Updates on Multiple Myeloma: What’s New in Risk Stratification, Treatment, and Prognosis

Abstract

Multiple myeloma accounts for 10% of hematological malignancy and 1% of all cancer. It manifests with anemia, hypercalcemia, renal failure, and bone lesions, with the latter being the most common cause of morbidity. Over the last two decades, many advances were achieved in different aspects of the disease, including, but not limited to risk stratification and treatment approaches. With the approval of Chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma, the main effort in clinical trials is toward studying different CAR T-cell products in different combinations at different disease stages. Although more options are becoming available, more trials are needed to compare their efficacy and safety in the long-term, as well it is essential to consider side effects and quality of life, which will be more noticeable with patients’ lives long after the myeloma diagnosis. There continue to be several unmet needs for multiple myeloma patients, including extramedullary plasmacytoma, plasma cell leukemia, CNS myeloma, and high-risk/ultra-high-risk disease. These are extremely challenging and further randomized clinical trials are highly needed.

1. Introduction

Multiple myeloma (MM) is a clonal plasma cell disorder that accounts for 1% of all cancers and approximately 10% of all hematologic malignancies with slight male predominance and is twice as common in African-Americans compared with Caucasians [1]. Almost all MM patients evolve either from a pre-malignant monoclonal gammopathy of undetermined significance (MGUS) or from a smoldering MM (SMM). MGUS is asymptomatic with over 50% of individuals would have the condition for over 10 years prior to the clinical diagnosis [2]. The risk of MGUS progression to multiple myeloma is estimated to be at a rate of 1% per year [3, 4], while smoldering MM progresses to symptomatic MM at a rate of approximately 10% per year over the first 5 years following the diagnosis, 3% per year over the next 5 years, and 1.5% per year, thereafter mainly determined by the underlying cytogenetic status [5, 6].

Multiple myeloma continues to advance at a rapid pace; noticeably over the last decade, with the approval of several new exciting therapies (either upfront or at relapse). The treatment landscape of multiple myeloma is now switching toward the early introduction of intensive, multicombination therapy (quadruplet, pentaplex); with efforts to incorporate risk stratification in making the appropriate treatment decision. That said, the autologous stem cell transplant continues to be a major treatment step during the disease journey.

In this chapter, we will summarize the recent major advances in multiple myeloma diagnosis, risk assessment, and treatment strategy.

2. Diagnosis and risk stratification

2.1 Diagnosis and staging

In 2014, the international myeloma working group IMWG updated the diagnostic criteria of multiple myeloma by adding new biomarkers, with or without CRAB criteria. Clonal bone marrow plasma cells greater than or equal to 60%, difference between involved and uninvolved light chain more than or equal to 100, and/or more than one focal lesion on MRI [7]. Those new criteria have allowed clinicians to diagnose and treat multiple myeloma earlier, before end organs damage manifest. Whereas in 2015, the International Staging System (ISS) was incorporated with additional laboratory elements, including serum lactate dehydrogenase (LDH) and chromosomal abnormalities, detected by interphase fluorescent in situ hybridization, after CD138 plasma cell purification [8], this has added an extra prognostic strength compared to conventional ISS staging system. Despite these efforts, multiple myeloma remains a heterogeneous disease with unpredictable disease behavior.

2.2 Cytogenetic risk stratification

Several definitions for the high-risk disease have evolved over time, current approach mainly relies on cytogenetic and clinical biomarkers, including the International Staging System (ISS) group III, the presence of adverse translocations, and 17p deletion (del17) (Table 1). Several cytogenetic abnormalities were also identified to confer poor prognosis, including t(4;14), del(17/17p), t(14;16), t(14;20), non-hyperdiploid, and gain(1q) [8]. mSMART had proposed an additional risk category as having two or three of the high-risk genetic abnormalities would be labeled as double hit or triple hit multiple myeloma, respectively, which are associated with poorer outcomes [9].

Variables	Stage	Median OS
International Staging System (ISS); Serum albumin and β2m levels	I: β2m <3.5 mg/L and serum albumin ≥3.5 g/dL	62 months
	II: Neither Stage I nor Stage III	44 months
	III: β2m >5.5 mg/L	29 months
Revised International Staging System (R-ISS); Serum albumin, β2m, LDH levels, and plasma cell FISH	I: ISS Stage I, normal LDH, standard-risk disease by FISH	NR
	II: Neither Stage I nor Stage III	83 months
	III: ISS Stage III, and abnormal LDH or high-risk disease by FISH (del(17p) and/or t(4;14) and/or t(16;16))	43 months
mSMART risk stratification; Serum albumin, β2m, and LDH levels, plasma cell FISH, plasma cell proliferation index, gene expression profiling (GEP)	Standard risk: Trisomies, t(11;14), or t(6;14)	~8–10 years
	High risk: t(4;14), t(14;16), t(14;20), del (17p), TP53 mutation, or gain (1q) by FISH Double/ triple hit MM R-ISS Stage III High plasma cell S-phase High-risk signature in GEP	~3 years

Table 1.

Risk stratification by stage and CG (Am J Hematol. 2022;97: S3–S25).

Although patients with high-risk signatures on gene expression profiling (GEP) are considered to have high-risk myeloma, this test is not recommended on a routine basis.

Careful analysis of cytogenetic subgroups is essential; not only for patients’ risk stratification but also may signify a treatment target as some treatment appears to overcome the high-risk abnormalities. Bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p).

2.3 Disease biology

The clinical presentation and the disease biology have been identified to be an important factor impacting the patients’ prognosis. The most important markers of adverse prognosis include atypical bone marrow plasma cell immunophenotype, increased plasma cell proliferative rate, plasmablastic morphology, increased circulating plasma cells, and the presence of extramedullary involvement.

3. Plasma cell leukemia (PCL)

The original definition of PCL was established in 1974 by Kyle requiring both elements of circulating plasma cells of more than 20% and an absolute count greater than 2 × 10⁹/l plasma cells in peripheral blood [10]. Lately, patients who have a much lower number of circulating plasma cells were found to have a similar poor outcome. For this reason, plasma cell leukemia may now be considered when the patient with symptomatic multiple myeloma has 5% or more circulating plasma cells in peripheral blood smears [11].

Plasma cell leukemia carries a poor prognosis with a lack of durable response to treatment. A database analysis by Ramsingh et al., done between 1973 and 2004 included 291 patients with plasma cell leukemia with a median age of 67 years. The median overall survival (OS) was 4 months and the median disease-specific survival (DSS) was 6 months for patients with PCL, the 1-year, 2-year, and 5-year OS rates were 27.8, 14.1, and 6.4%, respectively [12]. Despite the advances in therapy, there is still a need for better therapeutic options for these patients who still have an extremely poor outcomes.

4. Plasma cell proliferative rate

The plasma cell proliferative index provides an insight into plasma cell biology in plasma cell disorders and is an important prognostic marker in both symptomatic and smoldering myeloma. It detects cells in the S-phase of the cell cycle using a slide technique or flow cytometry.

The magnitude of the proliferative component of malignant plasma cells is an important factor affecting survival. A retrospective analysis of 176 newly diagnosed MM patients, with a measurable plasma cell labeling index (PCLI) at diagnosis and repeat measurement 4 months after initiation of therapy, showed that patients achieving a greater PCLI response had improved median overall survival of 54 months compared with 29 months in nonresponders [13].

4.1 Plasmablastic morphology

MM patients harboring plasmablastic plasma cells have worse outcomes, they commonly present with unfavorable clinical features, such as high proliferation index, high percentage of plasma cell infiltration in the bone marrow, abnormal karyotype, and del(13q) detected by karyotyping, which indicates highly proliferative disease. Despite being an indicator of poor outcome, plasmablastic morphology is not correlated with the well-established adverse prognostic cytogenetics, identified by FISH, like t(4;14), t(14;16), and del(17p) [14].

4.2 Extramedullary disease

Extramedullay disease (EMD) in multiple myeloma can evolves at any time of disease course either accompanying newly diagnosed disease or with disease progression/relapse, and is associated with shorter OS and PFS. The majority of patients presenting with EMD have highly complex cytogenetic abnormalities, and found high-risk features on gene expression profiling (GEP). This was described by Usmani et al., who analyzed the clinical and biological features of extramedullary disease in 936 patients with MM [15]. Multivariate analysis with logistic regression revealed that extramedullary disease feature was more prevalent in patients with molecular subtypes that are more prone to relapse, which include the MF subtype (MAF subtype, associated with over-expression of the MAF gene seen with chromosome translocation 14:16 or 14:20) and the PR subtype (Proliferation subtype, associated with overexpression of pro-proliferative genes).

Based on a multicenter retrospective study by Avivi et al., including 127 patients diagnosed with MM between 2010 and 2018 [16], immunomodulators IMiDs might provide a higher response rate with achievement of ≥VGPR, which predicts longer survival. In multivariate analyses, failure to achieve ≥VGPR was the only significant factor for worse OS (HR = 9.87, CI 95% 2.35–39) P = 0.001.

5. Treatment of multiple myeloma

5.1 Treatment of Newly Diagnosed Multiple Myeloma (NDMM)

Over the last era, numerous therapy combinations had developed in NDMM with an encouraging impact on patients’ outcomes. These mainly include proteasome inhibitors, immunomodulators, monoclonal antibodies, and more recently anti-BCMA and CAR T-cell therapy.

The treatment approach for newly diagnosed multiple myeloma is based on two major factors: transplant eligibility and disease risk category. Whether autologous stem cell transplant is performed early or delayed till relapse is controversial.

Until recent, the standard induction therapy for newly diagnosed multiple myeloma was composed of triplet (doublet in some transplant-ineligible patients), this has now changed with a tendency toward four and even five drug regimens. Nevertheless, we have to take into account the adverse events affecting the patient’s quality of life and his/her preferences for continuous versus fixed treatment duration.

5.2 Transplant eligible patients

Bortezomib, lenalidomide, and dexamethasone (VRd) are the most widely used induction therapy; a randomized trial by the Intergroupe Francophone du Myelome found that the 4-year OS rate with VRd was >80% with or without early ASCT [17].

Daratumumab has been incorporated into frontline therapy based on two phases III randomized trials, the first one compared the addition of daratumumab to a standard induction regimen of bortezomib, thalidomide, and dexamethasone (VTd) versus bortezomib, thalidomide, and dexamethasone alone (CASSIOPEIA Study) [18]. Patients were randomly assigned in (1:1) to daratumumab plus VTd or to VTd alone. The regimens were given as four pretransplant induction and two post-transplant consolidation cycles. 39% of patients in the D-VTd group versus 26% in the VTd group achieved a complete response or better, and 64% versus 44% achieved minimal residual disease (MRD)-negativity (10⁻⁵ sensitivity threshold, assessed by multiparametric flow cytometry) both p < 0·0001. The addition of daratumumab was associated with significantly prolonged PFS (HR of 0.53 (95% CI, 0.42-0.68)), with a 47% reduction in the risk of disease progression or death with daratumumab.

The second trial is Griffin Study [19], which investigated bortezomib, lenalidomide, and dexamethasone (VRd) with or without daratumumab; patients were stratified by the International Staging System (ISS) disease stage (I, II, or III) and creatinine clearance (30-50 or .50 mL/min), and randomized in 1:1 to D-VRd or VRd induction (4 cycles), followed by autologous stem cell transplant ASCT. Consolidation with D-VRd or VRd was given in 60-100 days post-transplant (cycles 5 and 6) then patients went on maintenance with daratumumab plus lenalidomide or lenalidomide alone (cycles 7-32). At a median follow-up of 38.6 months, median PFS was not reached in both groups. MRD negativity was analyzed at the 12-month maintenance therapy cut-off in the intent-to-treat (ITT) population showed sustained MRD negativity (10⁻⁵) for ≥6 and ≥ 12 months in the ITT population treated with D-VRd was 37.5 and 28.8%, respectively. Conversely, the VRd-treated cohort had 7.8 and 2.9% sustained MRD negativity rates at ≥6 and ≥ 12 months. Among those with MRD negative status, the sustained MRD negativity rate lasting >12 months was 46.2% (D-VRd) versus 10.7% (VRd).

Based on the data above, daratumumab has been approved for frontline therapy in transplant-eligible newly diagnosed multiple myeloma, yet the use of quadruplet regimens has some limitations of extended duration and a higher cost of therapy. More data are needed to evaluate the OS of quadruplets in comparison to triplets, so till then it is recommended that quadrable regimens are given to selected patients with high-risk diseases.

6. Autologous stem cell transplantation ASCT

High-dose chemotherapy and stem cell transplant remain a vital treatment options either upfront or delayed to the time of the first relapse. The Intergroupe Francophone Du Myelome (IFM) group in France and the Medical Research Council (MRC) group in the United Kingdom, have demonstrated improved PFS and OS with ASCT compared to no ASCT [20, 21]. Although early ASCT is preferred, patients with standard risk disease can have this delayed till the disease relapse [22].

Melphalan 200 mg/m² (High-dose melphalan HDM) remains the standard conditioning regimen, given its high efficacy and safety profile. The use of melphalan 140 mg/m² (Mel140) has been studied and is considered an alternative option in selected patients who can not tolerate the higher dose. A report by the EBMT to assess the treatment outcomes for multiple myeloma patients who underwent ASCT by Mel200 vs Mel140 [23]. In patients who were in PR or less pretransplant, there was a significantly better OS with Mel200 compared to Mel140 (HR 0.39; 95% CI: 0.19, 0.82; P = 0.013), but no significant differences in PFS, CIR, or NRM.

In a phase II study published in Blood 2021, high-dose chemotherapy combining bendamustine, etoposide, cytarabine, and melphalan (BeEAM) was evaluated as a conditioning regimen [24]. With a median follow-up of 44 months, three-year OS and PFS were 92 and 57%, respectively. When compared to conventional Mel200, BeEAM conditioning offered no benefit to Mel200 in terms of OS, PFS, or risk of relapse/progression.

The addition of bortezomib to high-dose melphalan conditioning was assessed in a phase III trial; patients were enrolled either in the experimental arm of bortezomib (1 mg/m2 intravenously) given on days −6, –3, +1, and + 4 plus melphalan (200 mg/m2 IV) on the day –2, or to the control arm consisted of HDM alone (200 mg/m2 IV). There were no differences in the depth of response. The sCR/CR rates at day 60 post-transplant was 22.1% in bortezomib arm versus 20.5% in the control arm (P = 0.844), with no differences in undetectable minimum residual disease rates; 41.3% versus 39.4% (P = 0.864). Median progression-free survival was 34 months versus 29.6 months for bortezomib and HDM, respectively (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = 0.244) with an estimated 3-year overall survival of 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = 0.374) [25].

7. Consolidation therapy

The role of consolidation in multiple myeloma is controversial, different additional interventions in addition to ASCT were evaluated in a three-arm phase III clinical trial by BMT-CTN. The study compared tandem ASCT followed by lenalidomide maintenance, ASCT plus four VRd consolidation followed by lenalidomide maintenance, and ASCT with lenalidomide maintenance only [26]. Second ASCT or VRd consolidation did not improve PFS or OS, with a 38-month PFS rate of 58.5% for the tandem transplant arm, 57.8% for the consolidation arm, and 53.9% for ASCT with lenalidomide maintenance alone. The OS rates were 81.8, 85.4, and 83.7%, respectively.

8. Maintenance therapy

The role of maintenance therapy in post-transplant is well established with lenalidomide being the first and the ideal agent with proven PFS and OS benefits [27, 28]. McCarthy et al. conducted a meta-analysis on newly diagnosed multiple myeloma who underwent ASCT followed by lenalidomide maintenance [29]. At a median follow-up time of 79.5 months for all survivors, the median OS had not been reached for the lenalidomide maintenance group versus 86.0 months for the placebo or observation group (HR, 0.75; 95% CI, 0.63 to 0.90; P = .001). The median PFS was 52.8 months for the lenalidomide group and 23.5 months for the placebo or observation group (HR, 0.48; 95% CI, 0.41 to 0.55). Although lenalidomide is fairly well tolerated and convenient, there is a two-to-three-fold risk of secondary primary malignancies.

Bortezomib is the drug of choice in patients with high-risk multiple myeloma and can be given either alone or in combination with lenalidomide. In high-risk multiple myeloma, particularly del 17p, bortezomib is the preferred drug, either as a single agent or in combination with low-dose lenalidomide. HOVON-65/ GMMG-HD4 Trial evaluated the efficacy of bortezomib induction and maintenance in patients with NDMM. In the subset of patients presenting with increased creatinine of more than 2 mg/dl, bortezomib has significant superior outcome in both PFS and OS (13 versus 30 months; HR, 0.45; 95% CI, 0.26 to 0.78; P < .004) (21 v 54 months; HR, 0.33; 95% CI, 0.16 to 0.65; P < .001), respectively, in comparison to vincristine, doxorubicin, and dexamethasone (VAD)/thalidomide [30].

Combining lenalidomide with bortezomib as maintenance in high-risk patients was evaluated by Nooka et al. [31]. Lenalidomide was given at 10 mg/day on days 1–21 of a 28-day cycle in combination with bortezomib 1.3 mg/m² per week subcutaneously/intravenously and low-dose dexamethasone 40 mg per week orally. A total of 45 high-risk patients were evaluated, and the median PFS was 32 months.

There are ongoing trials involving other drug options for maintenance, either alone or in combination, results of these trials are waited for. Ixazomib maintenance was studied in phase 3, double-blind, placebo-controlled TOURMALINE-MM3 [32]. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or to placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and ASCT. Treatment consisted of 3 mg of ixazomib on days 1, 8, and 15 of a 28-day cycle with a dose escalation to 4 mg allowed after cycle 4. Maintenance therapy continued for up to 24 months (26 cycles). With a median follow-up of 31 months, ixazomib maintenance led to a 28% reduction in the risk of progression and death. The median PFS was 26.5 months with ixazomib compared with 21.3 months with placebo (HR, 0.72; 95% CI, 0.582-0.890; P = 0.002), no major toxicity required drug discontinuation.

9. Transplant non-eligible patients

Melphalan based regimens (such as bortezomib, melphalan, prednisone (VMP)/ melphalan,pPrednisone (MP)/ melphalan, prednisone, thalidomide (MPT)/melphalan, prednisone, lenalidomide (MPR)/ and melphalan, prednisone, thalidomide (VMPT)), were the standard of care in transplant-ineligible newly diagnosed multiple myeloma. Subsequently, the FIRST trial showed that lenalidomide–dexamethasone (Rd) given until disease progression was associated with a significant improvement in PFS with an overall survival benefit. Continuous lenalidomide–dexamethasone was superior to MPT for all secondary efficacy endpoints. OS at 4 years was 59% with continuous Rd, 56% with 18 cycles of Rd, and 51% with MPT, median OS was 10 months longer with continuous Rd versus MPT [33].

SWOG S0777 trial is a randomized phase III trial, that compared bortezomib, lenalidomide, and dexamethasone (VRd) with lenalidomide and dexamethasone only (Rd). Combining bortezomib with lenalidomide and dexamethasone showed a clinically significant PFS and OS. The median PFS was 41 months for VRd versus 29 months for Rd, with a median OS for VRd is still not reached compared to 69 months for Rd [34].

The substitution of bortezomib with another potent proteasome inhibitor carfilzomib is an option. The ENDURANCE trial is a multicenter open-label, phase 3, RCT evaluated NDMM who are ineligible/not intended for immediate ASCT to receive an induction of either carfilzomib/lenalidomide/dexamethasone (KRd) or bortezomib, lenalidomide and dexamethasone (VRd) [35]. After completion of the induction phase, patients went on second randomization to indefinite versus 2 years of lenalidomide maintenance. KRd did not show any PFS benefit over VRd, at an estimated median follow-up of 9 months from randomization, the median PFS was 34·6 months for KRd compared with 34·4 months for VRd (HR was 1·04 (95% CI 0·83–1·31, P = 0·74), with significantly higher cardiopulmonary and renal toxicity in the carfilzomib arm.

Daratumumab is a suitable alternative to bortezomib in this setting, it was approved as an upfront therapy in transplant-ineligible NDMM prior to its approval in transplant eligible cohort. A pivotal phase III MAIA trial by Thierry Facon and colleagues evaluated the combination of daratumumab with lenalidomide plus dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) alone [36]. More than 700 newly diagnosed transplant-ineligible patients were included in the study for a median follow-up of 56.2 months. The median PFS was not reached in the daratumumab group versus 34.4 months in the Rd group (HR = 0.53, 95% CI = 0.43–0.66, P < .0001). The estimated 5-year OS rate was 66.3% in D-Rd versus 53.1% in Rd group; the estimated 5-year PFS rate was 52.5 and 28.7%, respectively, and the ORR was 92.9 and 81.6%, respectively (P < 0.0001). The main disadvantage of DRd in contrast to Rd, is that the DRd has to be given until disease progression, which can be inconvenient to many patients, hopefully, the subcutaneous administration of daratumumab overcomes this limitation.

The quadrable regimen using daratumumab was also studied in transplant-ineligible NDMM; ALCYONE trial is an open-label randomized phase III trial, conducted on 706 transplant-ineligible patients to either receive daratumumab-VMP or VMP alone at (1:1) ratio [37]. The updated analysis with a median follow-up of 40.1 months revealed a median PFS of 36.4 months with D-VMP versus 19.3 months with VMP alone. The 3-year OS was 78.0% with D-VMP versus 67.9% with VMP alone (HR 0.60, 95% CI 0.46–0.80; P = 0.0003). Many patients sustained MRD⁻ status for >1 year, OR (95% CI) of 5.63 (2.80–11.31) P value <0.0001.

10. Treatment of Relapsed/Refractory Multiple Myeloma (NDMM)

The traditional approach to relapsing patients is determined by the type of previous treatment and the choice of therapy is impacted by factors related to the patient’s condition, prior treatment side effects, and disease risk stratification at relapse.

Salvage ASCT is a reasonable option for those who are candidates, the American and European Associations for Bone and Marrow Transplantation and international myeloma working group IMWG have reported that high dose chemotherapy and ASCT should be considered in any patient relapsing after initial therapy that included an ASCT with initial remission duration of >18 months [38]. However, with the wide use of maintenance therapy post-ASCT, salvage ASCT is recommended for patients who relapse after primary therapy that includes an ASCT followed by lenalidomide maintenance and had a remission duration of >36 months.

In patients who are not candidates for salvage ASCT, options include carfilzomib, ixazomib, elotuzomab, and isatuximab in combination with lenalidomide if this was not used in the first-line or if the patient is not refractory. Pomalidomide is the drug of choice in patients exposed/ refractory to lenalidomide, as well as daratumumab remains an option if it was not used as primary therapy.

Daratumumab in combination with pomalidomide and dexamethasone (DPd) was evaluated by Dimopoulos et al., in phase 3 clinical trial (APOLLO), over a median follow-up of 16.9 months, the addition of daratumumab showed improved PFS; 12·4 months in DPD arm versus 6·9 months in Pd arm; HR 0·63 (95% CI 0·47-0·85) [39].

Carfilzomib and daratumumab are both approved as single agents or in combination with other therapies for the treatment of RRMM, the use of both drugs plus dexamethasone given until disease progression; KdD versus KD was assessed in a multicenter phase 3 trial by Dimopoulos et al. (CANDOR) [40]. There was a deeper response observed in patients treated with KdD versus KD with a median PFS was not reached in the KdD group versus 15·8 months in the KD group (HR 0·63; 95% CI 0·46–0·85). In spite that the majority of patients included were bortezomib and/or lenalidomide refractory, only few patients were refractory to anti-CD38 monoclonal antibody. This may make the use of this combination limited to those who were not exposed to either drug.

Isatuximab is a monoclonal antibody that targets CD38, approved for relapsed or refractory multiple myeloma in combination with pomalidomide/dexamethasone and carfilzomib/dexamethasone [41, 42] with significant improved PFS. When isatuximab was combined with carfilzomib and dexamethasone, the median progression-free survival was not reached in the isatuximab group compared with 19·15 months in the carfilzomib and dexamethasone group (HR, 0·53; 99% CI 0·32–0·89; one-sided p = 0·0007). Whereas, combining isatuximab with pomalidomide and dexamethasone improved PFS by 5 months, and nearly reached 1 year (11·5 months versus 6·5 months).

Venetoclax is a potent oral BCL-2 inhibitor, that induces apoptosis in BCL-2 expressing myeloma cells. In a randomized, double-blind, multicenter, phase 3 BELLINI trial, venetoclax was combined with bortezomib and dexamethasone in patients who received one to three prior lines of therapy [43]. Although there was increased mortality in the venetoclax group (mostly because of an increased rate of infections), there was a PFS improvement by almost 11 months. This was more perceptible in patients with t(11;14) or high BCL2 expression, with a favorable benefit-risk profile.

While the approval of daratumumab as initial therapy has made enormous progress in newly diagnosed multiple myeloma patients, this has made the treatment of relapsing patients more challenging. With daratumumab being broadly used as primary therapy, the use of immunotherapies and cellular therapies in RRMM patients have become more recognized. Targeting B-cell maturation antigen (BCMA), which is almost exclusively expressed on clonal plasma cells, has been demonstrated to be highly effective.

On August 2020, belantamab mafodotin; a B-cell maturation antigen-targeting antibody-drug conjugate, was granted accelerated FDA approval after the impressive results of the DREAMM2 trial, which is a phase II, open-label, randomized 2-dose study in RRMM after an anti-CD38 therapy [44]. Patients included in the trials were heavily pretreated with a median of seven prior lines of therapy, they were randomized to receive belantamab single agent either 2.5 mg/kg or 3.4 mg/kg intravenously, once every 3 weeks until disease progression or unacceptable toxicity. Median estimated duration of response 11.0 months, OS 13.7 months, and PFS 2.8 months. Among patients with ≥ VGPR who were tested for minimal residual disease, 38% achieved MRD negativity at the 1 × 10⁻⁵ sensitivity level, 100% with sCR, 40% with CR, and 17% with VGPR [45]. The most common grade 3-4 adverse events were keratopathy that was reported in 27% of patients in the 2·5 mg/kg arm and 21% of patients in the 3·4 mg/kg arm. Two deaths were potentially treatment-related (one case of sepsis in the 2·5 mg/kg arm and one case of hemophagocytic lymphohistiocytosis in the 3·4 mg/kg arm). Currently, belantamab mafodotin is being tested in several trials as a combination with other anti-myeloma therapy and results are highly waited for.

CAR T-cell therapy offered a promising result to patients who are extremely refractory with a very poor prognosis. The first FDA- approved CAR T-cell therapy in multiple myeloma is idecabtagene vicleucel (bb2121). The approval was based on phase II clinical trial (KarMMa) [46]; 128 patients received ide-cel target doses of 150 × 10⁶ to 450 × 10⁶ CAR-positive (CAR+) T cells, and patients had a median of six prior regimens (range 3-16), with 84% being triple-class refractory. At a median 24.8-month follow-up, the median OS was 24.8 months, the ORR was 73%, and the PFS was 8.6 months. Cytokine release syndrome (CRS) was mostly low grade at 78%. Investigators reported grade 3 CRS in 4% and grade 4/5 in less than 1%, whereas, neurotoxicity (NT) of any grade was reported in 18% of patients, with five cases (4%) of grade 3 NT with no Grade 4/5 events.

Cilta-cel is the second FDA-approved CAR-T cell therapy for patients with RRMM, the FDA approval of cilta-cel was based on the data of pivotal phase 1b/phase 2 CARTITUDE-1 trial [47]. Ninety-seven patients with relapsed and/or refractory multiple myeloma were included in a single-arm study. At a median follow-up of 18 months, results showed an ORR of 98% (95% CI, 92.7-99.7) with a median duration of response of 21.8 months, and OS in all patients was 80.9%.

There are other targets being evaluated in multiple myeloma, including bispecific antibody, targeting BCMA x CD3 (teclistamab), bispecific IgG4 antibody binding GPCR5D CD3 receptors (talquetamab), FcRH5 (cevostamab) and GPRC₅D-targeted CAR T-cell therapy.

In a phase I/II trial teclistamab, an off-the-shelf BCMA x CD3 bispecific antibody has shown a deep and durable response with an ORR of 62% in triple class refractory MM [48]. Talquetamab is a first-in-class bispecific IgG4 antibody binding GPCR5D and CD3 receptors; the initial safety and tolerability data are promising with suggested ORR of 67–70% in triple- and penta-refractory MM [49].

11. Conclusion

Multiple myeloma patients’ survival has improved significantly with highly effective therapies being used as a primary treatment. The outcomes of the available novel therapies are still below the expectations in treating certain disease entities, such as high-risk/ultra-high-risk myeloma, especially when these occur in young individuals. Many clinical trials are ongoing testing different disease therapeutic targets, expectantly the results of these trials would make a better impact on patient’s outcome, however, the biggest hope remains to cure the disease in the future.