Introduction
Multiple myeloma (MM) is a plasma cell malignancy that predominantly affects older patients, with approximately one-third of patients aged 75 years and older at diagnosis, and over half classified as older when using 65 years as the cutoff [ 1 ]. When treating older patients, various factors must be considered, including the high burden of comorbidities and frailty, limitations in mobility, and financial issues. Given the relatively high attrition rate in this population, the introduction of a first-line regimen that is both effective and tolerable is indispensable [ 2 ]. Especially considering the incurable nature of MM, the importance of the first-line treatment cannot be overstated.
Treatment outcomes of MM have continuously improved over the past two decades. Real-world data published by the Mayo Clinic demonstrated significant improvements in survival outcomes over time. In one study, among patients diagnosed between 2004 and 2007, the 4-year survival rate was 50%, whereas for those diagnosed between 2013 and 2017, it increased significantly to 75%. This improvement was also evident in older patients; in the same study, the subgroup analysis of patients aged 75 years and older showed that their 4-year survival rate had markedly improved from 24 to 56% over the same period [ 3 ]. This improvement in survival has largely been achieved with the introduction of novel agents, such as lenalidomide and bortezomib, expanded eligibility for hematopoietic stem cell transplantation, and advances in supportive care [ 4 , 5 ]. Furthermore, the recent incorporation of anti-CD38 monoclonal antibodies into first-line treatment has further improved survival outcomes while maintaining treatment tolerability, even in older patients [ 6 ]. However, older patients still experience a higher risk of death than younger individuals, a trend that is particularly pronounced in patients with high frailty who are often excluded from most clinical trials [ 7 ]. This review aims to discuss advancements and recent achievements in the treatment of patients with MM who are transplant ineligible as well as future directions for improving therapeutic strategies in this population, particularly through approaches based on frailty status.
Evolution of first-line treatment regimens for patients who are transplant ineligible
Before the widespread introduction of novel agents, the treatment of MM primarily involved the use of melphalan-based therapies. Since the 1960 s, combinations of melphalan and prednisone (MP) or melphalan with dexamethasone (MD) have been widely used [ 8 ]. Subsequently, in 1998, thalidomide was approved by the U.S. Food and Drug Administration (FDA), and the combination of thalidomide with melphalan and prednisone (MPT) demonstrated significant improvements over the standard MP regimen in the older population [ 9 ]. In one trial, the MPT regimen showed a higher overall response rate (ORR) (76.0% vs. 47.6%) and a significantly improved progression-free survival (PFS) (median: 21.8 months for MPT vs. 14.5 months for MP, p = 0.004), leading to its approval as a first-line treatment. However, no significant difference was observed in overall survival (OS), with values of 45.0 months for MPT vs. 47.6 months for MP ( p = 0.79) [ 10 ].
The introduction of bortezomib in the early 2000 s marked another transformation in the treatment of MM. The VISTA trial compared a combination of bortezomib, melphalan, and prednisone (VMP) with a standard MP regimen. The study demonstrated significant improvements in both PFS (21.7 months vs. 15.2 months) and OS (56.4 months vs. 43.1 months), establishing VMP as the new standard therapy for patients who are transplant ineligible [ 11 ]. The VMP regimen was generally well tolerated. However, the frequency of peripheral neuropathy was higher than that in the control group, with 13% of the patients experiencing grade 3 neuropathy and 44% reporting any grade of neuropathy. With the introduction of subcutaneous bortezomib, the previously reported efficacy was maintained while reducing the incidence of peripheral neuropathy [ 12 ]. Additionally, a study that modified the bortezomib regimen from twice weekly to once weekly also demonstrated comparable outcomes while significantly reducing peripheral neuropathy; this approach has since been widely adopted in clinical practice [ 13 , 14 ]. The approval of lenalidomide as a treatment for MM in the mid-2000s brought about another significant shift in the management of the disease. In the FIRST trial, a combination of lenalidomide and dexamethasone was administered in 28-day cycles until disease progression (continuous Rd). This regimen demonstrated significantly better PFS than the group that received Rd for 18 cycles followed by discontinuation (Rd18) and the group treated with MPT (median 25.5 vs. 20.7 vs. 21.2 months, p < 0.001) [ 15 ]. The continuous Rd regimen also showed significantly better OS than MPT (median 59.1 vs. 49.1 months, p = 0.0023), but did not demonstrate a significant difference when compared to Rd18 (median 62.3 months) with a median follow-up of 67 months [ 16 ]. The most common grade ≥ 3 non-hematologic adverse event in the continuous Rd group was infection (32%), and secondary malignancy occurred in 7% of the patients, with no increased risk compared to other cohorts in the study. Several subsequent studies have reported increased risk of secondary malignancies associated with lenalidomide. However, at least in the case of the continuous Rd regimen, the benefits of treatment are believed to outweigh these risks [ 17 , 18 ]. Although VMP and continuous Rd have different characteristics as first-line treatments for older patients, they exhibited relatively comparable efficacy [ 19 ]. Both regimens continue to serve as a backbone for the development of new treatment regimens.
In the SWOG S0777 trial published in 2017, the combination of bortezomib, lenalidomide, and dexamethasone (VRd) was compared with continuous Rd. This study used intravenous bortezomib, and lenalidomide was administered at 25 mg daily on days 1–14 in 3-week cycles for a total of eight cycles, after which the Rd regimen was continued for 28-day cycles. Continuous Rd was administered in the same manner as that in the FIRST trial. The results showed that VRd led to improved ORR (82% vs. 72%) and significantly better PFS (median 42 vs. 30 months, p = 0.0018) and OS (median 75 vs. 64 months, p = 0.025) than Rd. However, this study included not only patients who are transplant ineligible but also those who did not intend to undergo immediate autologous stem cell transplantation, resulting in a median age of approximately 10 years younger than that in other studies that focused on the older population (median age, 63 years for both groups), with 43% of the patients aged > 65 years [ 20 ]. In the subgroup analysis, patients under 65 years showed a significant benefit in OS, while no significant benefit was observed in patients aged 65 years and older (median 73 years old). The median PFS and OS for the latter group were 33.1 months and 62.9 months, respectively [ 21 ]. Although no clear survival benefit was observed in the older subgroup, the VRd regimen demonstrated potential as a non-cytotoxic triplet regimen for older patients. However, in patients aged 75 years and older, dose reduction is required in almost all cases.
A phase 2 study of RVD lite was conducted, with a focus on tolerability. In this study, lenalidomide was administered at 15 mg on days 1–21, bortezomib at 1.3 mg/m. 2 weekly, and dexamethasone at 20 mg on the day of and after bortezomib administration in a 35-day cycle. Compared to the dose intensities in the SWOG S0777 trial, in this trial, lenalidomide and bortezomib had dose intensities of approximately 54–60%. The ORR was 86.0% with a median PFS of 42 months. Grade ≥ 3 peripheral neuropathy was observed in only 2% of the patients, showing a significant improvement in tolerability compared to the 34.6% in the VRd group of the SWOG S0777 trial.[ 22 ]
Daratumumab, first used in the mid-2010s for relapsed/refractory MM, has since been continuously explored in combination with various existing drugs. Therefore, the combination of VMP and Rd has become the standard first-line treatment for older patients. In the ALCYONE study, the efficacy of daratumumab combined with VMP (D-VMP) was compared with that of VMP as a control. Patients who received D-VMP were treated with daratumumab until the disease progressed. The ORR was significantly higher in the D-VMP group than in the VMP group (90.9% vs. 73.9%), and the complete remission (CR) rate was also higher (42.6% vs. 24.4%) [ 23 ]. Survival outcomes had also significantly improved in the D-VMP group, with the PFS showing a significant difference (36.4 months vs. 19.3 months) and the OS being longer (82.7 months vs. 53.6 months). In terms of minimal residual disease (MRD) negativity, D-VMP showed significant improvement compared to VMP (28.3% vs. 7.0% at a threshold of 1 tumor cell per 10 5 white blood cells), and the proportion of patients with sustained MRD negativity for over 1 year was significantly higher in the D-VMP group (14.0% vs. 2.8%) [ 24 ]. Furthermore, MRD negativity was directly associated with improved OS. While most patients tolerated the treatment, Grade ≥ 3 infections occurred in 30% of patients in the D-VMP group, with pneumonia being the most common adverse event. This finding suggests that pneumonia is a critical adverse effect for monitoring Future daratumumab-based therapies. The superiority of D-VMP over VMP was also demonstrated in the phase 3 OCTANS study involving Asian patients. Additionally, in this study, D-VMP showed a significant PFS benefit even in the cytogenetically high-risk subgroup [ 25 ].
The MAIA study compared daratumumab combined with Rd (D-Rd) with continuous Rd and demonstrated significantly improved results in both the CR rate (47.6% vs. 24.9%) and MRD negativity (24.2% vs. 7.3%) [ 26 ]. It also showed significant improvements in PFS (median 61.9 vs. 34.4 months) and OS (90.3 vs. 64.1 months). Although higher frequencies of neutropenia (54% vs. 37%, for grade ≥ 3) and pneumonia (19% vs. 10%, for grade ≥ 3) were observed, the regimen maintained overall tolerability, making it the most preferred regimen for older patients in most countries [ 27 ]. Real-world data from studies such as TAURUS and PEGASUS have shown the relative superiority of D-Rd over VRd [ 28 , 29 ]. Furthermore, an adjusted comparison of patients aged 65 years and older in the MAIA and SWOG S0777 trials also demonstrated the relative superiority of D-Rd over VRd, establishing it as the most widely accepted first-line treatment regimen, regardless of age, in patients who are transplant ineligible and newly diagnosed MM.
Latest developments in treatment regimens for patients with MM who are transplant ineligible
As mentioned above, the treatment of MM has progressed from doublet regimens to triplet regimens, with a continuous trend toward excluding the use of cytotoxic agents such as melphalan as induction therapy. The introduction and evolution of representative regimens over time are shown in Fig. 1 . Recent studies have explored the introduction of quadruple regimens combining anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory drugs, and steroids to achieve survival benefits and meaningful responses, as indicated by MRD negativity [ 30 ]. These studies will continue to advance to improve treatment outcomes.
The IMROZ trial, published in 2024, compared isatuximab plus VRd (I-VRd) with VRd in patients aged 80 years or younger. In the I-VRd group, IV isatuximab (10 mg/kg) was administered once weekly during induction cycle 1 and subsequently every 2 weeks in later cycles, with each cycle lasting for 6 weeks. Following a 4-cycle induction phase, the maintenance phase was conducted every 4 weeks, and from cycle 18 onward, the dosing interval for isatuximab was extended monthly. In both groups, VRd was administered according to the same scheme used in the SWOG S0777 trial [ 31 ]. In terms of response, the I-VRd group showed significantly better results than the VRd group, with a CR rate of 74.7% vs. 64.1% ( p = 0.01) and MRD-negative CR rate of 55.5% vs. 40.9% ( p = 0.003). During a median follow-up of 59.7 months, the 5-year PFS rate significantly improved in the I-VRd group (63.2% vs. 45.2%). Additionally, sustained MRD negativity for > 1 year was significantly higher in the I-VRd group (46.8% vs. 24.3%). Although grade ≥ 3 neutropenia (54.4% vs. 37.0%) and pneumonia (20.2% vs. 12.7%) were relatively more frequent, the addition of isatuximab showed no negative effect on overall quality-of-life measures. Therefore, the FDA approved this quadruple induction regimen for patients with non-frailty aged 80 years or younger in September 2024. The BENEFIT trial, which had 18-month MRD negativity as its primary endpoint, compared I-VRd with isatuximab-Rd and, similar to the IMROZ trial, involved patients aged 80 years or younger. However, this study differed in that bortezomib was administered once weekly from the start, with a 4-week cycle of 12 cycles in the induction phase; from cycles 13 to 18, bortezomib was administered every 2 weeks. The MRD-negativity rate was significantly higher in the I-VRd group (53% vs. 26%, P < 0.0001), ultimately demonstrating that the addition of bortezomib to isatuximab-Rd improved efficacy [ 32 ]. In another quadruple induction trial, CEPHEUS, daratumumab-VRd (D-VRd) was compared with VRd, and similar to the IMROZ and BENEFIT studies, it involved patients aged 80 years or younger. With a median follow-up of 58.7 months, the primary endpoint of MRD-negative CR rate was significantly higher in the D-VRd group (60.9%) than in the VRd group (39.4%). The CR rate was significantly higher in the D-VRd group (81.2%) than in the VRd group (61.6%). Additionally, sustained MRD negativity (48.7% vs. 26.3%, p < 0.0001) and 54-month PFS (68.1% vs. 49.5%, p = 0.0005) showed significant benefits in the D-VRd group. Although grade ≥ 3 neutropenia (44.2% vs. 29.7%) and infection (40.1% vs. 31.8%) occurred more frequently in the D-VRd group, no significant differences were observed in other adverse events [ 33 ]. Overall, this study further demonstrates the efficacy of anti-CD38 monoclonal antibodies in the first-line setting. Table 1 summarizes the patient populations and key outcomes of pivotal trials for first-line treatment in patients who are transplant ineligible, both past and present.
Table 1
Key pivotal trials of first-line therapy in patients who are transplant ineligible
ORR overall response, CR complete response, MRD minimal residual disease, PFS progression-free survival, OS overall survival, NA not available, NR not reached
| Trial (Year) | Regimen | Age (med/range) | ORR/CR | MRD(-)CR/Sustained | PFS | OS |
| VISTA (2008) | VMP (vs. MP) | 71/57–90 | 71%/30.0% | NA | 24.0 m | 56.4 m (46.0%) |
| FIRST (2014) | Rd (vs. MPT/Rd18) | 73/44–91 | 81%/22% | NA | 26.0 m (32.6%/4Y) | 59.1 m (59.0%/4Y) |
| SWOG-S0777 (2017) | VRd (vs. Rd) | 63/29–87 | 82%/16% | NA | 43 m | 75 m (69%/5Y) |
| SWOG-S0777 (> 65yo) | VRd (vs. Rd) | 73/65–87 | NA | NA | 33.1 m (n.s.) | 62.9 m (n.s.) |
| RVD lite (2018) | RVd lite (Phase 2) | 73/65–91 | 86.0%/44.0% | NA | 42 m | NR (61.3%/5Y) |
| ALCYONE (2018) | D-VMP (vs. VMP) | 69/58–81 | 90.0%/42.6% | 26.9%/14.0% | 37.3 m (31.9%/6Y) | 82.7 m (55.7%/6Y) |
| MAIA (2019) | D-Rd (vs. Rd) | 73/50–90 | 92.9%/51.0% | 31.0%/18.8% | 61.9 m (52.5%) | 90.3 m (66.3%/5Y) |
| IMROZ (2024) | I-VRd (vs. VRd) | 72/60–80 | 91.3%/74.7% | 55.5%/46.8% | NR (63.2%/5Y) | NR (72.3%/5Y) |
| BENEFIT (2024) | I-VRd (vs. I-Rd) | 73/65–79 | 85.0%/58.0% | 37.0%/ | NR (80.0%/2Y) | NR (91.5%/2Y) |
| CEPHEUS (2024) | D-VRd (vs. VRd) | 70/31–80 | 97.0%/81.2% | 60.9%/48.7% | NR (68.1%/54 m) | NA |
The GEM2017FIT phase 3 trial, involving patients aged 65–80 years, compared two experimental arms—carfilzomib, lenalidomide, dexamethasone (KRd), and daratumumab-KRd (D-KRd)—with a control arm (VMP9-Rd9), where patients received nine cycles of VMP and Rd. The study found that after induction, the MRD-negativity rates were significantly higher in the KRd group (53.9%) and D-KRd group (61.4%) than in the VMP9-Rd9 group (26.6%). The trial also included an additional consolidation phase with four cycles of DRd for patients who did not receive daratumumab. After consolidation therapy, the MRD-negativity rate in the KRd-DRd group was 81.9%, which was significantly higher than that in the VMP9-Rd9-DRd group (62.2%). The D-KRd group that did not receive consolidation therapy, showed a rate of 85.3% [ 34 ]. This ongoing study suggests that the inclusion of daratumumab and carfilzomib in a quadruple induction/consolidation strategy could provide meaningful responses in relatively younger and fitter older patients. We look forward to further results after the maintenance phase, in addition to previous studies. In addition to anti-CD38 monoclonal antibodies, various new induction regimens incorporating belantamab mafodotin and bispecific antibodies are being explored. In a phase 1/2 study combining belantamab mafodotin with Rd, an overall CR rate of 52.8% was observed [ 35 ]. A phase 3 study ( NCT06679101 ) is currently ongoing to compare this regimen with the DRd regimen. Additionally, a phase 3 study ( NCT05552222 ) is ongoing to compare DRd with combinations of daratumumab, lenalidomide, and the bispecific antibodies teclistamab (Tec-DR) and talquetamab (Tal-DR). This study provides insights into the potentially expanded clinical roles of bispecific antibodies in older patients [ 36 ]. Interest in the use of chimeric antigen receptor T-cell (CAR-T) therapy in the frontline setting is also increasing. In a phase 2, single-arm CAREMM-001 study, 20 patients (median age, 69 years) received three cycles of induction therapy followed by CAR-T cell administration, followed by an additional three cycles of induction therapy and maintenance. The results showed that 75% of the patients achieved a stringent complete response, and all patients achieved MRD negativity after CAR-T cell infusion [ 37 ]. These studies may provide more data on the potential benefits of CAR-T therapy for the treatment of patients who are transplant ineligible in the future.
Assessment and management of patients with frailty
One of the challenges in treating older patients is ensuring treatment tolerability given their various physical statuses and associated difficulties in managing their treatment. Accurate frailty assessment is essential in the management of older patients with MM. Consequently, various methods have been proposed for precise frailty scoring[ 38 – 42 ] (Table 2 ). These frailty scores can serve as prognostic indicators, and continuous assessment is necessary, especially in older patients, as frailty may change throughout the treatment process [ 38 , 43 ].
Table 2
Frailty assessment scores, components, and classification
IMWG International Myeloma Working Group, CCI Charlson Comorbidity Index, IADL Instrumental Activities of Daily Living, ADL Activities of Daily Living, ECOG PS Eastern Cooperative Oncology Group performance status, R-MCI revised Myeloma Comorbidity Index, eGFR estimated glomerular filtration rate, KPS Karnofsky Performance Scale, UK MRP UK Myeloma Research Alliance Risk Profile, PS performance status, CRP C-reactive protein, ISS International Scoring System, NT-BNP B-natriuretic peptide
| Scores | Components | Frailty group classification |
| IMWG | Age, CCI, IADL, ADL | Fit/Intermediate-fit/Frail |
| Simplified IMWG | Age, CCI, ECOG PS | Non-frail/Frail |
| R-MCI | Age, eGFR, Lung disease, KPS, Frailty, Cytogenetics | Fit/Intermediate-fit/Frail |
| UK MRP | Age, PS, CRP, ISS | Low/Intermediate/High |
| Mayo frailty | Age, PS, NT-BNP | I/II/III/IV |
From a treatment perspective, in the MAIA trial, approximately 45% of the total patients (D-Rd, 172 [46.7%]; Rd, 169 [45.8%]) were classified as frail according to the simplified International Myeloma Working Group (IMWG) score. These patients with frailty exhibited a relatively poorer PFS than those without frailty; however, D-Rd demonstrated significantly better outcomes than Rd, thereby demonstrating the benefit of D-Rd in patients with frailty.[ 44 ] The HOVON 143 study included 65 patients with frailty, classified according to the IMWG frailty index, who were treated with ixazomib, daratumumab, and dexamethasone induction therapy, followed by maintenance therapy with ixazomib and daratumumab for up to 2 years. This study demonstrated a median PFS of 13.8 months and a tolerable safety profile, thus presenting another potential treatment option for patients with frailty [ 45 ].
Alongside treatment strategies for patients with frailty using anti-CD38 monoclonal antibodies and oral agents, recent approaches have explored the discontinuation or reduction of steroids to maintain treatment efficacy while preserving tolerability in patients with frailty. The IFM 2017–03 study compared patients with frailty with a simplified IMWG score of 2 or higher and evaluated the benefits and risks of a dexamethasone-sparing strategy by comparing the daratumumab and lenalidomide (DR) groups with the Rd group. In this study, the DR group showed significant benefits over the Rd group in terms of median PFS (53.4 vs. 22.5 months) and OS (not reached vs. 47.2 months), while maintaining a similar rate of grade ≥ 3 infections (19% vs. 21%) [ 46 ]. The Nordic Myeloma Study Group conducted a study with a treatment scheme similar to that of the BENEFIT trial, in which dexamethasone was administered only during the first two cycles and then discontinued. Among the 51 patients included in this study, 16 (31%) were aged 80 and older. The MRD-negative CR rate, i.e., the primary endpoint, was 37%, showing results similar to those of the BENEFIT trial. Additionally, the incidence of grade 3 pneumonia was approximately 20%, indicating a relatively tolerable outcome [ 47 ]. Compared to the IMROZ and BENEFIT studies, which involved patients aged 80 years or younger, this study demonstrated that by limiting the use of steroids in quadruple induction, efficacy could be maintained and tolerability could be improved in patients with frailty.
Conclusion
The treatment approaches for transplant-ineligible MM have rapidly evolved from melphalan-based regimens to the incorporation of proteasome inhibitors and immunomodulatory drugs, followed by the introduction of anti-CD38 antibodies. This shift has led to the progression from doublet and triplet regimens to the current quadruple induction therapy. Consequently, the focus has shifted from simply achieving survival benefits to maintaining tolerability while achieving meaningful responses, as exemplified by MRD negativity. Additionally, the development of treatment regimens has been accompanied by advancements in frailty assessment and ongoing research on tailored treatment strategies for patients with frailty. Recent trends include the continuous exploration of therapies such as bispecific antibodies and CAR-T cells, which are less affected by age. Treatment strategies for older patients are expected to continue evolving and improving.
Authors’ contributions
J.J. wrote and reviewed the manuscript.
Funding
This study received no specific grants from any funding agency in the public, commercial, or not-for-profit sector.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This review article was conducted in accordance with the principles of the Declaration of Helsinki. Human ethics and consent to participate in the declarations were not applicable, and ethics approval was not required owing to the nature of this study as a review article.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
Data Availability Statement
No datasets were generated or analysed during the current study.