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Multiple Myeloma (MM)

A hematologic malignancy characterized by the presence of abnormal clonal plasma cells in the bone marrow, producing monoclonal immunoglobulin.

Uncontrolled growth could cause hypercalcemia, renal insufficiency, anemia, and destructive bone lesions

It remains an incurable malignancy.
Prior to the development of B-cell maturation antigen (BCMA) targeting therapies, patients with triple-class refractory disease to an immunomodulatory drug (IMID), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb) had poor outcomes with a median overall survival (OS) between 6–12 months
Chimeric antigen receptor T-cell Therapies (CAR-T) and Bispecific T-cell engagers (BiTEs) are vital options in relapsed refractory multiple myeloma (rrMM)

Clin Lymphoma Myeloma Leuk. 2020 Jan;20(1):1–7.

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Bispecific T-Cell Engagers (BiTEs)

BiTE molecules are antibodies structured with two binding domains to link cancer cells to endogenous T-cells
Two targets in multiple myeloma (MM):

B-cell maturation antigen (BCMA): expressed on the surface of multiple myeloma cells, plasma cells, and plasma blasts
G protein-coupled receptor class C group 5 member D (GPRC5D): expressed primarily on malignant and nonmalignant plasma cells and hard keratinized healthy tissue (epithelial tissue of skin and tongue)

Three approved BiTEs in relapsed refractory multiple myeloma (rrMM):

Teclistamab-cqyv and Elranatamab-bcmm: BCMA
Talquetamab-tgvs: GPRC5D

Cancer. 2020;126(14):3192-3201.

Blood. 2024;143(13):1211-1217

CD: cluster of differentiation;

MHC: major histocompatibility complex

TCR: T-cell receptor

As you can see in this graph: a BiTE molecule is an antibody structured with 2 binding domains: the first domain recognizes tumor-expressed antigen on the cancer cell and the second domain recognizes CD3 on the T cells.

The BiTE molecule works by linking tumor-expressed antigens to endogenous T cells, which results in T-cell activation, the release of proinflammatory cytokines, and the lysis of antigen-expressing tumor cells.

In multiple myeloma, there are currently two targetable antigens: The first one is: B-cell maturation antigen or BCMA, which is expressed on the surface of multiple myeloma cells, plasma cells, and plasma blasts, And the second one is: G protein-coupled receptor class C group 5 member D or GPRC5D: which is primarily expressed on malignant and nonmalignant plasma cells and hard keratinized healthy tissue.

Both teclistamab and elranatamab target BCMA, while talquetamab targets GPRC5D

The binding domains are 2 single-chain variable fragment (scFv) regions from monoclonal antibodies, joined by a flexible peptide linker.

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Approved BiTEs in Relapsed/Refractory Multiple Myeloma (rrMM)

		Teclistamab-cqyv (MajesTEC-1)	Talquetamab-tgvs (MonumentTAL-1)	Elranatamab-bcmm (MagnetisMM-3)
Design – primary outcome		phase I/II single-arm, multicenter, open-label - objective response rate	phase I single-arm, multicenter, open-label - The frequency/type of dose-limiting toxicities	phase II single-arm, multicenter, open-label - objective response rate
Population		At least 3 prior therapies including IMID, PI, and anti-CD38 mAb	Prior lines of therapy including IMID and PI	Prior lines of therapy including IMID and PI, and anti-CD38 mAb
Recommended Phase II dose		Step-up over 1 week then 1.5 mg/kg weekly until progression/toxicity	Step-up over 1 week then 0.405 mg/kg weekly OR 0.8 mg/kg biweekly	Step-up over 1 week then 76 mg weekly for six 28-day cycles followed by biweekly in patients who maintained a PR for 2 months min
Demographics	Median age	64 (33-84)	64 (39–84)	68 (36–89)
	White (%)	81.2	82	58.5
	≥1 Extramedullary plasmacytoma (%)	17	32	31.7
	Median Tx lines	5 (2-14)	6 (3–20)	5 (2-22)
	High-risk cytogenetics(%)	25.7	16	25.2

N Engl J Med. 2022;387(6):495-505.

N Engl J Med. 2022;387(24):2232-2244

Nat Med. 2023;29(9):2259-2267

This table summarizes the three major studies that led to the approval of each BiTE agent as monotherapy treatment.

Now just to remind you, this table can NOT be used for a head-to-head comparison since these agents were not compared head to head.

So here we have, MajesTEC-1 trial for teclistamab, MonumenTAL-1 for talquetamab, and MagnetisMM-3 for elranatamab.

All of them had a single arm, multicenter, open label design.

Both MajesTEC-1 and MagnetisMM-3 trials evaluated the objective response rate as their primary outcome, while the MonumenTAL-1 evaluated the frequency and type of dose limiting toxicities, which is expected with the phase I nature of the study.

All trials included patients with refractory/relapsed multiple myeloma with prior lines of treatment.

when we look at the demographics, the median age was similar between all three trials, and closer to 65.

The majority of patient’s population were white in the MajestEC and Monumental trials.

We see more representation of an extramedullary plasmacytoma with Monumental and Magnetis trials when compared with the Majestic trial, and we can also observe slightly more patients with high-risk cytogenetics in the MajesTEC and Magnetis compared to the Monumental trial.

Study design: Dose escalating phase and dose expansion phase

High-risk cytogenetic profile (%): del(17p), t(4:14), t(14:16)

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Approved BiTEs in Relapsed/Refractory Multiple Myeloma (rrMM)

	Teclistamab-cqyv (MajesTEC-1)		Talquetamab-tgvs (MonumentTAL-1)		Elranatamab-bcmm (MagnetisMM-3)
Median follow-up (mo.)	14.1		11.7 (weekly) - 4.2 (biweekly)		14.7
Patients with response (%)	63% (43% CR or better)		Weekly: 70% (23% CR), Biweekly: 64% (23% CR)		61% (35% CR or better)
Median TtR (mo.)	1.2		0.9 (weekly) and 1.2 (biweekly)		1.2
Median DoR (mo.)	18.4		10.2 (weekly) and 7.8 (biweekly)		Not reached
	Any grade (%)	Grade 3-4 (%)	Any grade (%)	Grade 3-4 (%)	Any grade (%)	Grade 3-4 (%)
CRS	72.1	0.6	77 (weekly) and 80 (biweekly)	3 (weekly) and 0 (biweekly)	57.7	0
Neurotoxicity/ICANS	14.5	0.6	10 (weekly) and 5 (biweekly)	0	3.4	0
Anemia	52.1	37	60 (weekly) and 43 (biweekly)	30 (weekly) and 23 (biweekly)	48.8	37.4
Neutropenia	70.9	64.2	67 (weekly) and 36 (biweekly)	60 (weekly) and 32 (biweekly)	48.8	48.8
Thrombocytopenia	40	21.2	37 (weekly) and 23 (biweekly)	23 (weekly) and 11 (biweekly)	30.9	23.6
Lymphopenia	34.5	32.7	40 (weekly) and 39 (biweekly)	40 (weekly) and 39 (biweekly)	26.8	25.2
Infections	76.4	44.8	47 (weekly) and 34 (biweekly)	7 (weekly) and 7 (biweekly)	69.9	39.8
Significant to talquetamab	Weekly vs. biweekly: Skin related events (67% vs. 70%), nail related events (57% vs. 27%), dysgeusia (63% vs. 57%)- rarely grade 3-4

N Engl J Med. 2022;387(6):495-505.

N Engl J Med. 2022;387(24):2232-2244.

Nat Med. 2023;29(9):2259-2267.

When reviewing the results. The objective response rate with teclistamab was 63% compared to 61% with elranatamab. With talquetamab it was between 60-70% depending on the dosing scheme, however, again the Monumental study was a phase 1 study and it did not look at the objective response rate as a primary outcome.

The median time to response was 1.2 weeks with teclistamab, elranatamab, and biweekly talquetamab, And the duration of response varied between different studies.

Looking at the safety profile, CRS was more common with teclistamab and talquetamab than with elranatamab but it was mostly grade 1-2 across all three trials.

Neurotoxicity including ICANS had a slightly higher incidence in the teclistamab trial but was also mostly grade 1-2.

hematologic malignancies including anemia, neutropenia, thrombocytopenia, and lymphopenia were common with all three trials with significant presence of grades 3-4 toxicities across all of them.

As for infections, teclistamab and elranatamab were associated with a higher risk of infections compared to talquetamab and this is probably because BCMA-targeted therapies can lead to a substantial depletion of B lymphocytes and normal plasma cells, which increase the risk for infection

On the other hand since talquetamab targets GPRC5D which is expressed on normal keratinocytes, the incidence of oral, nail, and skin toxicities were significant with talqeutamab

In talquetamab study Among the 16 patients who received the doses recommended for a phase 2 study and who had had previous exposure to T-cell–redirecting B-cell maturation antigen (BCMA) directed bispecific antibodies or chimeric antigen receptor (CAR) T-cell therapies, 8 (50%) had a response.

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FDA Approvals

	Teclistamab-cqyv (Oct. 2022)	Talquetamab-tgvs (Aug. 2023)		Elranatamab-bcmm (Aug. 2023)
Premed	Dexamethasone 16 mg, diphenhydramine 50 mg and acetaminophen 650-1000 mg			Dexamethasone 20 mg, diphenhydramine 25 mg, acetaminophen 650-1000 mg
Step-up	0.06 mg/kg on D1, 0.3 mg/kg on D4, 1.5 mg/kg on D7 Step-up dose 2 and 1^st treatment (Tx) dose may be given between 2 to 4 days after last dose (up to 7 days)	Weekly	0.01 mg/kg on D1, 0.06 mg/kg on D4, 0.4 mg/kg on D7 Step-up dose 2 and 1^st Tx dose may be given between 2 to 4 days after last dose (up to 7 days)	12 mg on Day 1 and 32 mg on Day 4 (week 1), then 76 mg on Day 8 (week 2) A minimum of 2 days between step-up doses 1 and 2 (up to 14 days) A minimum of 3 days between step-up dose 2 and 1^st Tx dose (up to 14 days)
		Biweekly	0.01 mg/kg on D 1, 0.06 mg/kg on D4, 0.4 mg/kg on D7, 0.8 mg/kg on D10 Step-up dose 2 and 3 may be given between 2 to 4 days after last dose (up to 7 days) 1^st Tx dose may be administered 2-7 days after step-up dose 3
Weekly	1.5 mg/kg weekly until progression/toxicity	0.4 mg/kg weekly starting 1 week after 1^st Tx dose and until disease progression/unacceptable toxicity a minimum of 6 days between doses		76 mg weekly starting on week 3 through week 24 (23 TOTAL weekly doses) A minimum of 6 days between subsequent Tx doses (up to 42 days)
Biweekly	If CR or better is maintained for a minimum of 6 months, may decrease frequency to 1.5 mg/kg every two weeks until progression/toxicity	0.8 mg/kg every two weeks starting 2 weeks after 1^st Tx dose and until disease progression or unacceptable toxicity a minimum of 12 days between doses		- If PR or better is maintained for a minimum of 2 months, may decrease frequency to 76 mg every two weeks starting week 25 until disease progression or unacceptable toxicity

Tecvayli (teclistamab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; November 2024

Talvey (talquetamab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; August 2023.

Elrexfio (elranatamab) [prescribing information]. New York, NY: Pfizer Inc; August 2023.

REMS

All three agents are currently approved as monotherapy for the treatment of adult patients with r/r MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and anti-CD38 monoclonal antibody. And it’s important to note that all three agents are associated with black box warnings for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome leading to restricted procurement through Risk, evaluation, and mitigation strategy (REMS) program.

This table summarizes the approved dosing schemes for each of the bispecific antibodies. They all require premedications with dexamethasone, diphenhydramine, and acetaminophen prior to each dose of the step-up dosing regimen which also includes the first treatment dose.

Both teclistamab and eranatamab treatments are initiated with step up doses followed by a treatment dose weekly.

With teclistamab if the patient achieves and maintains a complete remission or better for 6 months then the treatment dose may be decreased in frequency to every two weeks until disease progression or unacceptable toxicity. With elranatamab on the over hand, a patient can transition their treatment dose to every two weeks if they achieve and maintain a partial response for a minimum of two months starting week 25 of treatment.

As for talquetamab, patient has the option to start with a weekly or a biweekly regimen from the beginning. The weekly schedule starts with 2 step-up doses followed by a treatment dose that continues weekly. The biweekly schedule starts with 3 step-up doses followed by a treatment dose that continues every 2 weeks until disease progression or unacceptable toxicity.

Now If you’re wondering about combining two agents together, there was a study published earlier this year in the new England journal of medicine which we will discuss in the next slide

Teclistamab:

pretreatment medications (PO or IV dex 16 mg, PO or IV diphenhydramine 50 mg), and acetaminophen (650-1000 mg) prior to each dose of the TECVAYLI step up dosing schedule (1^st THREE doses)
Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 48 hours after administration of all doses within the teclistamab step-up dosing schedule
If more than 7 days have passed from the last step-up dose 1 or 2 and up to 28 days (8-28 days) repeat THAT SAME dose level. If more than 28 days have passed repeat from the very beginning
If more than 28 days have passed from the last treatment dose but less than 56 days, repeat step up dose 2. if more than 56 days have passed repeat from the beginning
If more than 63 days have passed from the last biweekly treatment dose but less than 112 days, repeat step up dose 2. if more than 112 days have passed repeat from the beninnging
Consider initiation of antiviral prophylaxis to prevent herpes zoster reactivation per guideline prior to starting treatment with teclistamab

Talquetamab:

pretreatment medications (PO or IV dex 16 mg, PO or IV diphenhydramine 50 mg), and acetaminophen (650-1000 mg) prior to each dose of the talquetamab step up dosing schedule (1^st THREE doses in weekly schedule and 1^st FOUR doses in biweekly schedule)
Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 48 hours after administration of all doses within the talquetamab step-up dosing schedule
If more than 7 days have passed from the last step-up dose 1, 2, or 3 (in case of biweekly) and up to 28 days (8-28 days) repeat THAT SAME dose level. If more than 28 days have passed for step-up dose 1 and 2 repeat from the very beginning. If more than 28 days have passed for step up dose 3 (in case of biweekly) and up to 56 days (29-56) repeat step up dose 2. If more than 56 days have passed for step-up dose 3 (in case of biweekly) restart from the very beginning but consider permanent discontinuation.
If more than 28 days have passed from the last treatment dose but less than 56 days, repeat step up dose 2 (for weekly) or repeat step up dose 3 (for biweekly). if more than 56 days have passed repeat from the beginning but also consider permeant discontinuation.

Elranatamab:

pretreatment medications (PO or IV dex 20 mg, PO or IV diphenhydramine 25 mg), and acetaminophen (650-1000 mg) prior to each dose of the TECVAYLI step up dosing schedule (1^st THREE doses)
Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 48 hours after administration of the first step-up dose and for 24 hours after the administration of the second step-up dose
If more than 14 days have passed from step-up dose 1 repeat step-up dose 1
If more than 14 days have passed from step-up dose 2 and up to 28 days (15-28) repeat step-up dose 2. If more than 28 days have passed repeat from the very beginning
If more than 42 days have passed from the last treatment dose but less than 84 days (43-84), repeat step up dose 2. if more than 84 days have passed repeat from the beginning
Administer prophylactic antimicrobial and anti-viral medications according to current practice guidelines

REMS program requires pharmacies, providers, and healthcare settings to become certified by completing additional paperwork and training their relevant staff.

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Talquetamab & Teclistamab

phase I/II single-arm, multicenter, open-label trial

Of 94 patients with rrMM with at least 3 prior therapies (IMID, PI, & anti-CD38 mAb), 44 patients received the recommended phase 2 regimen

Talquetamab 0.01 mg/kg on Day 1, 0.06 mg/kg on Day 4, 0.4 mg/kg on Day 7, 0.8 mg/kg on Day 10 then biweekly

Teclistamab 0.06 mg/kg on Day 1, 0.3 mg/kg on Day 4, 1.5 mg/kg on Day 7, 3 mg/kg on Day 10 then biweekly

The primary outcomes: Adverse events and dose-limiting toxic effects

RedirecTT-1

BCMA & GPRC5D

N Engl J Med. 2025;392(2):138-149.

On the same day – 30 minutes apart

Premedication: dexamethasone, diphenhydramine, and acetaminophen

Could transition to monthly administration once partial response or better after cycle 4

RedirecTT-1 was a phase I/II single-arm, multicenter, open-label trial of talquetamab plus teclistamab in patients with relapsed or refractory multiple myeloma with at least 3 prior therapies, including an IMID, PI, and an anti-CD38 mAb.

In the phase 1 of the study, authors evaluated five dose levels in a dose-escalation study, and they selected Talquetamab at a dose of 0.8 mg per kilogram plus teclistamab at a dose of 3 mg per kilogram every other week as the recommended phase 2 regimen. The primary objective was to evaluate adverse events and dose-limiting toxicicities.

Step-up doses were adapted from schedules used with each monotherapy to mitigate severe cytokine release syndrome and were administered 2 to 4 days apart and before full treatment doses.

Both bispecific antibodies were administered on the same day, approximately 30 minutes apart, without specification of the order of administration. And Pretreatment was performed with dexamethasone, diphenhydramine, and acetaminophen prior to all step-up and first treatment dose

Patients could transition to monthly administration of both agents after the occurrence of a partial response or better after cycle 4.

Prophylactic medications were given for PJP and VZV and IVIG was given to maintain serum IgG above 400 mg/dL, regardless of active infection or history of infection.

Between December 9, 2020, and April 26, 2023

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Talquetamab & Teclistamab

Out of 94 enrolled patients with triple class rrMM, 44 patients received the recommended phase II regimen from that dose-escalation study

BCMA & GPRC5D

Demographics (n=44)	Phase II dose level
Median age	63 (41-80)
White (%)	73
≥1 Extramedullary plasmacytoma (%)	41
Median Tx lines	4 (2-10)
High-risk cytogenetics(%)	42

Median follow-up of 20.3 mon. (n=94)	Dose limiting toxicities
Oral herpes Grade 3	<Ph II dose
↑ LFTs, Grade 3	<Ph II dose
Thrombocytopenia, Grade 4	Ph II dose

Across all dosing levels:

93% cycle delays or dose modifications due to adverse events (AEs) primarily infections (68%)
16% discontinued one or both agents due to AEs
15% died due to AEs: pneumonia, adenovirus, COVID19, CMV pneumonia, sepsis, cardiac arrest, and respiratory failure

Efficacy and Safety
Median follow-up: 18.2 mo.
Patients with response (%)	80% (52% CR or better)
Median TtR (mo.)	1.4 (0.3-5.1)
Median follow-up: 20.3 mo.	Any grade (%)	Grade 3-4 (%)
Infections	89	64
CRS	79	2
Neurotoxicity/ICANS	3	1
Anemia	56	38
Neutropenia	73	68
Thrombocytopenia	43	30
Taste changes	65	0
Nonrash skin AEs	61	0
Nail-related AEs	52	0

N Engl J Med. 2025;392(2):138-149.

Out of 94 enrolled patients with triple class rrMM, 44 patients received the recommended phase II regimen.

Looking at the demographics: The median age of the patients was 63 and the majority of patients were white.

About 41% of patients had at least 1 extramedullary plasmacytoma and 42% had a high risk genetic profile, which is higher than what we saw in all previous trials.

Patients had received a median of four prior lines of therapy. Abd Of note, Seven patients had received bispecific antibodies and 4 had received CAR T-cell therapies. Patients had received previous therapy with a B-cell maturation antigen–directed bispecific antibody (alnuctamab in four patients, WVT078 in two, and teclistamab

Three patients had dose-limiting toxic effects which included grade 3 oral herpes, grade 3 elevated LFTs and a grade 4 thrombocytopenia.

In patients who received the recommended phase 2 dose level: a response occurred in 80% of patients with 52% of them achieving a complete response or better, and The median time to first response was 1.4 months

Across all dosing levels: infections of any grade occurred in 89% of patients, 64% of which was grade 3-4 and serious infection rate was higher than was seen in studies of each agent as monotherapy.

CRS occurred in 79% of patients but was mostly grade 1-2 and ICANs occurred in 3% of patients.

As for hematologic toxicities, anemia, neutropenia, and thrombocytopenia were all common

Oral, skin, and nail toxicities occurred in more than half of the patients, and the findings were consistent with the treatment profiles of the monotherapies.

Across all dosing levels: 93% had cycle delays or dose modifications that were due to adverse events, primarily infections .

Adverse events led to the discontinuation of one or both agents in 16% of patients. 7% of which were considered to be related to a study drug and in 5% was due to infections.

15% died because of adverse events, including pneumonia and adenovirus infection, and (Covid-19). aspiration pneumonia, cytomegalovirus-associated pneumonia, respiratory tract infection, sepsis, cardiac arrest, and respiratory failure.

Nonrash skin adverse events included skin exfoliation, dry skin, pruritus, and palmar–plantar erythrodysesthesia syndrome.

Taste changes (i.e., taste disorder, dysgeusia, hypogeusia, or ageusia)

Death with teclistamb: 41.2% died, with most attributed to progressive disease, while 11% of the total population died of adverse events (including >50% of COVID-19)

Death with talquetamab: 4% died (neuroendocrine carcinoma, sepsis and basilar-artery occlusion) none of the deaths were considered to be related to talquetamab.

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Bispecific T-Cell Engagers (BiTEs)

Common Toxicities

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Cytokine Release Syndrome (CRS)

A class effect of BiTE therapy resulting from the activation of T-cells and release of inflammatory cytokines
To limit the severity, BiTE therapy is initiated at subtherapeutic and gradually stepped up to the treatment dose and premedications are provided during step-up therapy.
Occurs at a median 2 days after treatment initiation.
Generally, presents with fever and constitutional symptoms such as fatigue, chills, headache. In more severe cases hypoxia, refractory hypotension, and organ toxicity.

Organ dysfunction might be secondary to hypotension or hypoxia but might also be due to the direct effects of cytokine release.

IFN-γ & IL-6

Tumor cell

T-cell

CD3

BiTE

Dendritic

cell

T-cell

Macrophage

T-cell

Blood. 2016 Sep 15;128(11):1533.

Lancet Oncol. 2023;24(6):e255-e269.

One of the good ones to start with is cytokine release syndrome or CRS. which is a systemic inflammatory response mediated by the activation of T lymphocytes, with dendritic cells and macrophages being the main source of cytokines such as IFN-γ and IL-6. IL-6 is the predominant cytokine most frequently elevated in patients with CRS, with high concentrations correlating with severe CRS.

To limit the severity of inflammatory toxicities, bispecific antibodies are initiated at subtherapeutic doses and are gradually “stepped up” to the treatment dose.

The vast majority of CRS events occur following step-up doses or the first treatment dose with a median of 2 days after the initial treatment administration

Patients generally present with fever and constitutional symptoms such as fatigue, chills, and headache. In more severe cases hypoxia, refractory hypotension, and organ toxicity. Organ dysfunction might be secondary to hypotension or hypoxia but might also be due to the direct effects of cytokine release.

Patients are commonly hospitalized during this step-up phase for roughly a week, depending on the antibody, during which CRS can be promptly detected and treated.

Dysfunction of all major organ systems, including the heart, lungs, liver, kidneys, and gastrointestinal tract, might be observed. Every effort should be made to prevent organ dysfunction, but when it does occur, it can often be reversible if symptoms are recognized and treated in a timely manner

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Cytokine Release Syndrome (CRS)

Grade (ASTCT 2019)	Symptoms	Teclistamab, Talquetamab, and Elranatamab
1	T ≥100.4°F (38°C)	Hold until CRS resolves. Provide premedication with the next dose
2	T ≥100.4°F + hypotension responsive to fluids and/or O2 requirement ≤6 L/min	Hold until CRS resolves. Provide premedication with the next dose and hospitalize x48hr with the administration of the next dose. Hospitalization is optional with elranatamab – remain within proximity of facility and daily monitoring x48 hr)
3	T ≥100.4°F + hypotension requiring ONE pressor and/or O2 requirement >6 L/min	Hold until CRS resolves. Provide premedication with the next dose and hospitalize x48hr with the administration of the next dose Provide supportive therapy, which may include intensive care level If prolonged or if it recurs: permanently discontinue
4	T ≥100.4°F + hypotension requiring MULTIPLE pressors and/or positive pressure O2 requirement	Permanently discontinue Provide supportive therapy, which may include intensive care level

Biol Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758

Tecvayli (teclistamab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; November 2024

Talvey (talquetamab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; August 2023.

Elrexfio (elranatamab) [prescribing information]. New York, NY: Pfizer Inc; August 2023.

The grading of CRS is based on the recommendations of the American Society for Transplantation and Cellular Therapy ASTCT from 2019. the package inserts for all three agents include the same CRS management.

Grade 1 usually presents with a temperature of at least 100.4 Fahrenheit and the recommendation is to hold until CRS is resolved which is usually fever free for at least 12 hours or 24 hours after a tocilizumab administration which we will talk more about in the next slide and also provide premedications prior to the next dose.

Grade 2 presents with hypotension responsive to fluids (usually 1-2 liters of fluids) OR hypoxia requiring low flow nasal cannula.

It’s good to mention that fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anticytokine therapy.

With grade 2, it is recommended to also hold until CRS resolves, provide predmedications prior to the next dose and also hospitalize patients for 48 hours following that next dose.

Grade 3 is when hypotension is refractory to IV fluids and requires one pressor OR if hypoxia is more severe. With grade 3, and in additional to the what’s recommended with grade 2, ICU level of care is recommended. And, if grade 3 recurs, that bispecific therapy should be permanently discontinued.

Grade 4 is when hypotension is requiring multiple pressors OR the hypoxia is requiring positive pressure support such as CPAP, BIPAP or mechanical ventilation. And at this point of CRS, it is recommended to permanently discontinue that bispecific agent

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Cytokine Release Syndrome (CRS)

Grade (ASTCT 2019)	Symptoms	Teclistamab, Talquetamab, and Elranatamab
1	T ≥100.4°F (38°C)	Supportive care including analgesics and antipyretics If fever is persistent, treat for neutropenic infections protocol Consider tocilizumab for persistent (>3 days) and refractory fever
2	T ≥100.4°F + hypotension responsive to fluids and/or O2 requirement ≤6 L/min	Intravenous fluid bolus to maintain SBP >90 mm Hg Administer tocilizumab early if persistent fever of ≥39°C, hypotension after two fluid boluses, or initiation of O2 supplementation. If persistent: add dexamethasone 10 mg IV Q6h
3	T ≥100.4°F + hypotension requiring ONE pressor and/or O2 requirement >6 L/min	Consider ICU care, initiate vasopressor and tocilizumab Continue with dexamethasone 10 mg and may increase to 20 mg If unresponsive, add anakinra 2 mg/kg daily for 3–5 days
4	T ≥100.4°F + hypotension requiring MULTIPLE pressors and/or positive pressure O2 requirement	ICU care, continue with vasopressors and tocilizumab High-dose methylprednisolone 1 g/day IV If condition is unresponsive, add anakinra or other alternative agents as appropriate

Biol Blood Marrow Transplant. 2019;25(4):625-638

Lancet Oncol. 2023;24(6):e255-e269.

Now in addition to what we discussed in the previous slide and to expand more outside the package insert recommendations. This table summarizes the recommendations by the consensus report of the European Myeloma Network for the management of CRS.

With grade 1: it is recommended to provide supportive care including analgesics and antipyretics such as acetaminophen, but if the fever persists, it’s recommended to treat with neutropenic infections protocol, so obtaining blood cultures and starting broad spectrum IV antibiotics. Tocilizumab could also be considered for persistent or refractory fever.

With grade 2: it’s recommended to provide intravenous fluids to maintain systolic blood pressure above 90 and the administration of tocilizumab could be considered early if persistent fever, hypotension after two fluid boluses, or if oxygen supplementation is initiated. Dexamethasone 10 mg every 6 hours is also an option in this scenario.

With grade 3: consider ICU level of care and initiate vasopressor along with tocilizumab. May also consider increasing dexamethasone dose and if unresponsive, may add anakinra

With grade 4 and in addition to what we would do with grade 3: we could add a high-dose methylprednisolone at 1 g per day and if unresponsive, could add anakinra or an alternative agent as appropriate. Examples include: anti-TNF antibodies such as infliximab, adalimumab, or a circulating receptor fusion protein such as etanercept. In addition, inhibitors of JAK–STAT signalling, such as ruxolitinib

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Neurotoxicity and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Neurotoxicity, including ICANS, is a disorder characterized by a pathological process affecting the central nervous system following BiTE therapy.
The exact underlying mechanisms is not fully known, but it involves the production of pro-inflammatory cytokines
Generally, presents with word-finding difficulties, confusion, and impairment of fine motor and cognitive skills. In more severe cases, cranial nerve palsy, Parkinson’s disease-like movement disorders, and seizures.
The Immune Effector Cell Encephalopathy score (ICE score) is a valuable instrument for monitoring ICANS

Orientation (oriented to year, month, city, hospital = 4 points)
Naming (name 3 objects, e.g., point to clock, pen, button = 3 points)
Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point)
Writing (ability to write a standard sentence = 1 point
Attention (count backwards from 100 by ten = 1 point)

Curr Hematol Malig Rep. 2024;19(6):237-245.

Biol Blood Marrow Transplant. 2019;25(4):625-638.

Now moving on to Neurotoxicity including ICANS, this is a disorder characterized by a pathological process affecting the CNS following bispecific therapy

The exact biological mechanisms underlying neurotoxicity are not fully understood, but similar to CRS, the production of pro-inflammatory cytokines, and the activation of immune cells such are thought to be responsible for the pathogenesis. As shown in this graph, The inflammatory cytokines diffuse into the bloodstream and eventually, lead to activation and disruption of endothelial cells, increased vascular permeability, and breakdown of the blood–brain barrier, with accumulation of cytokines in the CNS.

The Immune Effector Cell Encephalopathy score (ICE score) is a valuable instrument for monitoring ICANS, where patient is assessed by testing their orientation to time and place, their ability to name random objects in the room, following commands, writing tests, and attention.

Each one of these parameters is assigned to certain number of points which eventually assess the ICE score of 10

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Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Grade (ASTCT 2019)	Symptoms	Teclistamab, Talquetamab, and Elranatamab
1	ICE 7-9 OR awakens spontaneously	Hold until ICANS resolves. Consider a neuro consult/add seizure prophylaxis
2	ICE 3-6 OR awakens to voice	Hold until ICANS resolves. Consider a neuro consult add seizure prophylaxis dexamethasone 10 mg q6h until grade 1 then taper. Hospitalize x48hr with next dose (optional for elranatamab)
3	ICE 0 (with global aphasia)-2 OR awakens only to tactile stimulus OR seizures (resolves rapidly)	Hold until ICANS resolves. Consider a neuro consult add seizure prophylaxis dexamethasone 10 mg q6h until grade 1 then taper. Hospitalize x48hr with next dose Provide supportive therapy, which may include intensive care level If recurs: permanently discontinue
4	ICE 0 OR unarousable OR coma OR seizures (prolonged or repetitive without returning to baseline in between) OR symptomatic raised intracranial pressure	Permanently discontinue Consider a neuro consult add seizure prophylaxis dexamethasone 10 mg q6h until grade then taper (with elranatamab, consider MPD 1 g/d x 3days) Provide supportive therapy, which may include intensive care level

Tecvayli (teclistamab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; November 2024

Talvey (talquetamab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; August 2023.

Elrexfio (elranatamab) [prescribing information]. New York, NY: Pfizer Inc; August 2023.

The grading of ICANS is also based on the ASTCT recommendations from 2019. the package inserts for all three agents include similar management and the management is determined by the most severe event, not attributable to any other cause.

Grade 1 is when the ICE score is 7-9 OR patient awakens spontaneously. Here it is recommended to hold the bispecific agent until ICANS resolves and consider a neuro consult and adding seizure prophylaxis such as levetiracetam

Grade 2 is when ICE score is 3-6 OR patient awakens to voice. At this stage and in additional to above, it is recommended to add dexamethasone 10 mg q6h until improved to grade 1 and then start tapering.

Hospitalization after the next dose is recommended for 48 hours with teclistamab and talquetamab but it’s optional with elranatamab.

Gade 3 is when ICE score is 0-2 OR patient only awakens to tactile stilmui OR if they develop a seizure that rapidly resolves. At this stage and in addition to above, ICU level of care is recommended and hospitalization is required following the next dose with all three agents. However, It is recommended to permanently discontinue that bispecific agent if grade 3 recurs.

Grade 4 is when ICE score is 0, OR patient is unarousable, OR in the setting of prolonged or repetitive seizures without returning to baseline in between OR with symptomatic raised intracranial pressure, such as diffuse cerebral edema on neuroimaging, cranial nerve palsy, or papilledema. At this stage, and in addition to what we do for grade 3, it is recommended to permanently discontinue that agent. Also, elranatamab package insert recommends considering high dose methylprednisolone instead of dexamethasone.

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Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Grade (ASTCT 2019)	Symptoms	Teclistamab, Talquetamab, and Elranatamab
1	ICE 7-9 OR awakens spontaneously	Withhold oral food, medicine, fluid intake If patient is agitated, halperidol 0·5 mg or lorazepam 0·25–0·5 mg Q8h Consider early dexamethasone in patients at high risk MRI of brain, lumbar puncture, EEG
2	ICE 3-6 OR awakens to voice	Dexamethasone 10 mg, if persistent >48 hours: consider increasing to 20 mg Q6h or alternative agents such as tocilizumab or anakinra if concomitant CRS	Consider EEG and CT-MRI
3	ICE 0 (with global aphasia)-2 OR awakens only to tactile stimulus OR seizures (resolves rapidly)	Dexamethasone 10 mg, if persistent >24 hours: consider increasing to 20 mg Q6h or methylprednisolone (1–2 g/day), or anakinra Check CSF pressure; if increased use acetazolamide, mannitol, or hypertonic saline
4	ICE 0 OR unarousable OR coma OR seizures (prolonged or repetitive without returning to baseline in between) OR symptomatic raised intracranial pressure	Dexamethasone 20 mg Q6h, if persistent: methylprednisolone (2 mg/kg Q12h, if refractory: lymphodepletion with cyclophosphamide If CSF pressure >20 mm Hg, drain CSF to <20 mm Hg via Ommaya reservoir or cranial or lumbar catheter

Ludwig H, Terpos E, van de Donk N, et al. Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. Lancet Oncol. 2023;24(6):e255-e269. doi:10.1016/S1470-2045(23)00159-6

Now in addition to what we discussed in the previous slide and to again to expand more outside the package insert recommendations. This table summarizes the recommendations by the consensus report of the European Myeloma Network for the management of ICANS.

For grade 1: it’s recommended to hold oral food and medicine and switch to IV route if possible. early dexamethasone initiation could be considered in patient who are considered high risk including older age. MRI of the brain and a lumbar puncture could also be considered.

For Grade 2: may consider increasing dexamethasone dose to 20 mg every 6 hours if toxicity is persistent for greater than 48 hours or adding tocilizumab if CRS co-present.

For Grade 3: may consider increasing dexamethasone dose to 20 if toxicity persists for just longer than 24 hours or switching to a high dose methylprednisolone.

For Grade 4: we could start with dexamethasone 20 mg every 6 hours but with a very low threshold to switch to a higher dose, weight-based methylprednisolone, and if refractory, a lymphodepleting option such as cyclophosphamide may also be considered.

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Neurologic Toxicity (Excluding ICANS)

Grade (CTCAE 4.03)	Teclistamab-cqyv, Talquetamab-tgvs, and Elranatamab-bcmm
1	Hold until neurologic toxicity symptoms resolve
2 & 3 (1^st)	Hold until neurologic toxicity symptoms improve to grade 1 Provide supportive care
3 (2^nd) & 4	Permanently discontinue Provide supportive care, which may include intensive care

Tecvayli (teclistamab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; November 2024

Talvey (talquetamab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; August 2023.

Elrexfio (elranatamab) [prescribing information]. New York, NY: Pfizer Inc; August 2023.

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Cytopenia & Hypogammaglobulinemia

Cytopenia

Common complication of BiTEs. triggered by hematopoiesis impairment caused by the cytokines
Both supportive transfusions and bone marrow stimulating agents can be helpful
During the initial step-up period, granulocyte colony stimulating factors (G-CSF), should be avoided due to the high CRS risk.

Hypogammaglobulinemia

Particularly common with BCMA-targeted therapy
Prophylactic initiation of intravenous immunoglobulin (IVIG) 0.4 g/kg every 3–4 weeks with IgG level <400 mg/dL is recommended

For patients with markedly elevated paraprotein levels, IVIG should not be given until serum immunoglobulins are reduced

Treatment with IVIG might also be considered in patients with higher IgG concentrations and recurrent bacterial infections who do not respond to antibiotic therapy

Lancet Oncol. 2023;24(6):e255-e269.

Cytopenia and hypogammaglobulinemia!

Cytopenias are a common complication of bispecific antibody therapies and are triggered by hematopoiesis impairment caused by cytokines produced by the bone marrow

Both supportive transfusions and bone marrow stimulating agents can be helpful for the management.

However, it’s worth mentioning, that during the initial step-up period, granulocyte colony stimulating factors or G-CSF, should be avoided due to the high risk of CRS. And that’s because G-CSF promotes expansion of myeloid cells which can release IL-1, IL-6, and other inflammatory cytokines, increasing the risk for CRS.

Once patients are outside the step-up window, G-CSF can be employed in neutropenic patients.

Hypogammaglobulinaemia is also a common complication, particularly with BCMA-targeted therapies, because these therapies can lead to substantial depletion of B lymphocytes and normal plasma cells.

It’s worth mentioning, that for patients with markedly elevated paraprotein levels who may be at risk for hyperviscosity, IVIG should not be given until serum immunoglobulins are reduced with therapy.

Treatment with IVIG might also be considered in patients with higher IgG concentrations and recurrent bacterial infections who do not respond to antibiotic therapy because they might not be able to mount an adequate antibody response.

IVIG significantly reduces infection risk in patients receiving bispecific antibodies: In a 2022 study in patients treated with anti- BCMA BsAbs, immunoglobulin replacement resulted in an 80% reduction in grade 3 or worse infections compared with patients without this support
75% of low IgG concentrations (<500 mg/dL) was observed with anti-BCMA BiTe on repeated administration.

Consider use of ESAs for persistent Hgb < 10
Consider use of TPO-mimetics (thrombopoietic agents) for persistent high-grade thrombocytopenia.

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Infections

Risk factors:

Disease related: B-cell depletion, hypogammaglobulinaemia, and T-cell dysfunction.
Prior lines of therapy.
Treatment related: neutropaenia, lymphopaenia, T-cell exhaustion and hypogammaglobulinaemia,
CRS and immunosuppressive agents

	Viral	Bacterial	Fungal
Prevalence	46%	43%	11%
Onset	After 30 days	During neutropenia	After 30 days
Prophylaxis	Varicella zoster virus (VZV) and Herpes simplex virus (HSV)	High risk: history of recurrent bacterial infections, prolonged neutropenia, or hypogammaglobinemia	Candidiasis and Aspergillus: High risk: history of fungal infections, prolonged neutropenia, or glucocorticoid therapy Pneumocystis jirovecii (PJP): Standard of care in many protocols with BiTE and should be administered particularly in those with low CD4 counts (<200 cells per μL).

Clin Microbiol Infect. 2024;30(6):764-771.

Lancet Oncol. 2023;24(6):e255-e269.

Infections are common with BiTE therapies and the risk of acquiring infections in patients with bispecific agent is multifactorial.

First, multiple myeloma is associated with B-cell depletion, hypogammaglobulinaemia, and T-cell dysfunction.

Second, almost all patients who received BiTE therapies had already been treated with many prior lines of therapy, thereby increasing their susceptibility to infections.

Third, and as we saw in the previous trials, BiTE therapies are associated with significant neutropaenia, lymphopaenia, and hypogammaglobulinaemia, which can directly increase the risk of acquiring infections.

And finally, the development of CRS, which is treated with immunosuppressive agents.

As the table shows, Viral infections were the most common at 46%, followed by bacterial and then fungal infections.

After day 30, patients become more susceptible to reactivation of cytomegalovirus and varicella zoster virus, and they become more susceptible for infections with other viruses such as RSV and COVID-19, due to substantial lymphopenia and hypogammaglobulinaemia.

The risk of bacterial infections is mostly predominant during the first weeks of neutropenia.

Antiviral Prophylaxis is recommended against VZV and HSV with acyclovir or valacylcovir.

Fungal prophylaxis is only recommended in high risk patients, however PJP PPx has been the standard of care in many protocols with BiTEs and should be administer particulary in patients with low CD4 count.

Most infections occurred in the respiratory tract (58%), followed by urinary tract infections (15%), skin infections (15%), and gastrointestinal infections (8%). Cytomegalovirus reactivation was observed in 22%

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Special Considerations with related to GPRC5D bispecific antibodies

Oral toxicities: dysgeusia, xerostomia, and difficulty swallowing.

Saliva stimulating agents, steroid mouth washes, and referrals to nutritionists

Nail toxicities: brittle nails and separation of nails from the nailbed

wearing gloves when performing household tasks, regularly apply moisturizers to cuticles, and keep nails short and clean

Skin toxicities: xeroderma, pruritus, maculopapular rash, or palmar and plantar desquamation

Dry skin: Daily moisturizers that are petrolatum based
Palmar or plantar desquamation: Ammonium lactate 12% twice daily
Pruritic, maculopapular rashes: Antihistamines and topical steroids like triamcinolone 0.1% twice daily

J Dtsch Dermatol Ges. 2024;22(9):1282-1286.

Lancet Oncol. 2023;24(6):e255-e269.

As mentioned before, there are additional targeted toxicities observed with talquetamab due to the expression of GPRC5D on keratinocytes and they include oral, nail, and skin toxicities.

The oral toxicities related to GPRC5D bispecific antibodies include change in or loss of taste, dry mouth, and difficulty swallowing. The change in taste and dry mouth occur rapidly in almost all patients and which has been found to decrease oral health-related quality of life

Saliva stimulating agents, steroid mouth washes, and referrals to nutritionists are recommended to help mitigate these AEs.

Patients may also develop a number of nail toxicities, including brittle nails and separation of nails from the nailbed. All patients receiving talqeutamab should wear gloves when performing household tasks to minimize damage to nails, apply routine moisturizers to cuticles, and keep nails short and clean..

Skin toxicities are also common and may present as dry skin , pruritus, maculopapular rash, or palmar and plantar desquamation.

For dry skin, petrolatum-based moisturizers should be used daily.

For palmar or plantar desquamation, Ammonium lactate 12% should be used twice daily.

For Pruritic, maculopapular rashes, antihistamines and topical steroids like triamcinolone could be given.

A short course of oral methylprednisolone with a quick taper can be considered for more diffuse rashes Persistent rashes that fail to respond to these initial measures may warrant evaluation by a dermatologist with consideration of a skin biopsy.

Supportive care for grades 1-2. usually hold for grade 3

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