulos M, San Miguel J, Belch A. Daratumumab plus lenalidomide and dex-amethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POL-LUX. Haematologica. 2018; 103(12):2088-2096. PubMedhttps://doi.org/10.3324/haematol.2018.194282Google Scholar
- Spencer A, Lentzsch S, Weisel K. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CAS-TOR. Haematologica. 2018; 103(12):2079-2087. PubMedhttps://doi.org/10.3324/haematol.2018.194118Google Scholar
- Zweegman S, Palumbo A, Bringhen S, Sonneveld P. Age and aging in blood disorders: multiple myeloma. Haematologica. 2014; 99(7):1133-1137. PubMedhttps://doi.org/10.3324/haematol.2014.110296Google Scholar
- Castelli R, Pantaleo G, Gallipoli P. Salvage therapy with bortezomib and dex-amethasone in elderly patients with relapsed/refractory multiple myeloma. Anticancer Drugs. 2015; 26(10):1078-1082. Google Scholar
- Dimopoulos MA, Stewart AK, Masszi T. Carfilzomib, lenalidomide, and dexam-ethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study. Br J Haematol. 2017; 177(3):404-413. Google Scholar
- Dimopoulos MA, Stewart AK, Masszi T. Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment. Blood Cancer J. 2017; 7(4):e554. Google Scholar
- Niesvizky R, Ludwig H, Spencer A.Paper presented at: ; 1885. Google Scholar
- San Miguel JF, Schlag R, Khuageva NK. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359(9):906-917. PubMedhttps://doi.org/10.1056/NEJMoa0801479Google Scholar
- Mateos MV, Dimopoulos MA, Cavo M. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018; 378(6):518-528. Google Scholar
- Facon T, Kumar S, Plesner T. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019; 380(22):2104-2115. Google Scholar
- Richardson PG, San Miguel JF, Moreau P. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J. 2018; 8(11):109. Google Scholar