Bortezomib-melphalan-prednisone versus lenalidomide-dexamethasone in elderly patients with multiple myeloma: the Real MM phase IV trial

In patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem-cell transplantation (NTE), the standard first-line therapies until the introduction of daratumumab were bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd),¹ which were approved on the basis of data from the VISTA and FIRST phase III trials.^2,3 To our knowledge, the Real MM trial reported here (clinicaltrials.gov NCT03829371), funded by the Italian Medicines Agency AIFA (Independent Research program), is the first prospective, multicenter, randomized trial comparing VMP versus Rd in a real-life elderly population of NDMM patients.

Transplant ineligibility was defined by age ≥65 years or comorbidities. Patients were stratified by frailty (International Myeloma Working Group [IMWG] Frailty Score: fit vs. intermediate-fit vs. frail patients)⁴ and cytogenetic risk (high risk [presence of t(4;14), t(14;16), or del(17p)] by fluorescence in situ hybridization [FISH] vs. standard risk) and randomized 1:1 to receive VMP (9 cycles) or continuous Rd per approved schedule. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), progression after the next line of therapy (PFS2), time to next treatment (TNT), quality of life (QoL), and safety. This trial was reviewed and approved by the institutional review boards or independent ethics committees at each of the participating centers. All patients provided written informed consent before participating in the trial, which was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Following the introduction of daratumumab in first-line treatment for NTE patients, the protocol was amended, and, as of July 2022, enrolled patients have been randomized to receive daratumumab-VMP or daratumumab-Rd.

Between 10^th January 2019 and 26^th January 2022, 231 patients were randomized to receive VMP (N=114) versus Rd (N=117). Baseline characteristics were well balanced (Table 1). At the data cut-off (29^th May 2023), the median follow-up among surviving patients was 28.94 months (Interquartile Range [IQR]: 20.21-37.13), and 56% of VMP patients completed therapy, while 33.3% of Rd patients remained on treatment, with a median duration of treatment of 16 months (IQR: 5.7-32) (Online Supplementary Figure S1).

The median PFS was 28.8 versus 26.6 months in the VMP versus Rd arms (Hazard Ratio [HR]: 0.93, 95% Confidence Interval [CI]: 0.63-1.38, P=0.72) (Figure 1A). However, the HR changed over time (P from the Grambsch and Therneau test =0.076): 0.64 during the first year of treatment (95% CI: 0.37-1.12, P=0.12) and, thereafter, 1.32 (95% CI: 0.74-2.36, P=0.34). The prespecified subgroup analysis according to cytogenetic risk showed a significant effect modification in terms of PFS between VMP and Rd (interaction P=0.018), with a median PFS of 30.0 (95% CI: 16.5-not reached [NR]) versus 10.4 months (95% CI: 7.8-NR) in the high-risk group (HR: 0.33, 95% CI: 0.12-0.92) and of 22.7 (95% CI: 17.7-39.4) versus 33.3 months (95% CI: 26.1-NR) in the standard-risk group (HR: 1.30, 95% CI: 0.80-2.09). No significant differences in terms of PFS were observed in other subgroups (Figure 1B).

Overall response rate (71% vs. 73%, P=0.90) and the rates of very good partial response or better (≥VGPR) (49% vs. 44%, P=0.56) were similar in the two arms, with a trend toward a higher complete response or better (≥CR) in the VMP arm (13% vs. 5%, P=0.058).

The estimated 36-month OS was 83% with VMP versus 67% with Rd (HR: 0.52, 95% CI: 0.29-0.93, P=0.028) (Figure 2A). This advantage was also confirmed after censoring for daratumumab use in second line (HR: 0.53, 95% CI: 0.28-0.99, P=0.045). A survival advantage of VMP over Rd was also observed in both high-risk and standard-risk subgroups, with a greater benefit in high-risk patients (HR: 0.23 vs. 0.66) (Figure 2B), while frail patients (HR 0.41, 95% CI: 0.19-0.91) and intermediate-fit patients (HR: 0.46, 95% CI: 0.12-1.79) obtained a slight benefit from VMP as compared with fit patients (HR: 1.11, 95% CI: 0.29-4.15, interaction P=0.45). The estimated 36-month PFS2 was significantly better with VMP (82% vs. 63%, HR: 0.52, P=0.017) (Online Supplementary Figure S2A). Following disease progression (91 events), 67% of patients received second-line treatment. A second subsequent therapy line including daratumumab was more commonly used in the VMP versus Rd arm (60% vs. 23%). TNT was similar between the two arms (Online Supplementary Figure S2B).

Grade (G)3-4 treatment-emergent adverse events (AE) occurred in 42% of VMP versus 52% of Rd patients (Online Supplementary Table S1). The incidence of G3-4 neutropenia was similar in the two arms (19% vs. 25%); G3-4 thrombocytopenia occurred in 15% versus 0% (P<0.0001); G3-4 infections in 4% versus 9% of patients (P=0.17), of which 2% versus 4% were pneumonia; G3-4 peripheral neuropathy (PNP) in 6% versus 1% (P=0.06), while G1-2 PNP in 48% versus 10% (P<0.001); the incidence of G3-4 gastrointestinal disorders was similar in the two arms (5% vs. 4%); skin-related disorders occurred in 1% versus 11% (P=0.003).

Serious AE occurred in 37% versus 47% of patients in the VMP versus Rd arms: cardiac failure was the most common (8%) with VMP, while SARS-CoV-2 pneumonia was the most common (10%) with Rd. Treatment-emergent deaths were rare (≤1% in both arms).

Dose reductions were frequent in both arms. In the VMP arm, 66% of patients had ≥1 dose reduction, mainly in bortezomib (52%). Of note, 39% switched to once-weekly bortezomib administration before the fifth cycle. Rd patients also frequently required dose reductions of lenalidomide (49%) and dexamethasone (47%). In both arms, more treatment discontinuations occurred in frail (41% in the VMP vs. 67% in the Rd arm) than in intermediate-fit (36% vs. 59%) and fit (38% vs. 63%) patients.

Although this trial showed no significant difference in PFS between the VMP (median, 28.8 months) and Rd arm (median, 26.6), the results compared favorably with those of prior studies, likely reflecting better management over time through dose reductions, weekly bortezomib administration, and longer treatment durations. Interestingly, the HR for PFS changed over time, favoring VMP during the first 12 months (HR: 0.64), while favoring Rd thereafter (HR: 1.32), likely reflecting the benefit of continuous lenalidomide therapy, already confirmed in prior trials (e.g., FIRST and MM-015).^5,6

The aim of this study was also to identify the subgroups who would benefit most from each combination. In high-risk patients, VMP significantly improved PFS compared with Rd (HR: 0.33, interaction P=0.0018). No difference in PFS was observed in standard-risk, frail, or renally impaired patients. These findings are consistent with previous data, like those from the VISTA trial,⁷ suggesting that bortezomib may overcome poor outcomes associated with high-risk cytogenetics. At the same time, Real MM, with the support of centralized FISH testing and patient stratification by frailty and cytogenetics, confirmed the limited benefit of lenalidomide in high-risk patients observed in the FIRST trial.⁵ Although age has recently been associated with poorer PFS and OS in older patients,⁸ no significant interaction between age and treatment arm was observed in our trial. This is consistent with findings from the BENEFIT trial, in which the rate of minimal residual disease negativity was higher in the bortezomib-based arm among patients both above and below 75 years of age.⁹

Table 1.Baseline patient characteristics in the intention-to-treat population.

Figure 1.Progression-free survival in the intention-to-treat population. (A) Progression-free survival (PFS). (B) PFS subgroup analysis. CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HR: Hazard Ratio; IMWG: International Myeloma Working Group; ISS: International Staging System; Rd: lenalidomide-dexamethasone; VMP: bortezomib-melphalan-prednisone.

Figure 2.Overall survival in the intention-to-treat population. (A) Overall survival (OS). (B) OS: subgroup analysis. CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HR: Hazard Ratio; IMWG: International Myeloma Working Group; ISS: International Staging System; Rd: lenalidomide-dexamethasone; VMP: bortezomib-melphalan-prednisone.

Overall survival was notably longer in the VMP arm, with 17 deaths after a median follow-up of 28.9 months versus 32 in the Rd arm (HR: 0.52, P=0.028). This may reflect the PFS benefit in high-risk patients treated with VMP, lenalidomide refractoriness in the Rd arm, and differences in salvage therapy. More patients in the VMP arm received daratumumab at relapse, potentially improving outcomes. However, this benefit persisted after censoring for daratumumab use, highlighting the importance of treatment sequencing.

Our analysis is the first prospective evaluation of patients stratified by the IMWG frailty score. Frailty impacted discontinuation rates and mortality in both arms. However, no PFS differences emerged between the two arms in different frailty classes, while a slight OS benefit was observed in frail patients receiving VMP.

Our data showed that real-world practice can differ from the trial schedules, with 39% of patients in the VMP arm receiving once-weekly instead of twice-weekly bortezomib during the first four cycles, a strategy that has already been successfully explored with other modified regimens, such as lenalidomide-bortezomib-dexamethasone (RVD)-lite.¹⁰ The improved tolerability of bortezomib has also helped its integration into more intensive regimens incorporating anti-CD38 antibodies, showing promising results in the IMROZ, CEPHEUS, and BENEFIT trials, even in elderly patients.^9,11,12 Nonetheless, the optimal schedule for bortezomib remains unclear, as it was administered twice weekly in the IMROZ trial and once weekly – but for a longer duration – in the BENEFIT trial.

In our study, fixed-duration VMP led to a longer treatment-free interval, which translated into better health-related QoL compared with continuous Rd.¹³

Regarding safety, both regimens exhibited known toxicity profiles.^2,7,14 As expected, thrombocytopenia and peripheral neuropathy were more common with VMP, whereas infections and dermatologic reactions were more common with Rd. The higher incidence of infections observed with Rd could have been influenced by glucocorticoid use. Reduced doses of dexamethasone, switching to prednisone, or early discontinuation could be better options for elderly or frail patients.¹⁴

Based on our data, both VMP and Rd remain effective and well-tolerated regimens, but VMP proved to be a preferable option due to its advantages in terms of PFS (particularly in patients with high cytogenetic risk) and OS. This real-world, prospective evidence may help guide front-line choices, particularly in settings where access to daratumumab is limited or in patients who are ineligible for more intensive approaches.

Enrollment in the daratumumab-VMP and daratumumab-Rd arms is ongoing, and their future comparison will further clarify the role of daratumumab in these combinations.

Footnotes

• Received February 11, 2025
• Accepted July 22, 2025

Correspondence

S. BRINGHEN - sarabringhen@yahoo.com

Disclosures

SB has participated in the speakers’ bureaus for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and AbbVie; has served on the advisory boards for Bristol Myers Squibb, Janssen, Takeda, Pfizer, Stemline Therapeutics, and Oncopeptides; has received consultancy fees from Sanofi. NG has received fees for participation in consultancy advisory boards from Takeda, Amgen, Oncopeptides, and Bristol Myers Squibb; has received research support from Pfizer; has participated in the speakers’ bureaus for Amgen, Sanofi, and Takeda. SM has received honoraria from Bristol Myers Squibb, Sanofi, Amgen, GlaxoSmithKline, Takeda, Pfizer, and Janssen; has served on the advisory boards for Sanofi, Takeda, Bristol Myers Squibb, Pfizer, and Janssen. GB has served on the advisory boards and participated in the speakers’ bureaus for Bristol Myers Squibb, Novartis, GlaxoSmithKline, Menarini, and Janssen. EA has served on the advisory boards for GlaxoSmithKline, Sanofi, Pfizer, and Menarini Stemline. RZ has served on the advisory boards for Janssen, Amgen, GlaxoSmithKline, Sanofi, Menarini Stemline, Oncopeptides, and Pfizer. RR has participated in the speakers’ bureaus for Amgen, Bristol Myers Squibb, CSL Behring, Janssen Cilag, Octapharma, and Takeda; has provided consultancy for Amgen, Bristol Myers Squibb, CSL Behring, Janssen Cilag, Pfizer, Sanofi, and Takeda. SM has received honoraria from GlaxoSmithKline, Janssen, Menarini, and Pfizer. MD has received honoraria from GlaxoSmithKline, Sanofi, and Janssen; has served on the advisory boards for GlaxoSmithKline, Sanofi, Bristol Myers Squibb, and Adaptive Biotechnologies; has received research support from Janssen. AML has received sponsored research funding for her institution from Takeda, Roche, Celgene, AbbVie, Millennium, Janssen, Sanofi, Verastem, Novartis, Morphosys, GlaxoSmithKline, Oncopeptides, Karyopharm, Onconova, Archigen, Fibrogen, Dr. Reddy’s Lab., LoxoOncology, Beigene, Bristol Myers Squibb, and PSI; has received honoraria from IQVIA, Incyte, Celgene, AbbVie, Bristol Myers Squibb, and Janssen; has received support for travel from Takeda, Roche, Janssen, Celgene, Bristol Myers Squibb, AbbVie, Novartis, Sanofi, IQVIA, and Verastem. AMC has received honoraria for her participation in advisory boards from Amgen, Takeda, Bristol Myers Squibb, Janssen, and Sanofi. AB has served on the advisory boards for Amgen, Pfizer, Janssen, GlaxoSmithKline, and Menarini Stemline. FP has received honoraria for lectures from Menarini and Sanofi; has served on the advisory boards for Sanofi and Bristol Myers Squibb. KM has received honoraria from Sanofi, Amgen, Janssen, GlaxoSmithKline, Celgene, and Oncopeptides. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GlaxoSmithKline; has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Mundipharma. AL has received honoraria from and served on the advisory boards for Johnson & Johnson, GlaxoSmithKline, Menarini, and Sanofi. All the other authors have no conflicts of interest to disclose.

Contributions

Funding

The Real MM trial was funded by the Italian Medicines Agency AIFA - Independent Research.

Acknowledgments

We thank the University of Torino (Italy), which sponsored the Real MM trial, and the Italian Medicines Agency AIFA - Independent Research, which provided the funding to conduct the trial. We are also grateful to the European Myeloma Network (EMN). We are grateful to all patients, caregivers, physicians, nurses, and data managers involved in the Real MM trial at the following participating centers: Torino, Italy (Alessandra Larocca); Parma (Nicola Giuliani); Pavia (Silvia Mangiacavalli); Firenze (Elisabetta Antonioli); Padova (Renato Zambello); Bologna (Michele Cavo, Elena Zamagni); Bari (Roberto Ria); Reggio Calabria (Iolanda Donatella Vincelli); Messina (Donato Mannina); Meldola (Sonia Ronconi); Udine (Francesca Patriarca); Ancona (Massimo Offidani); Brescia (Giuseppe Rossi, Angelo Belotti); Milano (Anna Maria Cafro); San Giovanni Rotondo (Nicola Cascavilla, Antonietta Pia Falcone); Rimini (Patrizia Tosi); Messina (Caterina Musolino, Alessandro Allegra); Terni (Anna Marina Liberati, Gaetano Vaudo, Arcangelo Liso); Camposampiero (PD) (Ercole De Biasi, Maide Maria Cavalli); Modena (Giovanna Leonardi); Novara (Lorenzo De Paoli, Gloria Margiotta Casaluci); Bari (Paola Curci); Roma (Maurizio Martelli); Aviano (Mariagrazia Michieli); Cuneo (Mariella Grasso, Francesco Vassallo); Ascoli Piceno (Piero Galieni); Milano (Fabio Ciceri); Rionero in Vulture (Giuseppe Pietrantuono); Cagliari (Antonio Ledda, Rita Floris); Napoli (Fabrizio Pane); Reggio Emilia (Barbara Gamberi); Roma (Maria Cantonetti, Luca Franceschini); Biella (Annarita Conconi); Civitanova Marche (Riccardo Centurioni, Milena Mirabile); Monza (Sara Pezzatti); Pescara (Antonio Spadano, Francesca Fioritoni).