Advancing multiple myeloma therapy: A systematic analysis of corticosteroids and monoclonal antibodies as dual therapeutic agents

Abstract

BACKGROUND

Multiple myeloma (MM) is an incurable hematopoietic malignancy defined by the bone marrow's clonal expansion of neoplastic plasma cells. Corticosteroids and monoclonal antibodies (mAbs) have been approved for the treatment of MM over the past 20 years and are now key components of treatment regimens, improving clinical outcomes. Corticosteroids (dexamethasone and prednisone) are frequently used in combination with other agents [proteasome inhibitors and immunomodulatory drugs (IMiDs)], while mAbs (daratumumab, elotuzumab, and isatuximab) have transformed treatment paradigms, particularly for relapsed/refractory cases.

AIM

To evaluate the impact of corticosteroids and mAbs on the treatment of MM.

METHODS

This systematic review integrates results from randomized controlled trials and cohort studies published from 2003 to 2024. This resulted in the identification 26 articles assessing the role of corticosteroids and mAbs in various treatment settings: Newly diagnosed, relapsed, and refractory MM. Seventeen studies were included in the systematic review.

RESULTS

We show that corticosteroid-based combination regimens are critical for achieving rapid tumour regression and increasing overall survival (OS) when combined with proteasome inhibitors (bortezomib or carfilzomib). Moreover, mAb therapy, particularly with daratumumab, has also led to significant benefits, enhancing progression-free survival and OS when added to first- and later-line therapy. All IMiDs and proteasome inhibitors offer activity when combined with daratumumab, with the efficacy being better with daratumumab, even in higher-risk patients. However, treatment of high-risk MM, including those with extramedullary disease and patients with adverse genetics, still poses challenges.

CONCLUSION

While great strides have been made in the treatment, much remains to be learned about long-term safety, efficacy, and potential resistance mechanisms to these treatments.

Key Words: Multiple myeloma; Corticosteroids; Monoclonal antibodies; Dexamethasone; Daratumumab; Elotuzumab; Isatuximab; Systematic review; Chemotherapy; Efficacy

Core Tip: Corticosteroids and monoclonal antibodies (mAbs) deliver extensive therapeutic value to patients with multiple myeloma (MM) by providing survival improvements, particularly for people with relapsed or refractory disease. The essential medication dexamethasone, alongside other corticosteroids, has long proved beneficial in treatment regimens because it decreases tumor size and works better with other treatments. The development of daratumumab and other mAbs introduced specific tumor cell antigen targeting, producing significant study results for high-risk patients. Modern advancements in cancer therapy have produced promising results, although ongoing research aims to address corticosteroid-related long-term effects, prevent infusion responses in mAbs, and decrease their costly nature.

INTRODUCTION

Multiple myeloma (MM) is a malignant clonal hematologic disease defined as the pathological proliferation of malignant plasma cells in the bone marrow. It is an incurable disease with a multifactorial pathogenesis, including genetic mutations, interactions with the microenvironment of the bone marrow, and failure of the immune system. MM is the second most prevalent hematologic malignancy worldwide that primarily afflicts the geriatric population, with a median age at diagnosis of 69 years[1]. Although treatments for this disease have improved in the past half-century, MM remains a relapsing and refractory disease: MM patients typically go through phases of remission and relapse, with the majority having a poor prognosis. Over the years, conventional treatment strategies for MM included chemotherapy, high-dose chemotherapy with autologous stem cell transplantation, and corticosteroids (e.g., dexamethasone and prednisone). Although these therapies have led to improved rates of disease-free survival, they have been non-curative, as the disease inevitably relapses in most patients[2,3]. As MM remains uncured and often comes back, recent advances in treatment have focused on long-term survival, less risk of relapse, and improved quality of life with the use of new drug mixes.

In the last two decades, the introduction of new agents to the treatment of MM [e.g., proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs)] markedly changed the treatment landscape. These new agents have enhanced survival outcomes, particularly among relapsed or refractory MM, and have evolved into essential components of current treatment approaches. Dexamethasone, a corticosteroid, has stood the test of time as an effective regimen but has fallen short when it comes to the general well-being of the patient with MM[4]. Additionally, corticosteroids are often given as one component of combined treatment, usually alongside established chemotherapeutic agents or modern proteasome inhibitors, to enhance the therapeutic effect at hand[5]. On the other hand, when dexamethasone is combined with proteasome inhibitors such as bortezomib and IMiDs like lenalidomide, it has led to marked increases in progression-free survival (PFS) and overall survival (OS) for patients with MM who are either newly diagnosed or relapsed[6,7].

mAbs are one advance in the treatment of MM. They aim at targeted therapies. Any immune system components implicated in MM biology will suffice to engage specific antigens on the malignant plasma cell surface. The human mAb daratumum, directed against CD38, has revolutionized the treatment of MM. It not only prolongs the period free from relapse and development but also decreases times up for recurrence[8,9]. CD38 is a cell surface molecule that, in malignant plasma cells, has been shown to mediate immune-mediated cytotoxicity, the killing of plasma cells by T lymphocytes, and T cell memory, and the ability of daratumumab to inhibit the growth of tumours has been well established in clinical trials[10]. Currently, daratumumab has been established to treat newly diagnosed and relapsed/refractory MM, demonstrating significant efficacy when combined with bortezomib, lenalidomide, and other agents[11,12].

The mAb elotuzumab zaps SLAMF7 (signalling lymphocytic activation molecule family member 7), a plasma cell surface protein, leading to potential benefits when combined with IMiDs like lenalidomide[13]. Elotuzumab also showed considerable benefit in relapsed/refractory MM, including in patients with multiple lines of previous therapy[14]. A second anti-CD38 mAb, siltuximab, has also shown promising activity in relapsed/refractory MM as a single agent or in combination with other agents[15,16].

mAbs' application in MM treatment has contributed to a better survival outcome and improved extra survival for the patients. But, notwithstanding the encouraging efficacy of steroids and mAbs, there are considerable therapeutic hurdles to tackle yet to tailor these drugs for specific patient subtypes such as high-risk MM. High-risk MM is typically regarded with a bad prognosis and is defined by clinically statistically significant genomic alterations (e.g., MYC oncogene translocations), extramedullary disease, and therapy resistance[17]. Further research is needed to optimize therapeutic strategies for these high-risk populations effectively, especially regarding combination regimens incorporating mAbs and corticosteroids[18].

Considerations also had to be utilized regarding the safety profile of cancer treatments relative to their efficacy; corticosteroids and mAbs used to treat cancer have different safety profiles that need assessment beyond this efficacy. This medication has various side effects that warrant attention; for example, it can distort the bone, making it prone to fracture, reduce resistance, weaken the immune and digestive system, and cause hyperglycemic side effects[19]. These things can significantly affect a patient's life quality and prevent long-term treatment. While mAbs are generally well-tolerated, they can also cause infusion-related reactions such as fever, chills, and nausea, mainly with daratumumab or isatuximab agents[20]. If combined with other types of drugs, especially for old patients and those with pre-existing diseases, these drugs are safe and should be incorporated into carefully planned treatment regimens.

This systematic review seeks to summarise the evidence from randomized controlled trials (RCTs) and cohort studies investigating the efficacy of corticosteroids and mAbs in MM treatment over the last 20 years (2003-2024). The review will assess the effectiveness of these therapies as an expert opinion based on their contribution to survival benefit, PFS, or overall response rate (ORR) in newly diagnosed or relapsed/refractory MM patients. This review will also address the limitations of presently existing treatment algorithms, particularly in patients with high-risk MM. It will encourage further exploration of these therapies' safety, durability, and resistance mechanisms.

MATERIALS AND METHODS

This systematic aimed to evaluate the effectiveness of corticosteroids and mAbs in treating MM. A systematic literature search was performed to identify eligible RCTs and cohort studies published from 2003 to 2024. The studies were narrow in scope, and the review is highly selective. Systematic data extraction and synthesis were also conducted, and the risk of bias and quality of studies were examined. The following PICO criteria have been applied for the study selection.

Population (P): Patients with MM, including both newly diagnosed and relapsed/refractory MM patients, with a focus on high-risk MM cases.

Intervention (I): Corticosteroids and mAbs used for MM treatment.

Comparison (C): Standard treatment protocols, placebo, or other therapeutic agents used in MM treatment.

Outcome (O): Survival benefit, PFS, ORR, safety, durability, and resistance mechanisms of the therapies.

Inclusion criteria

In this review, studies eligible to be included were RCTs, which are considered the gold standard for evaluating clinical efficacy of interventions. Cohort studies were also used, which collect important facts when RCTs cannot be used. By including this method, we were able to support our findings with both clinical studies and other observations.

The results were expected to provide comparative data on the therapeutic effectiveness of corticosteroids vs mAbs for the treatment of MM.

Patient population: Studies eligible for inclusion included adult patients with a diagnosis of MM in newly diagnosed or relapsed/refractory settings.

Interventions: We only considered studies examining the synergism of corticosteroids (e.g., dexamethasone and prednisone) and mAbs (e.g., daratumumab, elotuzumab, and isatuximab). These therapies are the backbone of the current treatment landscape for MM, and combinations of these agents are linked to improved survival metrics.

Primary outcomes were PFS, OS, and response rates (e.g., complete and partial response and minimal residual disease). These remain key outcomes in assessing the utility of MM therapies. Secondary outcomes such as quality of life, adverse events, and safety profiles were also extracted where they were available.

Timespan: The analysis only included studies published between 2003 and 2024 since this range denotes the treatment landscape evolution for MM, most notably with the emergence of mAbs, such as daratumumab and elotuzumab.

Exclusion criteria

Studies were excluded from the review based on the following criteria:

Non-comparative studies: Studies that evaluated the effects of corticosteroids and mAbs vs other types of treatment regimens or placebos were excluded, as the scope of the review was limited to the relative efficacy of the therapeutic combinations.

Non-peer-reviewed studies/articles: We limited our research only to papers published in peer-reviewed journals. Even though peer review has limitations, it ensured that experts in the field had formally reviewed each study.

Exclusion of studies: We excluded studies that did not report key clinical outcomes, including PFS, OS, or response rates. This included studies that did not measure or report these outcomes sufficiently.

Animal studies and case reports: Animal studies and case reports do not provide generalizable clinical data, so they were excluded.

Studies on pediatric populations: Studies on pediatric patients or patients with primary plasma cell leukaemia were excluded as this review focuses on adult MM cases.

Data extraction and synthesis

The data extraction was done in a systematic way to maintain both consistency and completeness. Two independent reviewers (with experience in clinical research) extracted data from eligible studies. The following data were abstracted from each study:

Study characteristics: Author(s), year of publication, type of study, and number of participants.

Documented details encompassed: Interventions (corticosteroids and mAbs) used, dosages, treatment regimens, and combinations with other agents.

Outcomes: Primary and secondary outcomes (PFS, OS, response rates defined as complete and partial response), adverse events, and safety profiles.

Data were summarized in tables and analyzed descriptively.

Assessment of risk of bias and study quality

Assessment of risk of bias and quality of studies was key aspects of this systematic review to safeguard the reliability and validity of findings. Potential bias in the included studies was evaluated based on their study design, sample size, randomization process, blinding, and completeness of outcome data. Only RCTs and meta-analyses thereof were included in the analysis as this represents the highest quality evidence; however, cohort studies are also included to provide completeness of the data. Quality of studies was measured using standard tools, particularly the Cochrane Risk of Bias Tool for different domains of bias, including selection, performance, detection, attrition and reporting. Studies were assessed for risk of bias; high risk was defined as flaws in randomization, lack of blinding, or incomplete outcome data. In addition, an assessment of the methodological quality of each study was undertaken, focusing on sample sizes and analyses conducted. Studies that did not meet the minimum quality criteria, such as those with unclear methodological quality or lacking a suitable control group, were excluded from the review. This selection ensured that only sound and well−executed studies were selected, contributing to lower bias and higher quality of the synthesized evidence. This review seeks to elucidate the efficacy of corticosteroids and mAbs in managing MM by critically assessing the risk of bias.

RESULTS

This section will discuss the findings of the systematic review of corticosteroids and the effectiveness of mAbs in MM. These therapies have been clinically evaluated in newly diagnosed and relapsed/refractory MM patients, emphasizing PFS, OS, and response rates.

Corticosteroids efficacy

Corticosteroids, most notably dexamethasone, have formed a part of the backbone of MM therapy for several decades. Their efficacy has been demonstrated in newly diagnosed and relapsing/refractory patients. Rajkumar et al[1] compared high-dose dexamethasone plus lenalidomide vs low-dose dexamethasone alone in newly diagnosed MM patients. They showed a higher ORR for high-dose dexamethasone plus lenalidomide, providing the first evidence for the potency of dexamethasone-enhanced combinations. Similarly, Dimopoulos et al[6] and Facon et al[7] showed that a combination of corticosteroids with other agents significantly benefits patients for PFS and OS, including lenalidomide, bortezomib, and carfilzomib. These findings are consistent with earlier studies showing that using dexamethasone in combination with other myeloma agent’s decreases tumour burden and increases response rates.

Corticosteroids are also a critical component of relapsed/refractory MM treatment. In the OPTIMISM trial, a significant survival benefit was evident in those who received pomalidomide or bortezomib combined with dexamethasone in case of previous lenalidomide exposure[12]. This phenomenon indicates that corticosteroids retain their survival benefit when used even at more severe stages of disease.

While corticosteroids are very effective, they do have some notable side effects. The most significant adverse effects are immune suppression and metabolic disorders such as hyperglycemia and osteoporosis[13]. This is particularly damaging in older patients who are among the most affected populations of MM and may demonstrate a more significant outcome from corticosteroid therapy[14]. Thus, corticosteroids represent integral components of treatment regimens, but their long-term use must be carefully monitored, particularly in at-risk patient groups.

Research suggests that problems associated with corticosteroids are common and significant. The OPTIMISMM trial found that about 30% of patients who received pomalidomide-bortezomib-dexamethasone experienced severe infections, while cases of grade ≥ 3 hyperglycemia were seen in 7%-9%. Reports from studies indicate that corticosteroid use could raise blood sugar levels in up to 12%-18% of elderly MM patients, while rates of infection-related complications can be as high as 25%[21]. It suggests that regular monitoring of metabolism and possible infection is critical during corticosteroid treatments, especially for seniors and those with other health problems.

Monoclonal antibodies: Efficacy

In recent decades, mAbs targeting antigens present in malignant plasma cells have emerged as an attractive therapeutic modality for the treatment of MM, contributing to considerable clinical outcome improvements, particularly with their use in combination with other therapeutic compounds, including proteasome inhibitors and immunomodulatory drugs. Daratumumab is one such mAb displaying impressive activity in both newly diagnosed as well as relapsed/refractory patients. In the CASTOR trial evaluating daratumumab in combination with bortezomib and dexamethasone, this combination showed a statistically significant PFS benefit compared with bortezomib and dexamethasone alone[5]. This regimen has since become a standard of care for relapsed/refractory MM.

Moreover, the POLLUX study investigating daratumumab in combination with lenalidomide and dexamethasone demonstrated marked and significant PFS improvement over lenalidomide and dexamethasone alone[6]. This study indicated daratumumab's efficacy in improving survival in relapsed/refractory MM patients. Daratumumab's mechanism of action—binding to the CD38 surface protein on myeloma cells—has been critical to its success. Daratumumab targets the key mediator of MM pathogenesis, CD38, reducing the tumour burden, augmenting the immune response, and ultimately improving patient outcomes[7].

Apart from daratumumab, elotuzumab has shown promising results when used in combination with lenalidomide and dexamethasone in the ELOQUENT-2 trial. In both trials, the elotuzumab-based regimen was associated with improved PFS compared to lenalidomide and dexamethasone alone in relapsed/refractory MM patients[9]. Elotuzumab targets the SLAMF7 protein on myeloma and natural killer (NK) cells, leading to an increased immune response against MM cells.

Jakubowiak et al[15] conducted a more recent study (2021), which studied the combination of daratumumab with carfilzomib, lenalidomide, and dexamethasone in transplant-eligible, newly diagnosed patients. The four-drug combination achieved notable clinical improvements, including PFS and OS, highlighting the promise of these novel combinations of mAbs with other agents. These results are similar to previous studies that demonstrate the efficacy of daratumumab in combination regimens in patients with newly diagnosed and relapsed MM[5,6,8].

mAbs have much promise, but there are concerns about long-term safety. Infusion-related reactions (notably with daratumumab) and increased risk of infections are the most frequently observed side effects from clinical trials[16]. Careful management is needed for these side effects, as infections in immunosuppressed patients, such as in those receiving mAb therapy with MM, can be life-threatening.

Study selection

A total of 488 records were identified in the database, of which 273 were rejected due to being duplicates or related to automation, leaving 215 records for screening. After reviewing the title and abstract, 64 studies were reviewed, and 26 studies were found to meet the requirements for the analysis (Table 1). This structured selection process ensures that only relevant and high-quality studies contribute to the final analysis (Figure 1).

Figure 1 PRISMA flow diagram of article selection process.

Table 1 Characteristics of selected studies.

Ref.	Year	Sample size	Study type	Interventions	Outcomes	Key findings
Voorhees et al[10]	2020	207	RCT	Daratumumab + RVd vs RVd	Improved response rates and PFS	sCR rate 424% vs 32.0%
Kumar et al[8]	2020	1087	RCT	Carfilzomib + Rd vs Bortezomib + Rd	No PFS benefit for Carfilzomib over Bortezomib	No significant PFS benefit observed
Lonial et al[9]	2015	646	RCT	Elotuzumab + Rd vs Rd	Improved PFS and response rates with Elotuzumab	PFS improved by approximately 4.5 months (HR 0.70)
Bringhen et al[4]	2018	54	RCT	Weekly Carfilzomib + Cyclophosphamide + Dex	High response rates with Carfilzomib	ORR > 85%
Facon et al[7]	2019	737	RCT	Daratumumab + Rd vs Rd	Significant PFS and ORR improvement with Daratumumab	PFS improved by 13.5 months
Dimopoulos et al[6]	2016	569	RCT	Daratumumab + Rd vs Rd	Improved PFS with Daratumumab	Median PFS: 44.5 vs 18.4 months (HR 0.37)
Palumbo et al[5]	2016	498	RCT	Daratumumab + Bortezomib + Dex vs Bortezomib + Dex	Significantly longer PFS with Daratumumab	Daratumumab group had a 61% risk reduction (HR 0.39)
Facon et al[2]	2007	447	RCT	MPT vs MP vs MEL100	MPT superior to MP in OS	OS improved with MPT arm (P < 0.05)
Richardson et al[3]	2003	202	RCT	Bortezomib	Bortezomib effective in refractory MM	Significant ORR in heavily pretreated patients
Rajkumar et al[1]	2010	445	RCT	Lenalidomide + Low-dose Dex vs High-dose Dex	Better OS and lower toxicity with low-dose Dex	Low-dose Dex improved OS and had fewer AEs
Jakubowiak et al[15]	2021	22	RCT	Daratumumab + Carfilzomib + Lenalidomide + Dex	Improved outcomes, high response rates	VGPR or better: 100%
Richardson et al[12]	2019	559	RCT	Pomalidomide + Bortezomib + Dex vs Bortezomib + Dex	Improved PFS in the Pomalidomide group	PFS improved by 4.1 months (11.2 vs 7.1 months)
Moreau et al[20]	2021	302	RCT	Isatuximab + Carfilzomib + Dex vs Carfilzomib + Dex	Improved PFS with Isatuximab combination	Median PFS: 35.7 vs 19.2 months
Sonneveld et al[18]	2023	709	RCT	Daratumumab + VRd vs VRd alone	Significant improvement in PFS	PFS: NR vs 62.4 months
Bumma et al[13]	2023	503	Cohort Study	Bortezomib-based vs Lenalidomide maintenance	Different maintenance strategies impact long-term outcomes	Individualized maintenance affects survival
Leypoldt et al[19]	2023	125	RCT	Isatuximab + Carfilzomib + Lenalidomide + Dex	High minimal residual disease negativity rates, long-term PFS benefit	Long-term PFS benefit in high-risk MM
Richardson et al[17]	2021	722	RCT	Ixazomib + Lenalidomide + Dex vs Placebo + Rd	No significant OS benefit, but some subgroup advantages	PFS benefit in some subgroups
Takezako et al[16]	2021	40	RCT	Once-weekly vs twice-weekly carfilzomib	Once-weekly dosing had better ORR and PFS	Improved tolerability with similar efficacy
Slade et al[23]	2023	25	RCT	Elotuzumab + Pomalidomide + Dexamethasone (EPd)	1-year PFS: 72%; median PFS: 19 months; safe regimen	Median PFS: 19 months
Joseph et al[22]	2024	1326	Cohort Study	Daratumumab + RVd vs RVd alone	Quadruplet therapy improves response and PFS	Improved VGPR and CR rates
Wang et al[21]	2017	32	Retrospective	Low-dose Lenalidomide + Dexamethasone	ORR: 71.9%, median PFS: 13 months, mild side effects	Mild side effects, effective in elderly
Bringhen et al[24]	2014	58	RCT	Carfilzomib + Cyclophosphamide + Dexamethasone	High response rates, PFS: 76%, OS: 87% at 2 years	PFS: 76%, OS: 87% at 2 years
Moreau et al[25]	2021	159	RCT	Teclistamab (BCMA × CD3 bispecific antibody)	ORR: 65%, VGPR: 58%, well tolerated, durable responses	ORR: 65%, VGPR: 58%
Dimopoulos et al[11]	2020	466	RCT	KdD (Carfilzomib, Dexamethasone, Daratumumab) vs Kd	KdD improved PFS (28.6 vs 15.2 months), manageable safety profile	PFS: 28.6 vs 15.2 months
Mateos et al[26]	2022	119	RCT	Lenalidomide + Dexamethasone vs Observation	Median TTP to MM: 9.5 vs 2.1 years, OS benefit with Rd	Median TTP: 9.5 vs 2.1 years
Bahlis et al[14]	2024	112	RCT	DPd (Pomalidomide + Daratumumab + Dexamethasone)	ORR: Favorable OS, median 56.7 months; no new safety signals	Median OS: 56.7 months

sCR: Stringent complete response; VGPR: Very good partial response; TTP: Time to progression; RCT: Randomized Controlled Trial; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; AEs: Adverse events; Cohort Study: Observational study following a group over time; Retrospective: Retrospective observational study; RVd: Lenalidomide (Revlimid) + Bortezomib (Velcade) + Dexamethasone; Rd: Lenalidomide + Dexamethasone; VRd: Bortezomib (Velcade) + Lenalidomide + Dexamethasone; Kd: Carfilzomib + Dexamethasone; KdD: Carfilzomib + Dexamethasone + Daratumumab; DPd: Daratumumab + Pomalidomide + Dexamethasone; EPd: Elotuzumab + Pomalidomide + Dexamethasone; MPT: Melphalan + Prednisone + Thalidomide; MP: Melphalan + Prednisone; MEL100: High-dose Melphalan 100 mg/m²; Dex: Dexamethasone; CR: Complete response; BCMA: B-cell maturation antigen; CD3: Cluster of Differentiation 3.

Studies include RCTs and cohort studies, highlighting the variability of available data regarding the therapeutic applicability of corticosteroids and mAbs for managing MM. Nine studies evaluated mAbs in combination with corticosteroids (dexamethasone) in patients receiving other treatments (lenalidomide, bortezomib, and carfilzomib) or other mAbs (daratumumab and elotuzumab). These studies encompassed a diverse set of patient populations, including both newly diagnosed and relapsed/refractory MM patients.

Risk of bias assessment

The quality of the included studies was evaluated using the Cochrane Risk of Bias tool for RCTs. Table 2 evaluates the risk of bias across RCTs on MM treatments. Most studies demonstrated a low overall risk of bias, with low ratings in randomization, blinding, missing outcome data, and selective reporting. However, studies by Palumbo et al[5], Lonial et al[9], Bahlis et al[14], Takezako et al[16], and Moreau et al[20], had moderate bias in blinding and deviations from intended interventions, indicating potential methodological limitations. Despite these moderate risks, the general trend suggests that the studies were well-conducted and their findings reliable, reinforcing confidence in the reported outcomes for MM therapies (Table 2).

Table 2 Quality assessment for randomized controlled trials (Cochrane risk of bias).

Ref.	Random bias	Blinding bias	Deviations from intended interventions	Missing outcome data	Outcome measurement bias	Selective reporting bias	Overall risk of bias
Voorhees et al[10]	Low	Low	Low	Low	Low	Low	Low
Kumar et al[8]	Low	Low	Low	Low	Low	Low	Low
Lonial et al[9]	Low	Moderate	Low	Moderate	Low	Low	Moderate
Bringhen et al[4]	Low	Moderate	Low	Low	Low	Low	Low
Facon et al[7]	Low	Low	Low	Low	Low	Low	Low
Dimopoulos et al[6]	Low	Low	Low	Low	Low	Low	Low
Palumbo et al[5]	Low	Moderate	Low	Moderate	Low	Low	Moderate
Facon et al[2]	Low	Moderate	Low	Low	Low	Low	Low
Richardson et al[3]	Low	Low	Low	Low	Low	Low	Low
Rajkumar et al[1]	Low	Low	Low	Low	Low	Low	Low
Jakubowiak et al[15]	Low	Low	Low	Low	Low	Low	Low
Richardson et al[12]	Low	Low	Low	Low	Low	Low	Low
Moreau et al[20]	Low	Moderate	Low	Moderate	Low	Low	Moderate
Sonneveld et al[18]	Low	Moderate	Low	Low	Low	Low	Low
Leypoldt et al[19]	Low	Low	Low	Low	Low	Low	Low
Richardson et al[17]	Low	Low	Low	Low	Low	Low	Low
Takezako et al[16]	Low	Moderate	Low	Moderate	Low	Low	Moderate
Slade et al[23]	Low	Moderate	Low	Low	Low	Low	Low
Bringhen et al[24]	Low	Low	Low	Low	Low	Low	Low
Moreau et al[25]	Low	Low	Low	Low	Low	Low	Low
Dimopoulos et al[11]	Low	Low	Low	Low	Low	Low	Low
Mateos et al[26]	Low	Low	Low	Low	Low	Low	Low
Bahlis et al[14]	Low	Moderate	Low	Moderate	Low	Low	Moderate

The Newcastle-Ottawa Scale was used for cohort studies to assess selection bias, comparability, and outcome assessment. Table 3 presents a quality assessment of three studies, i.e., those conducted by Bumma et al[13], Wang et al[21], and Joseph et al[22], using a total score of 9 based on selection, comparability, and outcome criteria. Each study scored 4 in selection, 2 in comparability, and 3 in outcome, suggesting a high-quality methodology with robust patient selection and outcome measurement (Table 3).

Table 3 Quality assessment for observational/cross-sectional studies (Newcastle-Ottawa scale).

Ref.	Selection (4)	Comparability (2)	Outcome (3)	Total score
Bumma et al[13]	4	2	3	9
Joseph et al[22]	4	2	3	9
Wang et al[21]	4	2	3	9

While such potential biases do exist, they have a minimal impact on the overall body of evidence presented, which includes findings supporting the universally represented pooled efficacy of corticosteroids and mAbs upon clinical outcomes in MM patient populations. Sensitivity analyses performed during the review revealed that results were robust when studies at higher risk of bias were included.

Summary of findings

mAbs and corticosteroids have shown significant efficacy. Corticosteroids, such as dexamethasone, are still foundational agents and are particularly effective when combined with other agents such as lenalidomide and bortezomib. mAbs, notably daratumumab and elotuzumab, have demonstrated significant improvements in PFS and OS in patients with newly diagnosed and relapsed/refractory MM. Although these therapies prove effective, the long-term safety profile of these infusions (particularly about the risks of infection and infusion-related reactions) remains an essential subject of current research (Table 1).

Performance metrics and comparative outcome analysis

Many studies have reported key results in evaluating corticosteroids and mAbs for MM. Most trials focused on PFS, OS, and ORR as the main measures. Sometimes, researchers included rates for complete response, very good partial response, and minimal residual disease negativity in later studies[10,19]. Moreover, continuous elotuzumab + pomalidomide + dexamethasone maintenance after a second autologous transplant achieved broad responses with manageable toxicity, though progression was common on longer follow-up[23].

In several trials, daratumumab was used, and standard treatments performed better. For example, in the POLLUX trial, patients who got daratumumab plus lenalidomide/dexamethasone experienced a progression rate decline from 18.4 to 44.5 months. The CASTOR trial[5] found that the risk of progression dropped by 61% (hazard ratio = 0.39) in patients treated with daratumumab plus bortezomib/dexamethasone instead of the control.

When combined with different drugs, corticosteroids showed different levels of effectiveness. Taking low-dose dexamethasone together with lenalidomide was found to increase OS, but pomalidomide-bortezomib-dexamethasone increased PFS by 4.1 months relative to bortezomib-dexamethasone ( lenalidomide-exposed patients)[12].

In various studies, including recent ones, treatments with corticosteroids and mAbs have demonstrated very good outcomes. For people with high-risk disease, researchers found that daratumumab-based combinations had better outcomes compared to others[18,19].

Many studies analyzing time-to-event outcomes found that a backbone treatment of both a corticosteroid and mAbs often performed better than the separate use of either treatment.

DISCUSSION

This paper discusses the combination of the two and highlights the benefits of corticosteroids and mAbs as an essential improvement in MM—especially in recent years[1]. These agents demonstrated promising efficacy in improving PFS and OS in a broad range of patient populations, including newly diagnosed, relapsed, and refractory patients. As anti-inflammatory and immune-modulating drugs, corticosteroids like dexamethasone and prednisone have been a cornerstone of MM therapy for decades. However, despite their considerable therapeutic benefits, the side effects, especially after prolonged use, remain a significant problem. mAbs for the treatment of MM are very promising as they have revolutionized the treatment, but some concerns have been raised regarding their cost, accessibility, and long-term safety.

Corticosteroids, such as dexamethasone, have been a mainstay of MM treatment for decades; they are typically used in conjunction with a variety of other agents, including IMiDs and proteasome inhibitors. Several studies have also shown that they decrease intra-tumour burden whilst potentiating the activity of other chemotherapeutics. Rajkumar et al[1] demonstrated that when dexamethasone and lenalidomide (Revlimid) were combined in newly diagnosed patients, the response rates were higher than thosewith lenalidomide alone, highlighting the importance of corticosteroids. Similarly, the results reported by Dimopoulos et al[6] and Facon et al[7] showed that corticosteroid-based regimens with lenalidomide and carfilzomib have resulted in substantial improvement in PFS and OS. The results emphasize the continued utility of corticosteroids in combination therapies, including in high-risk MM populations. Lastly, the combination of pomalidomide with bortezomib and glucocorticoids (PVd) demonstrated improved OS in patients previously exposed to lenalidomide in the OPTIMISMM trial, thus making the PVd combination indispensable in relapsed and refractory MM[12].

While results from clinical trials are available, newer studies show that corticosteroids and mAbs work together to treat MM. Dexamethasone decreases inflammation by reducing the activity of certain cytokines, triggering the removal of malignant plasma cells, and reducing overall tumor-related inflammation. These actions could help daratumumab, which targets CD38, perform better in fighting against myeloma cells. The antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis processes are activated by daratumumab. Dexamethasone is believed to improve the action of NK cells by lowering the number of T cells and myeloid-derived suppressor cells. Corticosteroids can potentiate daratumumab's therapeutic effects, causing a stronger and longer response. Dexamethasone may also improve tolerability by reducing reactions linked to the infusion of mAbs, mainly through cytokine suppression[11,20].

Corticosteroids have proven therapeutic efficacy; however, they can cause numerous side effects that negatively impact the quality of life in MM patients. Persistent intake of corticosteroids results in overall immune suppression, which is particularly consequential in MM patients who exhibit inherent immune compromise due to their underlying disease pathology. This is an essential issue in connection with the required steroid immunotherapy. Additionally, corticosteroids cause metabolic derangements (e.g., hyperglycemia, weight gain, and increased appetite) that negatively influence existing comorbidities in MM patients. Another significant side effect is osteoporosis, which increases the risk of fractures, particularly in older people who are disproportionately affected by MM. These side effects can be especially concerning in the elderly population, who are often the predominant group of patients with MM. The difficulty in managing chronic side effects of corticosteroid therapy has led to investigating corticosteroid-sparing regimens and designing newer, less toxic agents, including mAbs and targeted therapies. Reducing corticosteroid doses or optimizing their use in combination regimens is attempting to minimize these toxicities without compromising their therapeutic effectiveness.

The most exciting approach for MM treatment is mAbs, targeted therapy that effectively retrieves molecular mechanisms of this malignancy. Since then, the approval of mAbs like daratumumab and elotuzumab is a move which makes pomalidomides such as IMiDs with alkylating agents or proteasome inhibitors as backbone agents more precise and personalized, especially for the relapsed/refractory MM patient population. The antibodies recognize specific antigens that are upregulated only in myeloma cells. That is why they can enhance therapies and reduce on-target effects compared to traditional chemotherapies. Daratumumab, an anti-CD38 mAb, targets CD38 (a cell surface protein vital for the establishment of the microenvironment supporting MM) in the CASTOR trial and significantly improved outcomes when added to bortezomib and dexamethasone[5]. The findings from this trial showed a considerably improved PFS in the combination regimen over bortezomib plus dexamethasone, emphasizing the contribution of mAbs in the route of standard therapies for MM.

The POLLUX trial also provided evidence for the combination of daratumumab with lenalidomide and dexamethasone[6]. Note that this study demonstrated that adding daratumumab significantly improved PFS and response rates compared to lenalidomide and dexamethasone alone. However, as mAbs were associated with enhanced efficacy in improving patient outcomes, their use should be considered a mainstay in the frontline treatment regimens, particularly in patients with high-risk MM. Moreover, mAbs have been shown to overcome the mechanisms of drug resistance developed in relapsed and refractory MM, particularly when conventional therapies (proteasome inhibitors and immunomodulatory drugs) have been exhausted. For example, the novel proteasome inhibitor carfilzomib was recently reported to produce high response rates in this patient population, but only when combined with lenalidomide[6].

A second anti-SLAMF7 mAb, elotuzumab, has shown activity when combined with lenalidomide and dexamethasone[9]. In patients with relapsed/refractory MM, elotuzumab-based combinations have been linked with significantly improved PFS compared to lenalidomide plus dexamethasone alone. This mechanism seems to increase the activity of NK cells involved in the immune response against myeloma cells. Moreover, this provides a new immunologic approach for the treatment of MM that is distinct from standard chemotherapies that rely on direct cytotoxicity. mAb therapy for the treatment of MM has been extended with the incorporation of elotuzumab and daratumumab, allowing patients to have more options to consider in the first line and the relapsed setting.

mAbs are effective, but they pose their challenges. One of the most significant changes is the affordability of such therapies. Daratumumab and elotuzumab are mAbs with high price tags, creating access concerns, especially in low-income and middle-income countries. mAb treatment imposes substantial economic burdens on healthcare systems in high-income settings and has economic consequences for patients with financial distress at treatment initiation with these therapies. This highlights a challenge concerning the cost of mAbs and a quandary concerning treatment affordability. This challenge will probably improve with biosimilars, that is, low-cost alternatives to branded mAbs. If successful, these biosimilars, like many for daratumumab, will represent an affordable solution for MM patients in terms of cost-effectiveness.

Another consideration is the safety of mAbs, particularly infusion-related reactions or infections, which need to be evaluated in the context of risk for active disease. Infusion reactions such as fever, chills, and hypotension are common when administering mAbs and can delay the continuation of therapy. Although these reactions are mild, they can affect treatment time and the patient's comfort. Due to their immunosuppressive capacity, mAbs can result in infusion-related responses and an increased infection risk, especially when combined with other immunosuppressive drugs. In clinical practice, though, careful monitoring of the patients for infections and adequate prophylactic strategies are crucial concerning mAbs.

Given their compelling effectiveness with other critical agents like proteasome inhibitors and IMiDs, an examination of mAbs as frontline therapies for high-risk MM patients is warranted. Multiple studies have shown that adding mAbs to frontline regimens significantly improves clinical outcomes. For instance, the combination of daratumumab with carfilzomib, lenalidomide, and dexamethasone has shown improved results in newly diagnosed, transplant-eligible patients[15]. The addition of mAbs to both standard double and triple drug first-line therapies holds the potential of improving survival, especially in patients at a higher risk for progression, as demonstrated by a QUADRUPLET regimen that provides significantly greater response rates and PFS compared to that in doublet regimens. However, the ideal timing and patient selection for mAb therapy remain under study due to cost and the potential for long-term side effects.

The paper introduces a fresh method to manage high-risk MM cases through simultaneous corticosteroid and mAb administration, and evaluates the combined effectiveness of corticosteroids and mAbs in extending survival rates, alongside discussing their associated safety risks and persistent adverse effects. This paper also examines how biosimilars might increase accessibility to medication, especially for people living in low-income communities. Through examination of high-risk patients combined with systematic review methodology, the authors create new possibilities to enhance therapeutic approaches for MM treatment.

The article contributes an innovative perspective to non-innovative treatment combinations of corticosteroids with mAbs in MM by focusing on synergistic effects in high-risk disease populations. The lengthy systematic review and analysis of research over the past two decades and the detailed evaluation of biosimilar safety and resistance properties and financial implications have brought a new direction to past studies. Due to the extensive knowledge gap and insufficient available research, the current paper delivers a comprehensive, unique evaluation integrating multiple MM therapies with high-risk patient management strategies and expense estimates.

To summarize the nature of the existing data, the use of corticosteroids and mAbs has changed the treatment landscape of MM, with corticosteroids being an essential contributor to tumour reduction and mAbs as agents that have a significant impact on PFS or OS. However, corticosteroids have adverse effects, especially with long-term use, and the costs of mAbs and associated safety considerations will need to be considered in clinical practice. Continued development of alternative therapies, including biosimilars and corticosteroid-sparing regimens, and characterization of the safety and efficacy of mAbs will be essential in improving treatment success and ensuring that effective therapies are widely available to all patients with MM.

CONCLUSION

The review demonstrates how corticosteroids and mAbs, particularly daratumumab and elotuzumab, are important advancements in MM treatment. Corticosteroid and mAb treatment approaches are vital to PFS and OS measurements, particularly for high-risk patient groups. Long-term corticosteroid treatments create health problems because they weaken the immune system and result in metabolic dysfunctions along with osteoporosis risks, which become particularly critical for senior patients. The therapeutic advantages of mAbs in cancer treatment come with financial burdens and infusion-related adverse effects that affect their availability, particularly in underserved healthcare settings. Future medical investigations need to assess mAbs' long-term effects and performance while studying how corticosteroids can be reduced in combination treatments and developing patient-specific indicators for therapeutic approaches. Further research can be explored by researching new treatment combinations that pair mAbs with bispecific antibodies or CAR T-cell approaches, as this could have a positive impact on patients’ outcomes since treatment with both has a potential synergy. Making mAbs affordable and accessible through biosimilars is key to enhancing MM treatment access to more patients. Research developments through the upcoming 5-10 years will modify MM treatment guidelines to create individualized therapy options that offer enhanced effectiveness and accessibility and aim to improve results for all persons receiving treatment.