In light of the recent approvals of combination anti-myeloma regimens containing monoclonal antibodies, as well as the robust pipeline of novel targeted agents likely to be approved in the next year, there is much optimism in the field of multiple myeloma.
In light of the recent approvals of combination anti-myeloma regimens containing monoclonal antibodies, as well as the robust pipeline of novel targeted agents likely to be approved in the next year, there is much optimism in the field of multiple myeloma (MM).1 However, elderly or frail patients with MM may not be eligible for certain treatments, such as adoptive T-cell therapies and bispecific antibodies, that hold the potential for serious adverse events (AEs) in this population. Therefore, inclusion of novel agents, such as monoclonal antibodies, as part of induction for elderly patients with newly diagnosed MM offers the potential to improve outcomes in this challenging population.
Considering the median age of diagnosis of MM is 69 years, and that most study results showing a benefit for consolidation with stem cell transplantation (SCT) have been limited to patients 70 years or younger, it is imperative to provide treatments that both prolong survival and maintain quality of life for older patients with newly diagnosed MM.2 Beyond biological age and performance status, geriatric assessments can provide quantitative measures of fitness that predictsurvivalandtreatmenttoxicities, there by stratifying patients fo rmore or less intensive therapies.3,4
Because most phase 3 studies of novel agents have used conventional enrollment criteria based on factors such as performance status, SCT candidacy, and baseline organ function, rather than stratifying according to frailty measures, questions remain as to whether a one-size-fits-allapproach is suitable for all patients who are elderly/transplant ineligible. Nevertheless, recent randomized controlled studies of up-front triplet and quadruplet induction regimens including monoclonal antibodies have consistently demonstrated durability and tolerability in elderly patients with MM.
The 2014 publication of data from the FIRST trial (NCT00689936) showed a survival benefit with continuous lenalidomide (Revlimid) and dexamethasone compared with the combination of melphalan, prednisone, and thalidomide ( Thalomid) in transplant-ineligible patients ranging from 40 to 92 years (median overall survival [OS], 59 vs 49 months; P=.0023).5,6 These data demonstrated that prolongedexposuretonovelagentswas effective and tolerable in elderly patients.
Further, building on data that showed the efficacy of the monoclonal antibody daratumumab (Darzalex), particularly in elderly patients with relapsed MM,7,8 recent study findings have similarly demonstrated a benefit of up-front daratumumab in this population. According to data from the phase 3 ALCYONE study (NCT02195479) of patients with newly diagnosed MM ineligible for SCT aged 40 to 93 years,9 the combination of daratumumab with bortezomib (Velcade), melphalan, and prednisone (D-VMP) was superior to VMP alone. Updated survival analysis showed a 78% versus 68% OS at 36 months (HR, 0.60; P = .0003), again preserved in patients 75 years or older.10 Grade 3 or 4 hematologic AEs were similar between treatment groups, although respiratory tract infections were more common in the D-VMP arm (11.3% vs 4%).10
In the phase 3 MAIA study (NCT02252172) comparing the combination of daratumumab, lenalidomide, and dexamethasone (D-Rd) to Rd in patients with a median age of 73 years (range, 45-90), a 38% reduction in progression was observed with D-Rd in the 44% of patients 75 years or older enrolled in the trial (HR, 0.62; 95% CI, 0.44-0.87).11,12 Although the OS analysis has yet to be read out, the median progression-free survival (PFS) at 36.4 months was not reached in the D-Rd group compared with 33.8 months with Rd.11 As in the ALCYONE study, the rate of grade 3 or 4 infections was higher in the daratumumab-containing arm (32.1% vs 23.3%).
Although there were no overall differences in serious AEs (62.9% vs 62.7%), of note, fewer patients discontinued treatment in the D-Rd arm (7.1% vs 15.9%). The benefit of up-front daratumumab was not preserved in patients with high-risk cytogenetics; however, considering this was a relatively smaller subgroup of patients, it may take more time to see a benefit than has been demonstrated with daratumumab regimens in the relapsed setting.13-15 Health- related quality-of-life measures in the MAIA study were superior with D-Rd, with no statistical differences in cognitive decline between either arm at 12 months.16 In addition, in my practice, I favor giving subcutaneous daratu- mumab with these regimens, considering the lower rate of infusion reactions observed in the phase 3 COLUMBA study (NCT03277105).17
Unpublished data using the anti-SLAMF7 monoclonal antibody elotuzumab (Empliciti) in combination with Rd compared with Rd alone in patients who are ineligible for SCT enrolled in the ELOQUENT-1 trial (NCT01335399) indicate that this study did not meet its primary end point of PFS.18 Encouraging early data from the combination of elotuzumab plus carfilzomib (Kyprolis), lenalidomide, and dexamethasone in the GMMG-CONCEPT trial (NCT03104842), which examined patients with newly diagnosed high-risk disease, showed a 100% overall response rate, with all 4 patients who were ineligible for SCT achieving a very good partial response.19
With recent approvals of the anti-CD38 isatuximab-irfc (Sarclisa) and the BMCA-targeting antibody-drug conjugate belantamab mafodotin-blmf (Blenrep) in the relapsed setting, it is likely that these agents will move into early lines of therapy. In fact, there are several ongoing studies of up-front monoclonal antibody combinations in elderly patients with MM or in cases which frontline SCT is not planned. Investigators are examining the oral proteasome inhibitor ixazomib (Ninlaro) in combination with daratumumab and low-dose dexamethasone in frail patients with MM in the phase 2 HOVON 143 study.20 In terms of quadruplet regimens, the ongoing phase 3 IMROZ (isatuximab plus lenalidomide, bortezomib, and dexamethasone; NCT03319667) and CEPHEUS (daratumumab plus RVD [lenalidomide, bortezomib, and dexamethasone]; NCT03652064) studies are both looking at patients with MM in which SCT is not planned as a frontline therapy. Notwithstanding the availability of alternative regimens that have also demonstrated efficacy in patients ineligible for SCT, such as RVD at either conventional or attenuated (RVD lite) doses,21,22 it is very likely that given their combined efficacy and tolerability, most elderly patients with MM will be candidates for frontline monoclonal antibodies. However, applying frailty measures may help stratify those who are more likely to develop higher-grade AEs. In these frail patients, dose-reduced triplet or doublet regimens may be more appropriate.
One question arises in the context of the largely positive data for up-front monoclonal antibody regimens in elderly patients with MM: Should all elderly patients receive these regimens? Although tolerability may be acceptable, the patients with higher frailty measures who were excluded from the phase 3 studies shown in table 1 9-12 might be better served with less intensive regimens. For example, frail patients with MM may not be able to travel to an infusion center for the initial weekly daratumumab induction period over 2 months. In addition, the annual cost of treatment for a regimen such as DRD (daratumumab, lenalidomide, and dexamethasone) is estimated to be $290,000, which will be even higher with quadruplet regimens, particularly when expanded over a several-year period.23 Because both D-VMP and D-Rd regimens have category 1 National Comprehensive Cancer Network recommendations, insurers are likely to cover these treatments, although potential financial toxicity should be a consideration, particularly for elderly patients receiving regimens containing oral agents.