Introduction

Multiple myeloma (MM) is caused by clonal proliferation of plasma cells (PCs), typically with an associated monoclonal gammopathy, and idiotypic rearrangement of the immunoglobulin (Ig) gene preceding malignant transformation of a plasma precursor cell. Table 1 presents the current International Myeloma Working Group criteria for the diagnosis of MM. When an emerging cell clone reaches a size of at least 5 × 10⁹ cells, its product, monoclonal Ig, also known as monoclonal protein (M protein), becomes visible as an abnormal peak in a serum protein electrophoresis gel. MM accounts for approximately 1.8% of adult cancer diagnoses and 10% of hematologic malignancy diagnoses.^1-5 The median age at diagnosis is approximately 65–70 years.^6-8 According to the 2016–2020 Surveillance, Epidemiology, and End Results data, the percentages of new cases by age group are: 0.4% for 20–34 year olds, 2.7% for 35–44 year olds, 9.7% for 45–54 year olds, 22.7% for 55–64 year olds, 31.9% for 65–74 year olds, 23.8% for 75–84 year olds, and 8.8% for over 84 year olds. Median age of death is approximately 75 years and overall survival (OS) at 5 years is 61%. In 2020, 176 404 (95% uncertainty interval [UI], 167 933–185 303) new cases of MM were reported worldwide.⁹ In the United States (USA), more than 35 000 new cases of MM are diagnosed each year, and approximately 13 000 patients die from the disease.¹⁰ From 2000 to 2020, 217 049 cases of MM were reported in the USA with the majority being men (54.85%) over 55 years of age, and African Americans being affected twice as often as white people.^9,11 Additionally, the age‑standardized incidence rate was 1.92 per 100 000 persons (95% UI, 1.68–2.12) in 2019, as compared with 1.72 per 100 000 persons (95% UI, 1.59–1.93) in 1990, indicating a significant increase in incidence over the last 30 years.⁷ Globally, the incidence of MM varies by region, with the highest rates observed in Australia, New Zealand, North America, and Western Europe, and the lowest in Asia.¹² Based on data from the National Cancer Registry in Poland, the number of new cases of MM in 2019 was 1713, affecting 808 men and 905 women, with MM being responsible for 683 deaths among men and 727 among women.

Development of multiple myeloma

Patients diagnosed with MM evolve from the premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS is asymptomatic and is present in approximately 3%–5% of the population over the age of 50 years. It may evolve into MM, light‑chain amyloidosis, or Waldenström macroglobulinemia.^13-15 On average, approximately 1% of people with MGUS progress to MM or a related disorder each year¹⁶ according to models based upon the level of M protein, Ig isotype, and free light‑chain ratios that predict the likelihood of evolving into MM. MGUS is 3 times more common in African American patients than in white patients.¹⁷ Smoldering multiple myeloma (SMM) is an asymptomatic clonal PC disorder that represents an intermediate stage between MGUS and MM. No single pathological, molecular, or clinical feature can reliably distinguish these 2 groups of patients.¹⁸ However, in everyday clinical practice, distinguishing SMM from MGUS is important, as the risk of progression of SMM to MM is 10 times higher than that of MGUS to MM in the first 5 years following diagnosis (10% per year in SMM vs 1% per year in MGUS).¹⁹

Current standards of care

Modern therapeutic landscape for MM is shaped by our increasingly nuanced understanding of the disease’s underlying biology and emergence of a diverse array of targeted and immunologically driven therapies. Historically, patients received treatments such as melphalan and prednisone, dexamethasone, and / or high‑dose chemotherapy followed by autologous stem cell transplantation (ASCT), but relapses were inevitable, and survival proved very limited. The advent of novel agents—specifically immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs)—substantially changed clinical outcomes and laid the groundwork for the next generation of MM management treatment strategies. Today, quadruplet regimens that integrate a CD38‑directed mAb, a PI, an IMiD, and dexamethasone have become a mainstay for many patients in the upfront setting, and in particular those who are eligible for transplant as well as the transplant ineligible population. At the same time, further advances including next‑generation small molecules, peptide‑drug conjugates, antibody‑drug conjugates (ADCs), and most recently cereblon E3 ligase modulators (CELMoDs) promise further gains, especially in the relapsed / refractory setting where therapeutic options must be both effective and noncross resistant, with manageable toxicity.

Evolution of frontline therapy and the role of quadruplet regimens

A critical turning point in frontline MM therapy was a finding that combining an IMiD (such as lenalidomide) with a PI (eg, bortezomib) and dexamethasone significantly improved remission rates, leading to higher percentages of patients achieving deep responses and improved outcomes. These 3‑drug (triplet) regimens replaced older doublets, becoming a global standard of care for newly‑diagnosed MM (NDMM) both in transplant eligible and transplant ineligible populations.²⁰ This approach was further enhanced upon introducing CD38‑targeting mAbs, with daratumumab at the forefront and now isatuximab. CD38 is a glycoprotein highly and uniformly expressed on PCs, making it an attractive target for selective immunotherapy. Early clinical studies of daratumumab in heavily pretreated populations revealed its single‑agent potency, prompting subsequent trials that placed it alongside bortezomib, lenalidomide, and dexamethasone (RVd) and also carfilzomib‑based (carfilzomib, lenalidomide, dexamethasone [KRd]) therapy. The Dara‑RVd quadruplet regimen has demonstrated superior depth of response, longer progression‑free survival (PFS), and higher minimal residual disease (MRD) negativity rates than the triplet backbone of RVd alone.²¹ Data from trials such as GRIFFIN (Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone [D‑RVd] Versus Lenalidomide, Bortezomib, and Dexamethasone [RVd] in Subjects With Newly Diagnosed Multiple Myeloma) and PERSEUS (Daratumumab, Velcalde [Bortezomib], Lenalidomide and Dexamethasone Compared to Velcalde, Lenalidomide and Dexamethasone in Subjects with Previously Untreated Multiple Myeloma) established this approach, showing that daratumumab‑based quadruplet therapies not only induce higher rates of stringent complete response (sCR) but also correlate with meaningful improvements in PFS.^21,22 In patients with high‑risk cytogenetics, including those harboring del(17p) or t(4;14) mutations, these more intensive inductions have generated deeper responses and helped mitigate the poor prognostic impact traditionally associated with these cytogenetic abnormalities.²² For transplant‑eligible patients, the integration of quadruplet induction followed by high‑dose therapy and ASCT remains a key strategy, with most institutions later implementing maintenance therapy (typically with lenalidomide, sometimes in combination with a mAb and / or PI) to prolong remission. Quadruplet therapy, therefore, has become emblematic of the modern frontline approach, aiming to deliver powerful cytoreduction that sets the stage for durable disease control.

Additional monoclonal antibodies in the CD38 and SLAMF7 space

While daratumumab established the importance of targeting CD38 in MM, isatuximab further validated this target. Isatuximab, similarly to daratumumab, relies on antibody‑dependent cellular cytotoxicity, complement‑dependent cytotoxicity, and direct proapoptotic signals. In combination with agents such as carfilzomib, lenalidomide, and dexamethasone in NDMM patients and especially in high‑risk individuals, this quadruplet has proved highly effective. According to previous studies comparing the use of isatuximab with carfilzomib and dexamethasone (Isa‑KD) or isatuximab with pomalidomide and dexamethasone (Isa‑PD) in the relapsed setting, isatuximab has repeatedly shown activity in patients with advanced disease.^23-25 Its different epitope binding and pharmacologic profile in comparison with daratumumab offer clinicians additional therapeutic flexibility, especially in patients who have already received daratumumab‑containing regimens or with specific disease characteristics, such as 1q amplification. Moreover, the availability of subcutaneous administration of these antibodies has significantly reduced infusion‑related reactions and decreased chair times, further improving patient quality of life.²⁶ Elotuzumab, a monoclonal antibody that targets SLAMF7, has a distinctly different mechanism of action. SLAMF7 is expressed by malignant PCs and natural killer (NK) cells but is generally absent on other normal cell types. This enables elotuzumab to activate NK‑cell function, while disrupting myeloma cell adhesion within the bone marrow microenvironment.²⁷ Combinations of elotuzumab with lenalidomide or pomalidomide and dexamethasone have shown durable responses in the relapsed setting. Though elotuzumab may be less commonly used in frontline settings than either daratumumab‑based or isatuximab‑based quadruplets, it remains a valuable option in certain relapsed / refractory cases, especially where immunomodulatory mechanisms are pivotal for disease control.^28,29

Autologous stem cell transplantation, the role of maintenance, and future directions in an evolving landscape

Despite the influx of novel agents, ASCT retains a central role in MM therapy for transplant‑eligible patients. Studies consistently show that high‑dose melphalan followed by ASCT deepens response rates, often driving patients into MRD negativity—a key predictor of prolonged PFS and possibly OS, although the lack of OS benefit in recent studies of early ASCT, as compared with novel therapy, points to both competing risk and increasing efficacy of salvage strategies. Maintenance strategies post‑ASCT commonly include lenalidomide, although the combination of lenalidomide with a CD38‑targeting antibody or a second‑agent PI is increasingly tested, aiming to extend remission durability.^30,31 As quadruplet induction regimens, innovative immunotherapies, and new targeted agents continue to advance, further questions arise about the optimal timing of ASCT, with multiple additional trials now investigating delayed transplantation in patients who achieve deep remissions via novel therapies alone. Emerging research is also evaluating whether post‑transplant therapy may incorporate T‑cell redirections or ADC in MRD settings, potentially eradicating clonal disease at a point of low tumor burden. Personalized medicine approaches, leveraging genomic and immunologic profiling, are likely to guide these decisions. Biomarkers, including cytogenetics, gene expression signatures, and MRD status assessed by next‑generation sequencing or flow cytometry, are poised to inform which patients might benefit from intensifying or deintensifying certain therapies. The phase 3 ATLAS trial (Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem‑cell Transplant for Multiple Myeloma) evaluated maintenance therapy with KRd vs lenalidomide alone in patients with NDMM post–autologous hematopoietic stem cells transplantation (HSCT). At median follow‑up of 33.8 months, median PFS was 59.1 months with KRd vs 41.4 months with lenalidomide alone (hazard ratio, 0.51; P = 0.012). MRD negativity after 6 cycles was achieved in 44% of patients receiving KRd vs 27% with lenalidomide alone (P = 0.027). These findings suggest that KRd maintenance may offer superior PFS and higher MRD negativity rates in this patient population.³²

Bispecific T‑cell engagers: teclistamab, elranatamab, and beyond

In parallel with CD38 and SLAMF7 mAbs, a major leap in immunotherapy came with bispecific T‑cell engagers (TCEs). These agents are engineered to bind simultaneously to a tumor‑associated antigen on myeloma cells (often B‑cell maturation antigen [BCMA]) and CD3 on T cells, catalyzing a targeted immune synapse that triggers T‑cell mediated cytotoxicity. Unlike CAR‑T cells—which require complex ex vivo manipulation, patient‑specific manufacturing, and extended lead times—TCEs are “off‑the‑shelf” therapies. This means they can be administered rapidly and repeated as necessary. Teclistamab emerged as a leading BCMA‑directed TCE, boasting high response rates among patients who have exhausted standard classes of therapy, including PIs, IMiDs, and CD38 mAbs. While cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) can occur, step‑up dosing schedules and vigilant monitoring have significantly improved the tolerability profile.^33,34 Other BCMA‑directed TCEs, such as elranatamab, are advancing through clinical trials with similarly high overall response rates (ORR). Non‑BCMA targets have also entered the arena, most notably talquetamab (G protein–coupled receptor class C group 5 member D [GPRC5D] × CD3), which has showed strong activity in patients who have progressed on BCMA‑based strategies.³⁴ Although talquetamab has a unique adverse event profile—including cutaneous, nail, and taste disturbances—ongoing dose optimization, prophylaxis, and toxicity management strategies aim to refine its therapeutic index.³⁵ In Poland, the following bispecific antibody (BsAb) therapies are currently available through the national drug program: teclistamab, talquetamab, and elranatamab. These agents are indicated in patients with relapsed / refractory MM (RRMM) who have received at least 3 prior lines of therapy (LOT), including an IMiD, PI, and an anti‑CD38 mAb.

Antibody‑drug conjugates: belantamab mafodotin, and other next‑generation agents

ADCs combine the specificity of a mAb with the potent cytotoxicity of a chemotherapy payload. This combination allows for targeted killing of malignant cells while reducing collateral damage to healthy tissues. Belantamab mafodotin, targeting BCMA, was the first ADC of its kind to demonstrate robust activity in patients with triple‑class refractory MM.³⁶ Encouraging results from the DREAMM‑2 study (A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Participants with Multiple Myeloma Who Have Failed Prior Treatment With an Anti‑CD38 Antibody), including durable responses, brought the drug to market in certain regions; however, ocular toxicities, particularly keratopathy, posed significant challenges to long‑term use.^37,38 Even so, belantamab mafodotin remains under active investigation in combination regimens (such as with PIs or IMiDs) and is provided at modified doses to balance efficacy against corneal side effects, with strict clinical benefit seen in continuation with bortezomib in the DREAMM‑7 trial (Japan Expansion Cohort: Evaluation of Efficacy and Safety of Belantamab Mafodotin, Bortezomib and Dexamethasone Versus Daratumumab, Bortezomib and Dexamethasone in Participants with Relapsed / Refractory Multiple Myeloma) and a similarly impressive clinical benefit in the DREAMM‑8 study (Belantamab Mafodotin Plus Pomalidomide and Dexamethasone (Pd) Versus Bortezomib Plus Pd in Relapsed / Refractory Multiple Myeloma) with pomalidomide.^39,40 Apart from belantamab, other ADCs are being developed to target GPRC5D, reflecting ongoing efforts to expand this therapeutic class. These next‑generation ADCs employ novel linkers, payloads, or antibodies, aiming to achieve higher response rates, maintain durability, and minimize off‑target toxicities. As combination therapies become more prevalent, ADCs may be used synergistically with IMiDs or CELMoDs to target the disease from multiple angles. In a similar context, a peptide drug conjugate melfufen provides a novel aminopeptidase targeted approach to directly deliver a cytotoxic warhead to a tumor, thus sparing normal tissue. It has been approved for the treatment of relapsed / refractory disease in Europe based upon positive results from the HORIZON trial (A Study of Melphalan Flufenamide [Melflufen] Plus Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma) and the OCEAN study (A Study of Melphalan Flufenamide [Melflufen]-Dex or Pomalidomide‑dex for RRMM Patients Refractory to Lenalidomide). Melflufen has also showed promise in combination with both bortezomib and daratumumab.^41-44

Cereblon E3 ligase modulators: extending the concept of immunomodulatory drugs

IMiDs revolutionized MM treatment by binding to cereblon, altering the function of an E3 ubiquitin ligase complex, and leading to selective degradation of transcription factors (Ikaros and Aiolos) integral to myeloma cell growth.⁴⁵ CELMoDs, exemplified by iberdomide (CC‑220) and mezigdomide (CC‑92480), are engineered to enhance these effects. They display greater affinity for cereblon, promoting more pronounced degradation of target proteins, which can translate into both direct cytotoxic effects against myeloma cells and enhanced immune stimulation via T and NK cells. Early‑phase clinical trials have yielded very promising efficacy data, even in heavily pretreated populations resistant to prior IMiDs, PI, and BCMA‑based therapies. Mezigdomide has showed an encouraging ORR, including deep responses such as CR, with a manageable toxicity profile dominated by hematologic adverse events, namely neutropenia and thrombocytopenia.⁴⁶ Iberdomide demonstrates a similar therapeutic index, and has sparked interest as a combination partner with established regimens.⁴⁵ Taken together, these findings signal that CELMoDs could become integral components of future MM treatment, moving beyond salvage therapy into earlier LOT once their efficacy and safety in combination approaches are more clearly defined in the context of ongoing phase 3 clinical trials.⁴⁷

Cell therapies: general information

The improvement in treatment and outcomes in MM over the past 20 years is unprecedented. Life expectancy has improved significantly, and MM is now considered a chronic disease in many patients. Before the introduction of CAR‑T–cell therapies and TCEs, patients with myeloma refractory to anti‑CD38 mAbs, IMiDs, and PIs (triple‑class refractory patients) had survival rates of less than 1 year, and patients with penta‑class refractory (anti‑CD38 mAbs, 2 IMiDs, and 2 PIs) disease usually survived less than 6 months.⁴⁸ Due to the ever‑growing population of triple‑class and penta‑class refractory patients, there is still an unmet need for new treatment options to improve OS, which has contributed to the development of new therapeutic modalities.⁴⁹ Treatment history of MM and current therapeutic landscape are summarized in Figure 1.

New antigens as targets

Overview of the most important clinical trials using cellular therapies: chimeric antigen receptor‑T cells

Side effects

The use of immunotherapies can be associated with potentially severe and life‑threatening complications, including CRS, ICANS, delayed neurotoxicity, cytopenias, and infection.

Conclusions and future directions

In recent years, enormous progress has been made in the treatment of MM. However, significant disparities remain in the availability of new therapies across different regions and health care jurisdictions. Government and health care experts should work to reduce these gaps in access, primarily by expanding modern hospital networks and increasing the number of departments offering cell therapies as well as managing costs. Despite the promising efficacy of the therapies described above, they are not without serious and potentially life‑threatening side effects. Moreover, high price of the treatment and limited number of hospitals providing molecular‑targeted and immune therapies make rapid improvements in access unlikely in many countries. An emerging challenge in clinical practice is the increasing number of patients who become resistant to novel molecular‑targeted therapies but, fortunately, the therapeutic armamentarium continues to expand, both with immune therapy and other novel agents including small molecules. As this number continues to grow in the coming years, it underscores the urgent need to enhance existing treatments, optimize supportive care, minimize complications and refine treatment sequencing for newly‑diagnosed and relapsed disease, with strategic considerations paramount for individual patients, thus providing truly tailored care. Further research and innovation will be essential to improve patient outcomes in MM but continued progress and achievement of functional cure in an increasing proportion of patients appears now more possible than ever before.