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Advances in our knowledge of the pathogenesis of multiple myeloma and the resultant development of novel therapies have significantly improved patient survival during the past two decades. Whether multiple myeloma can be cured, at least in some patients, is increasingly the topic of discussion. Current myeloma treatment strategies may lead to ∼30% “exceptional responders,” who are free of disease progression at ≥ 8 years. Advanced techniques including next-generation sequencing or next-generation flow cytometry detect very low levels of disease. Indeed, achieving minimal residual disease negativity at a sensitivity of 10–5–10−6 (1 cell per 100,000/1 million) is a strong surrogate parameter of progression-free and overall survival, far surpassing stringent complete response. Of note, recent data suggest that sustained minimal residual disease negativity more than minimal residual disease negativity at a single timepoint represents a reliable indicator of cure. Ongoing trials explore minimal residual disease-driven risk- and response-adapted treatment strategies as well as novel agents and precision medicine approaches to increase the cure fraction.
The present review article defines the term “cure,” discusses methods that help to identify cure, and summarizes therapeutic approaches aimed at finally achieving cure.
Only 20 years ago multiple myeloma (MM) was a difficult-to-treat disease with an average survival rate of 4 years. Indeed, until the early 2000s, chemotherapeutic agents and autologous stem cell transplantation (ASCT) together with steroids represented the mainstay of MM therapy, which was burdensome for older patients in particular. A “cure” for MM was considered an “impossible” dream. Continuous advances in our knowledge of the molecular complexity of the disease have resulted in the approval of 19 new agents and more than 35 therapeutic regimens over the past two decades. Specifically, the clinical introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs) and, most recently, modern immunotherapeutic modalities including antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T cells, and bispecific antibodies (bsAbs) have led to increasingly deeper and longer-lasting response rates with less frequent disease relapses. The use of triplet and, even more so, quadruplet combination therapies in newly diagnosed transplant-eligible but also non-transplant-eligible MM patients resulted in unprecedented overall response rates (ORR), progression-free survival (PFS), and overall survival (OS). Based on their exceptional anti-tumor activity in heavily pretreated patients, CAR T cells and bsAbs are currently changing the MM treatment landscape once again, also in earlier lines of therapy. Doubtlessly, cure for MM is on the horizon [1‐3].
Definition of the term “cure”
The term “cure” in tumor diseases was first defined by Drs. Eason and Russell in Hodgkin’s lymphoma and later expanded by Dr. Kwan and colleagues. A patient is “truly” cured of cancer when (a) the tumor has completely disappeared without further treatment and (b) will not return throughout the lifetime, while (c) therapy- or disease-associated comorbidities are absent, and (d) mortality is comparable to that of a healthy, age-matched individual (Fig. 1). “Functional cure” is distinguished from “true cure” by the complete suppression of growth but incomplete eradication of tumor cells, without affecting the patient’s daily life. In addition to true and functional cure, “relative cure” defines a long-lasting state in which tumor cells have been completely removed, while quality of life is maintained only in part or at lower levels than before therapy [4, 5].
Fig. 1
Definition of “true” cure in multiple myeloma. (Generated with BioRender)
What is the meaning of “cure” in MM patients [6‐9]? In the early 1990s, the use of high-dose therapy (HDT) followed by allogeneic SCT offered the only possibility of long-term remission or cure. Indeed, a plateau of the survival curves indicated the curative potential of this therapeutic approach, which could be used only in few patients and which was associated with high mortality rates of 40–60% [10‐12]. In 1991, Dr. Barlogie introduced the wording “cure in MM” for the first time [13‐15]. He dedicated a large part of his career to the development of a “total therapy” (TT), which utilized all available anti-MM chemotherapeutic agents during induction therapy, followed by HDT and tandem ASCT, in order to combat drug-resistant subclones and achieve long-term complete remissions (CR; [16‐19]). After 16.6 years, the longest follow-up period ever documented for a phase 3 MM trial, a recent analysis of the TT studies showed a median survival of 13.3 years. Specifically, ∼30% of patients treated according to the TT2 protocol and 50% of patients treated according to the TT3a protocol were still alive 20 years and 15 years, respectively, after initial diagnosis. These results emphasize the potential long-term benefits of a time-limited treatment. However, TT could only be offered to selected patients and was extremely complex [20]. Based on these results, Dr. Powles and colleagues coined the term “surgical or functional cure of MM” for a small minority of patients who had been in CR for ≥ 10 years after HDT and ASCT with an on/off therapy [21]. The gradual replacement of chemotherapeutic agents with IMiDs, PIs, and mAbs, as well as the implementation of CAR T cells and bsAbs into MM treatment strategies, has subsequently led to a continuous increase in CR rates, both in the frontline and the RR setting. Indeed, novel agents increased OS from 22.4 months during 1980–1990 to 37.4 months during 1991–2000, 61.8 months during 2001–2010, and 103.6 months during 2011–2020. While well tolerated, the median survival of patients treated with a combination of at least two novel agents during the induction phase was significantly longer than that of patients treated with a single new agent or conventional therapy (143.3 vs. 61.0 vs. 42.2 months; p < 0.001). Survival improvement was evident in all patients regardless of the age at diagnosis. Overall, 13.2% of patients were long-term survivors (median OS ≥ 10 years). Independent clinical predictors of long-term survival included ECOG < 1, age at diagnosis ≤ 65 years, IgG and non-IgA subtype, ISS‑1 and standard risk cytogenetics. Achieving CR after undergoing ASCT was associated with survival rates of more than 10 years [22]. Consequently, it can be assumed that current therapeutic approaches induce a chronic or even curable disease, at least in some patients. Despite this unique success, the question remains of whether each patient should be treated with an aggressive multidrug regimen aimed at a cure; or whether a sequential therapeutic approach that prioritizes quality of life (QoL) and OS (especially in older and frail patients) is a better choice [23, 24].
Methods to detect a cure
Modern combination therapies are characterized by a PFS that persists for many years and an OS of > 8 years. Nevertheless, diagnostics used in routine practice (serum and urine electrophoresis, immune fixation, free light chain determination and bone marrow analysis including cytogenetics and histology, as well as imaging diagnostics such as whole-body CT and MRI) only recognize the “tip of the iceberg” (> 1010 MM cells) that “lies above the surface.” Therefore, there is an urgent need for more sensitive methods that also detect the part of the iceberg that lies “below the surface.” These methods should enable earlier diagnosis of the initial disease or a relapse, more precise risk stratification, and the development of further improved and personalized treatment strategies. As with other hematologic malignancies that are considered curable, the achievement of a durable, deep minimal residual disease (MRD)-negative remission in MM indicates disease control or even cure. In fact, two large meta-analyses showed that MRD negativity is associated with a significantly improved OS and PFS and is also superior to other traditional response criteria such as CR. Remarkably, achieving MRD negativity also overcomes, at least in part, unfavorable risk factors including high-risk cytogenetics, ISS, or R‑ISS [25‐28]. Due to the outstanding prognostic significance of the MRD status, the FDA’s Oncologic Drug Advisory Committee (ODAC) unanimously voted in favor of MRD testing as an early endpoint in MM clinical trials in order to support accelerated approvals (9–12 months vs. ≥ 8 years previously) of new treatments on 12 April 2024. Importantly, follow-up analyses of several pivotal clinical trials including MAIA, ALCYONE, POLLUX, CASTOR, and PERSEUS demonstrate that sustained MRD negativity (≥ 12 months) has an even higher prognostic value than MRD negativity measured at a single timepoint [29‐32]. However, the question remains, whether determination of sustained MRD negativity eliminates the potential utility of one-timepoint MRD negativity as an early surrogate for PFS and OS. The bone marrow (BM)-based MRD status is measured either by next-generation (multicolor) flow cytometry (NGF) or by next-generation sequencing (NGS). MRD negativity is defined as the absence of MM cells in a population of 100,000 (cut-off 10−5) or 1,000,000 (cut-off 10−6) cells [33]. FACS-based analysis uses either 8‑ or 10-color antibody panels to identify phenotypically aberrant plasma cells according to the validated protocols of EuroFlow or the MSKCC [34, 35]. NGS-based MRD determination is based on the identification and tracking of tumor-specific immunoglobulin V(D)J rearrangements using the clonoSEQ® (Adaptive Biotechnologies, Seattle, USA) assay (Adaptive Biotechnologies). MRD determination should always be supplemented by a PET-CT. In fact, achieving CR and MRD negativity (cut-off 10−5) in the absence of FDG-avid lesions is defined as the deepest therapeutic response reachable by current IMWG response criteria [33]. Nevertheless, false-negative MRD status determination may occur. Reasons include the presence of extramedullary disease (EMD), the patchy involvement of the BM, or a diluted sample. Liquid biopsies, as a minimally invasive measure, may overcome these pitfalls by detecting circulating tumor cells (CTCs), circulating DNA or RNA (cDNA, cRNA), and vesicular cell-free RNA (cfRNA) and proteins in the peripheral blood. Early results suggest that mass spectrometry of the monoclonal protein in the peripheral blood using MALDI-TOF or qTOF probably represents the most powerful tool to supplement MRD status determination in the BM or guide the necessity of a BM puncture [36, 37]. In addition, whole-genome sequencing (WGS) enables the identification of driver mutations as potential new therapeutic targets, but also of resistance modes, and of derived personalized treatment approaches. Moreover, single-cell sequencing takes into account the genetic and phenotypic heterogeneity within individual tumor cells as well as within the BM microenvironment. Next-generation molecular imaging using specific radio-isotopes (e.g., [11C]-methionine or [11C]-fluciclovine) as well as PET-MRI and DW-MRI promise to further improve diagnostics [38]. In the near future, artificial intelligence and machine learning algorithms will help to integrate the multitude of clinical, molecular, and genetic information for rational medical decision-making and personalized therapeutic approaches (Fig. 2).
Fig. 2
The evolution of multiple myeloma diagnostics. See Abbreviations list for definitions. (Generated with BioRender)
Two main factors determine the prognosis of MM: (1) the achievement of MRD-negativity; and (2) the biology of the disease (standard-risk vs. high-risk patients). The fact that a considerable number of patients remain MRD-positive after induction therapy and ASCT points to the need to use agents with complementary mechanisms of action and favorable toxicity profiles or new treatment strategies to ultimately achieve and sustain MRD negativity. Therapeutic approaches to deepen response rates and thereby increase the likelihood of cure in MM include: (1) early intervention to prevent the progression of high-risk smoldering MM (HR-SMM) to active MM with end-organ damage; (2) regimen-based therapies; (3) response- and risk-adapted therapies; and (4) novel agents and precision medicine approaches.
Early intervention
Patients with HR-SMM are defined according to the Mayo, PETHEMA, or the “2/20/20” risk score models [39‐41]. Intensified, so-called cure regimens intend to prevent the progression of HR-SMM to active MM with end-organ damage. They include 6 × KRd > HD-Mel > ASZT > 2 × KRd > 24 × Rd maintenance (phase 2 GEM-CESAR trial; [42, 43]), and 4 × Dara-KRd > HD-Mel > ASZT or Dara-KRd without ASZT > 4 × Dara-KRd consolidation > 12 × Dara-KRd maintenance (phase 2 ASCENT trial; [44]). Results of the GEM-CESAR study showed a promising MRD negativity of 40% after 6 years, a PFS of 94% after 70 months, and an OS of 98% after 28 months. In the ASCENT trial, an MRD negativity rate of 84% was observed after 3 years. Based on these data, a significant improvement in the cure rate is expected after 20 years. Furthermore, the phase 2 CAR PRISM trial [45] is currently investigating the use of ciltacabtagene autoleucel (Cilta-cel) in HR-SMM patients without induction therapy. In addition to these intensive regimens, less intensive regimens have also been investigated. For example, the use of lenalidomide alone or in combination with dexamethasone, as well as daratumumab alone, has shown promising efficacy and tolerability in SMM patients with intermediate- or high-risk features. Finally, results of the randomized phase 3 AQUILA trial [46] represented one of the highlights in the field of plasma cell diseases at the ASH 2024 meeting. Specifically, Dara monotherapy significantly delayed or even prevented the progression of HR-SMM to active MM with end-organ damage, and thereby prolonged OS. An application for approval of Dara in this setting has been submitted to the U.S. Food and Drug Administration (FDA). For daily practice, the question remains as to whether all asymptomatic patients with HR plasma cell precursor diseases should be treated in general. In the author’s view, there is a need for further improvement in SMM risk stratification.
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Regimen-orientated therapy strategies
Regimen-orientated studies focus on induction, consolidation, or maintenance therapy.
Induction and consolidation
Based on results of the phase 3 PERSEUS trial [32], Dara-VRd > HD-Mel-ASCT > DR maintenance, represents the current standard of care for newly diagnosed, transplant-eligible MM patients (after a follow-up of 47.5 months PFS was 84.3% and MRD negativity was 65.1%, at a cut-off of 10−6). Promising results were also obtained with the quadruplet therapies Isatuximab-RVd (Isa-RVd; i.e., in the phase 3 GMMG-HD7 trial; [47, 48]), Isa-KRd (i.e., in the academic, investigator-initiated, multicenter, phase 2 GMMG-CONCEPT trial; [49]), and with BCMA-targeted bsAb- and CD38mAb-containing quadruplet or quintuplet combination regimens (i.e., the phase 2 MajesTEC-5 trial; [50]). Moreover, early results of the BCMA-targeted ADC belantamab mafodotin (Belamaf) in combination with VRd in newly diagnosed non-transplant-eligible patients (phase 1 DREAMM-9 trial) are similarly promising [51]. The pivotal phase 3 DREAMM-10 trial, which evaluates Belamaf-Rd vs. Dara-Rd in newly diagnosed non-transplant-eligible MM patients has recently been initiated. CAR T cells (Cilta-cel and Idecabtagene vicleucel/Ide-cel) and bsAbs (teclistamab, elranatamab, talquetamab) are currently revolutionizing MM therapy, achieving unprecedented deep and durable response rates, even in highly pretreated MM patients [52‐56]. More recent data demonstrate even higher anti-MM efficacy of CAR T cells when used in earlier lines of therapy [57, 58]. Whether CAR T cells may replace ASCT is additionally under investigation. For example, the phase 3 CARTITUDE-6 trial compares the efficacy of Dara-VRd followed by Cilta-cel vs. Dara-VRd followed by ASCT in transplant-eligible newly diagnosed MM patients.
Maintenance
Maintenance therapy as the final part of first-line treatment aims to completely eradicate tumor cells, again, in order to minimize the risk of recurrence and increase the chance of cure. The approval of lenalidomide as continuous maintenance therapy is based on a meta-analysis that demonstrated a significantly longer median PFS of 52.8 months and an OS of ~2.4 years. The benefit of lenalidomide maintenance lasting longer than 3 years is unclear. In MRD-positive patients, results speak in favor of continuing lenalidomide until disease progression [59, 60]. Results of the phase 3 CASSIOPEIA trial indicate that Dara monotherapy could represent an alternative to lenalidomide in maintenance therapy [61]. Other clinical trials are currently investigating whether the efficacy of lenalidomide is increased when combined with other drugs. For example, the combination with Dara in the phase 3 PERSEUS trial (18) and with carfilzomib in the phase 2 UNITO-MM-01/FORTE trial [62, 63]. Of note, 64% of patients in the Dara-VRd > D‑R maintenance arm discontinued Dara after reaching sustained MRD negativity (persistent MRD negativity for ≥ 12 months, cut-off 10−5) per protocol. In addition to lenalidomide, Dara, carfilzomib, and bortezomib are also frequently used as off-label maintenance therapy, especially in high-risk patients. However, its use and duration are often limited by side effects. Finally, the phase 3 MagnetisMM‑7 and MajesTEC‑4 (EMN30) studies, respectively, are investigating the anti-MM effect of the bsAbs elranatamab or teclistamab in combination with lenalidomide vs. lenalidomide monotherapy.
Response- and risk-adapted therapies
Response- and risk-adapted therapy approaches in MM aim at optimally adapting treatment to the individual needs of patients in order to improve the prognosis and, ideally, to achieve cure. As the MRD status enables the assessment of the dynamic risk, new treatment strategies have been developed. Results from the single-arm phase 2 MASTER trial with Dara-KRd were among the first to demonstrate the applicability of an MRD-based, response-adapted consolidation strategy in newly diagnosed MM [64]. High-risk MM patients, in particular, challenge the path to cure in everyday clinical practice. In contrast to standard-risk patients, the OS of high-risk patients is < 3 years. Results from the phase 3 PETHEMA/GEM2012MENOS65 study have shown for the first time that achieving MRD negativity can overcome the poor prognosis of high-risk patients [65]. Furthermore, results of the phase 2 UK OPTIMUM/MUKnine [66] and GMMG-CONCEPT [49] trials indicate the high efficacy of an intensified therapy regimen using quadruplet consolidation after ASCT for ultra-high-risk MM patients. Long-term results are eagerly awaited. The high anti-MM efficacy of Dara-KRd and Dara-RVd was also demonstrated in a sub-analysis of the MASTER and GRIFFIN trials, at least for those subgroups with no or with one high-risk cytogenetic abnormality (HRCA), but not for the subgroup with two or more HRCAs [67]. Similar results were also observed in the phase 2 SKylaRk trial [68, 69]. However, there is an urgent need for a uniform definition of high-risk MM patients as a prerequisite for the objective comparison of treatment regimens in this patient population. The pending BARCELONA high-risk criteria for MM are expected to address this need. The multicenter, randomized phase 2 ADVANCE trial investigates the feasibility of MRD-driven therapy in newly diagnosed MM patients. Specifically, after completion of 8 × Dara-KRd or KRd, patients in this trial will only be offered ASCT if they are still MRD-positive; all other patients will continue with maintenance therapy alone. The aim of this translational study is to define the underlying biology of persistent MRD negativity in MM patients.
Novel substances and precision medicine approaches
In addition to the available CAR T cell products Cilta-cel and Ide-cel and bsAbs, a number of other “next-generation” CAR T cell products as well as bispecific but also trispecific Abs and ADCs, immunotoxins, radioimmunoconjugates, and inhibitors of Bcl‑2, FGFR3, mutant IDH, Mcl‑1, Mdm2, and SETD2 methyltransferase as well as protein degraders (i.e., CELMoDs) are under clinical evaluation. Furthermore, a number of clinical trials aim at optimizing T‑cell response and hematopoietic regeneration and at identifying resistance mechanisms [70]. Results of precision therapy studies such as the MyDrug study are eagerly awaited.
Take-home message
Unprecedented advances in our knowledge of the pathogenesis of MM during the past two decades have led to the development of a multitude of novel substances.
Modern triplet and quadruplet combination therapies have significantly increased ORR and long-term remissions, with a life expectancy exceeding 8 years.
MRD negativity and, even more so, sustained MRD negativity are the best early prognostic factors for PFS and OS, potentially indicating cure.
Besides conventional diagnostics, NGS and NGF, liquid biopsy, mass spectrometry, and modern imaging will further advance MRD evaluation.
Regimen-oriented and MRD-adapted studies as well as novel agents and next-generation CAR T cells and bsAbs are likely to further improve MM outcomes in the near future and propel the cure for MM.
Funding
This investigation was supported by Technopol grant K3-F-730/003-2020 (KP).
Conflict of interest
K. Podar has received speaker’s honoraria from Celgene, Amgen Inc., and Janssen Pharmaceuticals, consultancy fees from Celgene, Takeda, Sanofi and Janssen Pharmaceuticals, and research support from Roche Pharmaceuticals. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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