Introduction

Multiple myeloma (MM) is a chronic hematologic malignancy that remains incurable because most patients eventually relapse or become refractory to treatment [1]. It is predominately diagnosed in people aged 65–75 years and is responsible for 10–15% of all hematologic malignancies, and in 2022, 21.9% of deaths in the United States related to hematologic cancers [2]. Due to an ageing population, the incidence is increasing. Basic research has made huge progress in the understanding of the molecular mechanisms of the disease, the immune system, and the tumor microenvironment, which has translated into the manufacture of revolutionary immunotherapies such as immunomodulatory drugs, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor (CAR)-T cell therapy. Dendritic vaccines (before and after autologous stem cell transplant [ASCT]) are starting to show promising results in high-risk patients [3]. However, this increase in the choice of treatment coupled with the fact that MM patients are a highly heterogeneous group, presents a huge challenge to clinicians who lack robust guidelines to select the most appropriate treatment for a given patient. While there are currently some hot debates about some specific therapeutic approaches (eg. quadruplet induction versus triplet, early transplant versus no transplant, immunotherapies for earlier relapse or frontline treatment, etc.), this perspective review aims to discuss a few non-therapy-related key issues which we believe would represent a pre-requisite towards improving MM outcomes in the next few years.

Role of real-world evidence

Knowledge from well-designed clinical trials must be combined with real-world (RW) data to improve therapeutic strategies and hence outcomes of MM patients everywhere. There may be great variation in prognostic patient and disease characteristics between clinical trial populations and RW cohorts, such differences may drive differences in outcomes. A large Canadian population-based cohort study has highlighted the significant efficacy-effectiveness gap between registrational randomized controlled trials and RW usage of treatment regimens, with MM patients treated in RW settings having death rates 75% higher than those in clinical trials [4]. Improvements in outcomes of patients with MM depend on the use of approved regimens; those based on efficacy results from large phase III randomized controlled trials (RCTs). Such trials are the gold standard for treatment outcomes; however, they must be unbiased in design and paramount to this is the selection of appropriately assessed endpoints. Patient selection for RCTs is problematic as many RW patients will not meet the stringent trial inclusion criteria and so the effectiveness of treatments in the RW setting will be unknown [5].

A better definition of frailty

Frail and/or elderly patients are rarely included in clinical trials [6], thus the benefits are less clear-cut in this patient group. However, existing frailty scores including that of the International Myeloma Working Group (IMWG) are problematic as they weigh age heavily, mis-categorizing the ‘fit elderly’ as frail [7]. Frailty prevalence varies greatly across trials ranging from 17 to 74% [7]. Not all frail people are old; are fit elderly patients the same as young frail patients? It is imperative that frail patients are identified more accurately with a standardized tool that is easy to use in the RW setting. A frailty score should encompass not only traditional clinical parameters but also the physical, psychological, and social aspects of a patient’s well-being. Frailty assessment tools must be easy to administer and although they are being increasingly incorporated into trial designs, there remains wide heterogeneity in the categorization and cut-off for frailty which will limit our ability to evaluate any associated outcomes. Recruitment of frail patients will allow a better understanding of treatment toxicity and determine if discontinuation is the real reason behind their poorer outcomes.

In their frailty-adjusted therapy study in transplant non-eligible newly diagnosed MM (NDMM) patients, the authors demonstrated the feasibility of recruiting older, less fit patients to clinical trials [8]. This phase III, multi-center, RCT investigated whether dose adjustments dependent on frailty would improve a patient’s ability to remain on therapy, reduce toxicity, and improve clinical outcomes. They showed that the IMWG frailty score demonstrated a dynamic biomarker potential both representing improved functionality in relation to disease response to therapy, as well as deterioration consequential to treatment-emergent toxicity. In addition, the concept of ultra-frail represents an opportunity to further stratify patients who may need additional support in order to improve their outcomes [8]. Further work in these two areas is needed. Dynamic frailty scoring would improve trial design as frailty is not a static concept, it may improve or deteriorate at each post diagnosis landmark interval. Frailty status at varying time points has also been shown to be a better predictor of outcomes than frailty status at time of diagnosis [9]. This limitation of evaluation of frailty-associated outcomes is an area that is largely unexplored and needs more attention.

Towards a dynamic disease risk assessment

First-line therapy for MM is still largely based on the eligibility of patients to undergo ASCT rather than on the biological characteristics of the disease itself or the depth of response achieved during therapy. Prognostic factors detected both before and throughout treatment may enable a more precise prediction of MM patients’ outcome that would allow personalized approaches. Cumulative evidence from trials has confirmed the robust association of minimal residual disease (MRD) status and survival outcomes in MM and has highlighted the primary importance of MRD in guiding treatment decisions. It can be accepted that MRD negativity should be a new endpoint in MM therapy (in addition to the classical other endpoints such as PFS and OS), regardless of cytogenetic risk, depth of response at MRD assessment, and the time of MRD measurement (NDMM or relapsed/refractory disease, and before or after maintenance therapy initiation) [10]. Therefore, it is essential that trials adopt standardized methodologies to assess MRD at specific time points. An exploratory analysis of the ongoing POLLUX and CASTOR studies in relapsed/refractory patients, found that sustained MRD negativity (defined as the maintenance of MRD negativity in bone marrow confirmed ≥6 or ≥12 months apart) is associated with improved progression-free survival (PFS) compared with patients who obtain MRD-negative status but not MRD durability [11]. This supports the concept that sustained MRD negativity may serve as a surrogate end point for PFS in ongoing and future clinical trials.

As a matter of fact, some uniformity is needed in how MRD is reported and at what threshold. Usually, MRD is measured at specific timepoints during therapy e.g., post-induction, +100 days post-ASCT, post-consolidation, pre-maintenance, and during maintenance. Data suggest that the duration of MRD negativity may be important, but little data are available on sustained MRD negativity (i.e., the need to confirm MRD at different timepoints) and on its optimal duration. Future trials should allow the exploration of different time cutoffs for sustained MRD negativity. In addition, one may wonder whether the sensitivity of the technique impact the reliability of MRD evaluation. The French IFM/DFCI 2009 trial [12] found that among 163 patients who were MRD-negative pre-maintenance using multiparameter flow cytometry (MFC) with a sensitivity of 10−4, 84 (56%) were indeed MRD-positive using next-generation sequencing (NGS) with a sensitivity of 10−6 (3-year PFS, 86 vs. 66% in NGS-negative vs. NGS-positive among MFC-negative patients). To avoid unacceptable risk of undertreatment, clinical trials exploring treatment interruption based on MRD levels must use techniques of adequate and high sensitivity.

As a corollary, if MRD negativity is a major prognostic determinant, it would be important to question whether treatment administered and baseline risk stratification matter so long as MRD negativity is achieved. Regarding MM patients who are at high-risk according to baseline prognostic factors such as high-risk cytogenetics, MRD-negative patients evaluated at a low level of sensitivity (10−4) still showed inferior clinical outcomes compared with standard-risk patients. Conversely, achieving MRD negativity at a sensitivity of 10−5 to 10−6 has been shown to overcome the inferior outcome observed in high-risk vs. standard-risk patients. MRD-driven clinical trials are needed to determine if treatment de-escalation or deintensification in MRD-negative patients is feasible without impairing patient prognosis [13].

Currently, there is no consensus on how or when to use the available ultrasensitive MRD assessment techniques for detecting and monitoring MRD status. Prospectively gathered clinical data will be useful in developing future paradigms for MRD analysis as a clinical practice decision tool. Future clinical trials must consider MRD negativity as an additional primary endpoint. Therefore, a second urgent need for the development and incorporation of MRD into clinical trials is in new drug development and registration. The development and approval of novel agents both for initial therapy and treatment of relapsed MM has already extended both PFS and overall survival (OS) several-fold. Therefore, at present, it is no longer possible to examine the impact of a novel agent to treat NDMM, alone or in combination, utilizing PFS and OS as endpoints, as these metrics would require clinical trials lasting well over a decade. Such a delayed determination of efficacy is unfair for patients and caregivers alike; moreover, it would slow drug development due to the prohibitive cost of such trials. There is therefore a crucial need for a parameter or surrogate marker, such as MRD, which can be examined earlier after treatment and predict subsequent PFS and OS. MRD negativity may not be an appropriate goal in all patient subsets (e.g., frail patients), but we may be able to inform the intensity or duration of therapy upon MRD status. Obviously, quality of life and patient-reported outcomes measurement can also be included in dynamic risk assessment, particularly in frail older patients where MRD may not always be a goal per se.

More widespread incorporation of MRD into clinical trials will allow us to determine whether patients should receive consolidation therapy to achieve MRD or if the duration of maintenance therapy can be defined by MRD status. The recent positive opinion of the Oncologic Drugs Advisory Committee (ODAC) of the FDA, is an important step in the right direction.

A better definition of high-risk disease

It is critical to establish a definition of high-risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice, but the definition of high-risk disease is a challenge [14]. High-risk MM at diagnosis is currently recognized according to the Revised International Staging System (R-ISS) which was set up in 2015 [15] as a more accurate prognostic model for NDMM, incorporating ISS stage, serum lactate dehydrogenase (LDH), and high-risk cytogenetics assessed by interphase fluorescent in situ hybridization (FISH). High-risk cytogenetic abnormalities defined as the presence of del(17p) and/or t(4;14) and/or t(14;16) or an elevated LDH above the upper limit of normal are risk factors that upstage patients in the R-ISS system. More recently, the “R2-ISS” revised the R-ISS by analyzing the additive value of each single risk feature, including chromosome 1q gain/amplification (1q+). This R2-ISS proved to be a simple prognostic staging system allowing a better stratification of patients with intermediate-risk newly-diagnosed MM [16]. Since then, an expert consensus was reached regarding the opportunity to revise the R-ISS including chromosome 1 abnormality by FISH, TP53 mutation or deletion by NGS, amount of circulating plasma cells by NGFC (next-generation flow cytometry), and multiple extramedullary plasmacytomas at PET-CT (positron emission tomography–computed tomography; H. Avet-Loiseau, personal communication). Clinicians are waiting for results of prospective trials that integrate high-risk features and MRD in the decision algorithm.

Despite several validated risk stratification systems in clinical use, a uniform approach to risk in NDMM remains elusive. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined, as some patients relapse early, while they were defined as low-risk based on their genomic profile at diagnosis. It is critical to establish a definition of high-risk disease in order to move towards risk-adapted treatment approaches. Current thinking is that defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice [17, 18]. The International Myeloma Society (IMS) has worked recently on a consensus on genomic definition of high-risk MM. The panel considered (i) del17p (in more than 20% of sorted plasma cells), (ii) TP53 mut (with no threshold for VAF), (iii) del(1p32)del/del, (iv) t(4;14) or t(14;16) or t(14;20) + gain/amp 1q or del(1p32)del/wt, and (v) gain/amp 1q + del(1p32)del/wt as markers of high-risk MM (J. Corr, personal communication). The routine application of the latter definition is likely to impact the field significantly.

Ensuring diversity and representation of underrepresented groups

MM patients of racial and ethnic minority are frequently underrepresented in clinical trials [19]. In the USA, it is estimated that approximately 20% of all patients with MM are of African American descent and yet, representation in clinical trials has historically been somewhere between 5 and 8%, and arguably even less in pivotal trials that have led to drug approval. There needs to be an understanding of the efficacy and [20] (eg. skin and nail toxicities in a black patient when using talquetamab) of these agents in different patient groups. For example, there are differences in the rates of cytokine release syndrome and neurological toxicities in patients of African descent and in Hispanic American patients. Thus, clinical trial teams should ensure that the materials are designed to be able to be read by and supported by a diverse population, that health care providers are trained in understanding culturally sensitive care, and that teams should include a diversity officer [21].

Recommendations on eliminating racial disparities in MM therapies have been made, including for pre- and post-approval of clinical trials, and relating to patient and industry perspectives [22, 23]. There is positivity related to the latter in that clinical trial sponsors are now aware of such recommendations. Ultimately, an improved understanding of disparities in MM should translate to clinical trial designs to help to guide appropriate treatment choices and ensure that there is equitable treatment for all.

Establishing strategies to widen access to state-of-the art care

Supportive care is key component of optimal management of MM patients. The MM disease by itself is associated with a wide variety of debilitating complications, but also MM therapy is the source of many complications, including an increased risk of infection. All of these complications remain a frequent cause of morbidity and mortality. Therefore, more attention should be paid to these complications, and specific trials could focus on management of specific clinical situations (eg. prevention of infections, patients under dialysis, etc.) Vaccination is one of the most efficient methods to reduce morbidity and mortality. This is also true for MM. Screening for certain pathogens is recommended before starting and during aggressive therapies. Prophylactic medication with anti-virals, antibiotics, anti-fungals, immunoglobulin substitution can be recommended and should be validated in certain indications. In addition, adherence to high hygiene standards, including for example dietary recommendations, identifying, developing, and implementing evidence-based symptom management, or encouraging physical exercise, should be part of good clinical practice. The latter would likely improve patient QoL both in clinical trials and in routine practice.

Furthermore, one must acknowledge that not all drugs are available in all countries and even in the developed ones, certain drugs may not be available [24, 25]. Pharmacoeconomic concerns are amplified in MM due to the need for multidrug regimens that combine two or more expensive new drugs, continuous therapy, and the prolonged disease course in most patients. The enormous costs of the combination of next-generation novel agents with immune antibody-based therapies must be addressed in order to assure access to these therapies for patients worldwide. First, trials should be able to identify drugs that work well in each subtype, but more importantly from a cost standpoint, we also need trials that can identify drugs that are unlikely to work in a given cytogenetic or risk subtype. Also, we need to determine whether an equivalent degree of survival benefit can be obtained with a short course of therapy compared with the current approach of prolonged therapy for many years. Approximately 15% of patients with NDMM can enjoy a long remission for a prolonged period of time with just lenalidomide and dexamethasone, or the latter combination plus ASCT [26, 27]. It is likely that with some modern combinations, a subset of patients can be identified who can do well for many years following around one year of initial therapy. Finally, we need to determine whether we can adjust therapy based on response, so that patients who have achieved MRD-negativity can safely stop therapy, thereby providing improved value and quality of life [28].

Concluding remarks

The landscape of MM treatment is poised for transformation in 2024 and beyond. Embracing improved trial design, prioritizing patient-centric approaches, and fostering collaboration will be instrumental in achieving meaningful progress. By implementing the outlined action items, we can collectively propel MM research into a new era of innovation, ensuring that advancements translate into tangible improvements in patient outcomes.