Differential Diagnosis and Therapeutic Advances in Multiple Myeloma: A Review Article

Figures & data

Table 1 Differential Diagnosis of MM

Disease	Incidence	Blood Findings	Bone Marrow Examination	Clinical Manifestation
MGUS^Citation1	1–2% of adults older than 50 years	M protein level< 3g/dl	<10% plasma cells	Absence of myeloma-defining conditions or myeloma-related organ or tissue damage
Smoldering (Asymptomatic MM)	5 to 7 in 1,000,000	M protein level≥3 g/dl	10 to 59% plasma cells on bone marrow biopsy	Absence of myeloma-defining conditions or myeloma-related organ or tissue damage Definition of smoldering multiple myeloma include serum monoclonal protein (IgG or IgA) ≥3 g/dl or urinary monoclonal protein ≥500 mg per 24 hours and/or clonal bone marrow plasma cells 10 to 59% with absence of myeloma defining events or amyloidosis
Symptomatic MM	5 to 7 in 1,000,000	M protein level≥3 g/dl	≥60% plasma cells on bone marrow biopsy	Presence of at least one myeloma-defining condition or myeloma-related organ or tissue damage Myeloma-related organ damage includes. Hypercalcemia (Calcium >1 mg/dl upper limit of normal or >11 mg/dl) Kidney injury creatinine >2 mg/dl or Creatinine clearance <40 mL/min per 1.73 m2 Anemia hemoglobin < 10 g/dl or >2 g/dl below lower normal limits 1 ≥ lytic lesion on imaging studies Myeloma defining condition Plasma cells ≥60% on bone marrow biopsy Ratio of involved-to-uninvolved serum light chain is ≥100 or involved protein level ≥10 mg/dl or higher >1 lytic lesion ≥5 mm on MRI^Citation2 Definition of multiple myeloma include clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the Myeloma-related organ damage
Waldenström macroglobulinemia	7 to 10 per 1,000,000	IgM paraprotein	Hypercellular bone marrow with plasma cells, lymphocytes, and lymphoplasmacytic	Vision changes, Epistaxis, retinal changes, and Neurological changes. Monoclonal gammopathy of an IgM should be present in serum irrespective of size.^Citation3 Bone marrow biopsy must demonstrate infiltration ≥10% by small lymphocytes that show plasmacytoid or plasma cell differentiation with intertrabecular pattern.^Citation4 Immunophenotype of infiltrates should be (IgM+, CD5-/+, CD10-, CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-) with plasmacytic component CD138+, CD38+ and CD45- or dim
Light-chain (AL) Amyloidosis	5 to 13 per 1,000,000	Immunoglobulin light chain	<10% plasma cells, Congo red staining on bone marrow biopsy or fat pad biopsy	Peripheral Neuropathy, Gastrointestinal symptoms, congestive heart failure
Plasmacytoma	Rare	N/A	Tumor positive for plasma cells, but bone marrow is negative for plasma cell neoplasms	Depending on up location Bone pain or compressive symptoms

Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; MRI, Magnetic resonance imaging.

Table 2 Risk Stratification of MGUS-Based Mayo Clinic Risk Models

Risk Factors	Risk Category	% of Patients	Risk of Progression at 20 Years After Diagnosis
Serum M-protein <15 gm/l, IgG subtype and FLC ratio 0.26–1.65	Low risk	39	5
Any one factor	Intermediate risk	37	21
Any two abnormal factors	High intermediate risk	20	37
All three abnormal factors	High risk	5	58

Note: Data from Rajkumar et al.¹⁹

Table 3 Various Risk Stratification Models of Smoldering Multiple Myeloma Progression

Risk Stratification Models of Smoldering Multiple Myeloma
Mayo 20/20/2 Score Model
Risk factors	Score
Bone marrow plasma cells >20%	1
M-protein> 2 g/dl	1
FLC ratio >20	1
Risk category	Progression Risk
0 - Low	10% at 2 years 23% at 5 years
1 - Intermediate	26% at 2 years 47% at 5 years
>2 - High	47% at 2 years 82% at 5 years
IMWG score model
Risk factors	Score
FLC ratio (involved to uninvolved)
0–10	0
>10–25	2
>25–40	3
>40	5
M-protein level (g/dl)
0–1.5	0
>1.5–3	3
>3	4
Bone marrow plasma cells in %
0–15	0
>15–20	2
>20–30	3
>30–40	5
>40	6
FISH t (4;14), t (14;16), +1q, del 13q, monosomy 13	2
Risk category	Progression Risk
0–4 – Low	4% at 2 years 20% at 5 years
5–8 – Low-intermediate	26% at 2 years 55% at 5 years
9–12 Intermediate	51% at 2 years 70% at 5 years
>12 – High	73% at 2 years 85% at 5 years
PETHEMA score model
Risk factors	Score
≥95% aberrant plasma cells in bone marrow by multiparameter flow cytometry	1
Presence of immunoparesis	1
Risk category (score)	Median TTP
0	NR
1	73 months
2	23 months

Table 4 Overview of Various Therapeutic Agents for Treatment of MM

Class	Target	Relevant Consideration	Effects on MM
Proteasome inhibitor (PI)
Bortezomib Carfilzomib Ixazomib	Proteasome	Peripheral Neuropathy Risk of Herpes zoster Dose adjustment in hepatic dysfunction Heart failure Hypertension Renal failure	Bortezomib stimulates osteoblast differentiation and inhibits osteoclast activation induced by RANKL. PI inhibits auto and paracrine signaling in MSCs. Pls decrease MM cell adhesion to BMSCs
Immunomodulator drugs (IMiD)
Thalidomide Lenalidomide Pomalidomide	CRBN	VTE prophylaxis Can interfere with stem cell mobilization. Risk of secondary malignancies Dose adjustment in renal dysfunction	T-cell co-stimulatory effects Anti-angiogenesis Anti-inflammatory effects Promotes anti-proliferative effects
Monoclonal antibodies
Daratumumab Isatuximab Elotuzumab	Daratumumab and Isatuximab acts as anti-CD38 Elotuzumab acts via SLAMF7.	Acute or delayed infusion reaction Herpes zoster and opportunistic infection Interfere with SPEP and Immunofixation It can interfere with crossing matching and antibody screening	Increases helper and cytotoxic T cell counts and memory T cells. Augment NK cell cytotoxicity Destroys CD+38 immune suppressor cells like Tregs and Bregs Elotuzumab Causes TAM activation Mediates ADCP Isatuximab Destruction of C38+ immunosuppressive cells like Tregs
Alkylating agents
Melphalan Cyclophosphamide	DNA fragmentation and damage	Myelosuppression Alopecia Mucositis
Nuclear export inhibitor
Selinexor	Exportin 1	GI toxicity Hyponatremia Neurological symptoms	Enhanced NK cell cytotoxicity and ADCC Decreases pro-survival signals from the bone marrow microenvironment
BiTE therapy
Teclistamab Talquetamab	Teclistamab BCMA X CD3 Talquetamab GPRC5D X CD3	CRS Neurotoxicity Serious infection Hepatoxicity	Teclistamab Bridging between myeloma cells and T cells causing cell death. Talquetamab Actively kills GPRC5 D positive myeloma cells.
CAR-T cell therapy
Idecabtagene Vicleucel	TNFRSF 17 (BCMA)	CRS Neurotoxicity Pancytopenia Prolonged hypogammaglobinemia	T cells are recruited and linked to antigen on myeloma cells and decrease BM induced immunosuppression.
Ciltacabtagene autoleucel	TNFRSF 17 (BCMA)		Reduces BCMA cell expression and BM induced immunosuppression
Corticosteroids
Dexamethasone Prednisone	Glucose response element (NF-kB)	Hyperglycemia Insomnia Fluid retention	Induces apoptosis of MM cells
Venetoclax	T (11, 14)	Infection Bladder pain	Restores process of apoptosis

Abbreviations: RANKL, Transmembrane molecule expressed by mesenchymal cell and lymphocyte; VTE, Venous thromboembolic; SLAMF7, Signaling lymphocytic activation molecule 7; SPEP, serum protein electrophoresis; TAM, Targeting Tyro3 Axl and Mer TK; ADCP, Antibody dependent cellular phagocytosis; GI, Gastrointestinal; CRS, Cytokine releasing syndrome; BM, Bone marrow; BCMA, B-cell maturation antigen; NF-Kb, nuclear factor kappa light-chain enhancer of activated B cells.

Figure 1 Mechanism of proteasome inhibitor action on multiple myeloma cells.

Table 5 Various Phase III Clinical Trials Showed Improved Outcomes with Autologous Stem Cell Transplantation

Clinical Trials/Study	Patients	Intervention	PFS	OS
Palumbo et al^Citation87	Total 273 ASCT group=141 Non-ASCT=132	RD 4 cycles followed by ASCT vs MPR 6 cycles Followed by maintenance with ±R	Median PFS 43 months vs 22.4 months p<0.001	4-year OS 81.6% vs 65.3% p=0.02
Cavo et al^Citation88	Total 1192 ASCT group=695 Non-ASCT=497	Induction therapy with bortezomib based regimen followed by ASCT vs VMP+VRD x 4 and maintenance with R	3-year PFS 64% vs 57% p=0.002	3-year OS: 85% in both groups
Attal et al^Citation89	Total 700 ASCT group=350 Non-ASCT=350	VRD 3 cycles followed ASCT vs VRD 5 cycles +Maintenance with R	Median PFS 50 months vs 36 months p<0.001	4-year OS 81% vs 82% p=0.87
Gay et al^Citation90	Total 256 ASCT group=127 Non-ASCT=129	RD 4 cycles followed by ASCT vs RCD 6 cycles Followed by maintenance with R	Median PFS 43.3 months vs 28.6 p<0.0001	4-Years OS 86% vs 73% p=0.004

Abbreviations: ASCT, autologous stem cell transplantation; PFS, progression free survival; OS, overall survival, RD, Lenalidomide-dexamethasone; MPR, melphalan-prednisone-Lenalidomide; VMP, bortezomib-melphalan-prednisone; VRD, bortezomib-Lenalidomide-dexamethasone.

Table 6 Different Bispecific Antibodies Targets Used in MM

BCMA	GPRC5D	FcRH5
Teclistimab (FDA approved)	Talquetamab (FDA approved)	Cevostamab
Erranatamab (FDA approved)
Linvoseltamab
Alnuctamab
ABBV-383 (TNB-383B)
Pavurutamab
Pacanalotamab (AMG 420)

Table 7 Summary of the Approved BCMA Bispecific Antibodies

Variable	Teclistamab	Elranatamab
No. of patients	165	123
Dosing per study	Every week until progression	Every week initially, after six cycles (for those with at least PR for 2 mo) dosing interval changed to every other week
Inclusion criteria of study (blood markers)	Platelets ≥50 ANC>1000 Hb>8	Platelets ≥25 ANC>1000 Hb>8
Age, median (range)	64 (33–84)	68 (36–89)
Penta drug exposure	70%	71%
Penta drug refractory	30%	42%
Median prior lines (range)	5 (2–14)	5 (2–22)
EMD % (definition was different)	17% (soft tissue plasmacytomas that were not associated with bone)	32% (extramedullary and/or paramedullary with a soft-tissue component)
Prior BCMA	No	No
ORR	63%	61%
PFS	11.3 months	NR (15-mo PFS:51%)
Median follow up	14.1 months	14.7 months
DOR	18.4 months	NR (15-mo DOR: 72%)
OS	18.3 months	NR (15-mo OS: 57%)
Infections	76%	70%
G III/IV infections	45%	40%
Death (%)	68 (41%)	55 (45%)
Death due to progression	41 (25%)	37 (30%)
CRS	72%	56%
G III CRS	1%	0%
Recurrent CRS	33%	15%

Abbreviations: PR, partial response; NR, not reached; CRS, cytokine release syndrome; OS, overall survival; ORR, overall response rate; BCMA, B cell maturation antigen; PFS, progression free survival; EMD, extramedullary disease.

Table 8 Ongoing Clinical Trials for CAR-T Cell Therapy

Clinical Trials/Study	Patients	Status	ORR (%)	Response	CRS of Any Grade (%)	Neurotoxicity (%)	Infection (%)	Reference
NCT03274219 (Bb21217)	72	Phase 1	69	28% sCR+CR; 58% > VGPR	75	15%	N/A	[133]
NCT04394650 (CC-98633-MM-001)	66	Phase 1	98.1	57.4% VGPR or better 29.6% CR or better	80	10.9%	N/A	[134]
NCT03070327 (MCARH17)	11	Phase 1	64	N/A	40	10	N/A	[135]
NCT04309981 (ARI0002h)	35	Phase 1	96.3	18.6% VGPR. 33.3 PR 44.4% sCR.	87	0	N/A	[136]
NCT04662099 (CS-1 BCMA)	16	Phase 1	81	VGPR 18.75%, PR 25%, 37.5%sCR	38	0	N/A	[137]
NCT03602612 (FHVH33)	25	Phase 1	92	sCR 72%	N/A	N/A	N/A	[138]
NCT 04318327 (PHE885)	31	Phase 1	100	CR 17%, VGPR33%, PR 50%	93.5	3.1	N/A	[139]

Figure 2 Mechanism of CAR T cell therapy in MM. It includes collection of T cells, multiplication and infusion to patient.

Notes: Adapted from Parikh RH, Lonial S. Chimeric antigen receptor T-cell therapy in multiple myeloma: A comprehensive review of current data and implications for clinical practice. CA. 2023;73(3):275–85. © 2023 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.¹⁴³

Table 9 Summary of Phase III Trials of CAR-T Cell Therapy in Multiple Myeloma

Variable	KarMMa-3	CARTITUDE-4
Number of patients	386	419
Median age (years)	63	61.5
Prior lines of therapy (median)	3	2
Triple class refractory	65%	14%
Refractory to anti-CD38	95%	24%
Median follow up (months)	18.6	15.9
ORR	71%	84.6%
PFS (median)	13.3 months	NR
12-months PFS	55%	75.9%

Table 10 Ongoing Trials of New Therapies for Multiple Myeloma

Drug	Target	Phase	Clinical Trial	Reference
MIK 665	BCL-2-Mcl-1 inhibitors	Phase 1	NCT04702425	[147]
PRT1419	Mcl-1 inhibitors	Phase 1	NCT04543305	[148]
AMG 176	Mcl-1 inhibitors	Phase 1	NCT02675452	[149]
Ibrutinib	BTK inhibitors	Phase 1	NCT03702725	[150]
Acalabrutinib	BTK inhibitors	Phase 1	NCT02211014	[151]
Anti-BCMA CAR-NK	NK cells	Phase 1	NCT03940833	[152]
Anti-BCMA CAR-NK	NK cells	Phase 1	NCT05008536	[153]

Kaseb H, Annamaraju P, Babiker HM. Monoclonal gammopathy of undetermined significance. In: StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC; 2022.

 Google Scholar

Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–48. doi:10.1016/S1470-2045(14)70442-5

 PubMed Web of Science ®Google Scholar

Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. doi:10.1182/blood-2016-01-643569

 PubMed Web of Science ®Google Scholar

Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. Diagnosis and management of Waldenstrom’s macroglobulinemia. J Clin Oncol. 2005;23(7):1564–1577. doi:10.1200/JCO.2005.03.144

 PubMed Web of Science ®Google Scholar

Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106(3):812–817. doi:10.1182/blood-2005-03-1038

 PubMed Web of Science ®Google Scholar

Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905. doi:10.1056/NEJMoa1402888

 PubMed Web of Science ®Google Scholar

Cavo M, Gay F, Beksac M, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020;7(6):e456–e68. doi:10.1016/S2352-3026(20)30099-5

 PubMed Web of Science ®Google Scholar

Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311–1320. doi:10.1056/NEJMoa1611750

 PubMed Web of Science ®Google Scholar

Gay F, Oliva S, Petrucci MT, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16(16):1617–1629. doi:10.1016/S1470-2045(15)00389-7

 PubMed Web of Science ®Google Scholar

Study of bb21217 in multiple myeloma; 2021.

 Google Scholar

bluebird bio. A Phase 1 Study of bb21217, an Anti-BCMA CAR T Cell Drug Product, in Relapsed and/or Refractory Multiple Myeloma [Internet]. clinicaltrials.gov; 2021 Mar [cited 2023 Sep 11]. Report No.: NCT03274219. Available from: https://clinicaltrials.gov/study/NCT03274219.

 Google Scholar

Juno Therapeutics, a Subsidiary of Celgene. A Phase I, Multi Center, Open Label Study of CC-98633, BCMA Targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed and/or Refractory Multiple Myeloma [Internet]. clinicaltrials.gov; 2023 Feb [cited 2023 Sep 11]. Report No.: NCT04394650. Available from: https://clinicaltrials.gov/study/NCT04394650.

 Google Scholar

clinicaltrial.gov. BCMA Targeted CAR T Cells With or Without Lenalidomide for the Treatment of Multiple Myeloma. NCT03070327; Available from: https://classic.clinicaltrials.gov/ct2/show/NCT03070327.

 Google Scholar

Latorre SV. Pilot Study of the Infusion of Differentiated Autologous T-cells From Peripheral Blood, Expanded and Transduced With a Lentivirus to Express a Chimeric Antigen Receptor With Anti-BCMA (TNFRSF17) Specificity Humanized Conjugated With the Co-stimulatory Region 4-1BB and Signal-transduction CD3z (ARI0002h) in Patients With Relapsed/Refractory Multiple Myeloma With Previous Treatment With Proteasome Inhibitor, Immunomodulatory Drug and Anti-CD38 Monoclonal Antibody [Internet]. clinicaltrials.gov; 2023 Aug [cited 2023 Sep 11]. Report No.: NCT04309981. Available from: https://clinicaltrials.gov/study/NCT04309981.

 Google Scholar

clinicaltrial.gov. T cells expressing a novel fully-human anti-BCMA CAR for treating multiple myeloma. NCT03602612; 2023.

 Google Scholar

clinicaltrial.gov. BCMA-directed CAR-T cell therapy in adult patients with multiple myeloma. NCT04318327; 2023.

 Google Scholar

Parikh RH, Lonial S. Chimeric antigen receptor T-cell therapy in multiple myeloma: a comprehensive review of current data and implications for clinical practice. CA. 2023;73(3):275–285. doi:10.3322/caac.21771

 Google Scholar

ClinicalTrials.gov. Novartis Pharmaceuticals. NCT04702425; 2023.

 Google Scholar

ClinicalTrials.gov. A study of PRT1419 in patients with relapsed/refractory hematologic malignancies. NCT04543305; 2023.

 Google Scholar

Caenepeel S, Brown SP, Belmontes B, et al. AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov. 2018;8(12):1582–1597. doi:10.1158/2159-8290.CD-18-0387

 PubMed Web of Science ®Google Scholar

Chari A, Cornell RF, Gasparetto C, et al. Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma. Hematol Oncol. 2020;38(3):353–362. doi:10.1002/hon.2723

 PubMed Web of Science ®Google Scholar

Von Suskil M, Sultana KN, Elbezanti WO, et al. Bruton’s tyrosine kinase targeting in multiple myeloma. Int J Mol Sci. 2021;22(11):5707. doi:10.3390/ijms22115707

 PubMed Web of Science ®Google Scholar

ClinicalTrials.gov. Clinical research of adoptive BCMA CAR-NK cells on relapse/refractory MM. NCT03940833; 2023.

 Google Scholar

ClinicalTrials.gov. Anti-BCMA CAR-NK cell therapy for the relapsed or refractory multiple myeloma. NCT05008536; 2023.

 Google Scholar