From May 13–19, 2026, the 12th World Congress on Multiple Myeloma (COMy 2026) was held in Paris, France. As one of the most influential international meetings in the field of multiple myeloma (MM), the congress brought together leading experts from around the world to discuss the latest advances in research, novel therapies, and patient care.With the continued aging of the global population, newly diagnosed transplant-ineligible (NTE) patients—most of whom are older adults—now represent an increasingly large proportion of the MM population. Optimizing treatment strategies for these patients has therefore become a central focus of clinical research and practice worldwide.
At the meeting, Professor Salomon Manier of the University of Lille, France, delivered a comprehensive presentation reviewing the evolution of frontline treatment for NTE multiple myeloma, from traditional triplet regimens to emerging quadruplet approaches, while also highlighting frailty-adapted treatment strategies that are reshaping clinical practice.
MAIA Establishes D-Rd as the Foundation of Long-Term Benefit
For patients with newly diagnosed transplant-ineligible multiple myeloma, the primary treatment goal is to maximize survival while preserving quality of life and maintaining treatment tolerability.
Professor Manier began by reviewing the landmark MAIA trial, which laid the foundation for modern treatment of NTE patients. This randomized, open-label phase III study compared daratumumab plus lenalidomide and dexamethasone (D-Rd) with lenalidomide and dexamethasone alone (Rd) in transplant-ineligible patients.
Long-term follow-up data have provided compelling evidence supporting the clinical value of D-Rd. The median progression-free survival (mPFS) reached 61.9 months, approaching five years, while the median overall survival (mOS) extended to 90 months, or approximately 7.5 years.
These results are particularly remarkable given that only a decade ago, achieving a median overall survival approaching eight years in older, transplant-ineligible patients would have been difficult to imagine.
Professor Manier emphasized that the success of MAIA not only established D-Rd as a standard-of-care regimen for NTE patients but also underscored the central role of anti-CD38 immunotherapy in this population. Unlike younger, transplant-eligible patients, older adults frequently present with comorbidities and diminished functional reserve. Achieving such substantial survival benefits with a relatively well-tolerated regimen therefore represents a major milestone.
Today, D-Rd is recommended by major international guidelines as one of the preferred frontline treatment options for transplant-ineligible multiple myeloma and serves as the benchmark against which newer treatment combinations are evaluated.
Moving Toward Deeper Responses: Quadruplet Regimens Significantly Improve MRD Negativity
Although D-Rd has delivered impressive outcomes, efforts to further improve treatment efficacy continue.
Professor Manier highlighted an important question: for fit transplant-ineligible patients, could the addition of an anti-CD38 antibody to the established proteasome inhibitor–immunomodulatory drug–dexamethasone backbone (PI + IMiD + dexamethasone, such as VRd) achieve deeper responses and superior long-term outcomes?
Several major clinical trials have explored this strategy, including IMROZ, CEPHEUS, and BENEFIT.
The IMROZ trial evaluated isatuximab plus VRd (Isa-VRd) versus VRd alone in NTE patients. Results demonstrated a five-year progression-free survival rate of 63% in the Isa-VRd arm compared with 45% in the control group, while median PFS had not yet been reached in the experimental arm.
Similarly, the CEPHEUS trial investigated daratumumab plus VRd (Dara-VRd) and reported a 4.5-year progression-free survival rate of 68%, further supporting the potential of quadruplet therapy.
Particularly noteworthy was the French IFM Group’s BENEFIT study (IFM 2020-05), which directly compared Isa-VRd with Isa-Rd, thereby evaluating the specific contribution of bortezomib. To improve tolerability, bortezomib was administered once weekly.
Preliminary findings revealed a striking difference in minimal residual disease (MRD) negativity at the 10^-5 level: 63% with Isa-VRd compared with 26% with Isa-Rd.
Professor Manier noted that MRD negativity is strongly associated with prolonged progression-free survival, making quadruplet therapy an attractive option for fit NTE patients seeking deeper disease control.
However, he also cautioned that the increased efficacy of quadruplet regimens must be balanced against potential toxicities, particularly infections and peripheral neuropathy. Careful patient selection, optimized dosing schedules, and proactive supportive care are essential to maximize benefit while minimizing treatment burden.
Managing Frail Patients: Steroid-Sparing Strategies Improve Tolerability
The treatment priorities for frail patients differ substantially from those for fit individuals.
Many frail patients are over 80 years of age, have multiple comorbidities, and possess limited organ reserve, making them particularly vulnerable to treatment-related toxicities.
Professor Manier stressed that in this population, the primary goal is not necessarily to achieve MRD negativity but rather to control disease while preserving quality of life and minimizing adverse effects.
To address this challenge, the French IFM Group conducted the IFM 2017-03 study, which explored a steroid-sparing approach using daratumumab plus lenalidomide (Dara-Len). Low-dose dexamethasone was administered only during the first two treatment cycles before being discontinued entirely.
The enrolled population reflected a truly frail cohort, with a median age of 81 years, more than 60% of patients aged 80 years or older, and inclusion of individuals with ECOG performance status scores of 3–4.
Despite this high-risk profile, outcomes were impressive. Median progression-free survival reached 53.4 months, nearly 4.5 years.
Equally important, although treatment duration was longer because of improved disease control, rates of grade 3–4 infections remained low and comparable between treatment groups (19% vs 21%).
These findings suggest that early discontinuation of dexamethasone does not compromise efficacy and may reduce steroid-related complications, including immunosuppression, hyperglycemia, mood disturbances, and other toxicities.
Professor Manier concluded that steroid-sparing strategies represent an important paradigm shift in the management of frail patients—from rigid, fixed treatment approaches toward dynamic, individualized care focused on optimizing tolerability.
Validated frailty assessment tools, such as the IMWG Frailty Index and simplified geriatric assessment instruments, should therefore play an integral role in guiding treatment selection and dose modification.
Looking Ahead: Frontline Integration of Novel Immunotherapies
In the final part of his presentation, Professor Manier explored the future role of next-generation immunotherapies, including bispecific antibodies and CAR-T cell therapies, in transplant-ineligible patients.
Early data have generated considerable excitement.
The TecLille study (IFM 2021-01) evaluated teclistamab plus daratumumab as frontline therapy in NTE patients. Preliminary results demonstrated that all evaluable patients achieved at least a very good partial response (VGPR) within six months, while rates of ultra-deep MRD negativity at the 10^-6 level were particularly impressive.
Although the study remains limited by small sample size and short follow-up, the universal response rate has attracted significant attention.
Several phase III registration studies are now underway, including:
- MAJESTEC-7: teclistamab plus daratumumab and lenalidomide
- MAGNETISMM-6: elranatamab plus daratumumab and lenalidomide
These studies are expected to provide definitive evidence regarding the frontline use of bispecific antibodies in transplant-ineligible patients.
At the same time, CAR-T cell therapy is moving earlier in the treatment paradigm.
The CARTITUDE-5 trial is evaluating cilta-cel in newly diagnosed transplant-ineligible patients following RVd induction therapy. Importantly, this study employs a fixed-duration treatment strategy, eliminating the need for continuous maintenance therapy after CAR-T infusion.
If successful, this approach could fundamentally challenge the current paradigm of indefinite treatment until disease progression, offering the possibility of durable disease control after a single cellular therapy intervention.
Professor Manier emphasized that these emerging immunotherapeutic strategies align naturally with frailty-based treatment selection. Fit patients may benefit from highly potent T-cell–redirecting therapies aimed at achieving deep responses and potentially functional cure, whereas frail individuals may be better served by lower-intensity, steroid-sparing immunotherapy approaches.
Summary and Outlook
Professor Salomon Manier’s presentation provided a clear roadmap for the evolving management of transplant-ineligible multiple myeloma.
The field is undergoing a profound transformation—from broad categorization based solely on transplant eligibility to a more nuanced approach guided by fitness, frailty, comorbidities, and functional reserve.
The central message is clear: transplant-ineligible patients should no longer be viewed as a homogeneous population. Instead, treatment goals and therapeutic intensity should be individualized according to each patient’s biological age, overall health status, and personal priorities.
As novel immunotherapies continue to mature and frailty assessment becomes increasingly standardized, the future of NTE multiple myeloma management is likely to be defined by personalized, precision-guided, and dynamically adapted care.
In this emerging era, every patient—regardless of age or frailty status—will have a greater opportunity to receive a treatment strategy optimized not only for efficacy but also for quality of life.
