Vestibular symptoms after talquetamab therapy in heavily pretreated multiple myeloma

TO THE EDITOR:

Several therapeutic targets in multiple myeloma (MM) have emerged for T-cell engagers, including G protein–coupled receptor, class C, group 5, member D (GPRC5D). Talquetamab, a bispecific antibody against GPRC5D and CD3, was approved for the treatment of MM refractory to 4 prior lines of therapy in 2023.¹ The side effects of talquetamab include cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, and skin, nail, and oral toxicities thought to be related to on-target, off-tumor effects.² Talquetamab may have additional centrally acting effects associated with dizziness and ataxia. One series described 4 patients with heavily pretreated MM and prior anti–B-cell maturation antigen chimeric antigen receptor T-cell treatment. They developed dizziness (100%), diplopia (50%), dyskinesia (25%), truncal ataxia (25%), tremors (25%), or broad-based gait (25%) after starting talquetamab that improved or resolved after withdrawal; subsequent magnetic resonance imaging (MRI) results were normal or unchanged.³ The phase 1 clinical trial for MCARH109, an anti–GPRC5D chimeric antigen receptor T-cell therapy, included 2 of 17 patients who developed grade 3 cerebellar dysfunction, including vertigo, broad-based gait, saccades, and truncal ataxia with normal MRI results.⁴ We present 5 patients in our own clinic who have presented with similar symptoms (Table 1).

Table 1.

Side effect profiles in our 5 patients

Age (y)/sex	Vestibular symptoms			Known on-target, off-tumor effects
	At diagnosis	Before talquetamab	After talquetamab
69 F	None	None	Vertigo (G2)	Anorexia (G1), dysgeusia (G2), xerostomia (G2)
68/M	None∗	None	Blurred vision (G2), vertigo (G2)	Anorexia (G1), xeroderma (G1), xerostomia (G1)
67/F	None	None	Ataxia (G2), vertigo (G3)	None
61/M	None	None	Ataxia† (G3), blurred vision (G3), vertigo (G3)	None
74/M	None	None	Ataxia (G2), vertigo (G2)	None

The typical finding of ataxia and vertigo as reported by Janakiram et al³ was present in 3 of 5 patients. The remaining 2 of 5 had strong evidence of talquetamab’s on-target, off-tumor side effect profiles and new-onset vertigo.

F, female; G1, grade 1; ICANS, immune effector cell–associated neurotoxicity syndrome; M, male.

^∗This patient reported worsening peripheral neuropathy on talquetamab, which returned to baseline after dose reduction. His dizziness improved on dose reduction and recurred on rechallenge with full-dose talquetamab.

^†This patient was treated with high-dose steroids for presumed ICANS with temporary relief, but these symptoms recurred with future cycles of talquetamab.

Case 1 is a 69-year-old woman with relapsed, triple-exposed immunoglobulin A-λ (IgA-λ) plus free-λ MM. She was admitted for talquetamab step-up dosing, developed grade 1 CRS, and received tocilizumab. She started on talquetamab 0.8 mg every 2 weeks and with cycle 2 developed severe xerostomia, decreased appetite, and new-onset vertigo. Talquetamab was discontinued. MRI of the brain and spine disclosed bone marrow signal abnormalities of the calvaria reported as heterogeneous bone marrow signal intensity, skull base and upper cervical spine, and an extensive, compressive epidural tumor extending from C5 to T5. She underwent cerebrospinal fluid analysis obtained via lumbar puncture, which was negative for myeloma or meningoencephalitis. Her symptoms resolved upon withdrawal of talquetamab. The calvarial bone marrow signal intensity was unchanged on follow-up MRI after 3 months. She initiated therapy with the combination of elranatamab and pomalidomide and received radiotherapy. Her vertigo resolved 2 weeks after withdrawing talquetamab.

Case 2 is a 68-year-old man with penta-exposed IgG-λ MM. He was admitted for talquetamab step-up dosing with dexamethasone, developed grade 1 CRS, and received tocilizumab. With cycle 4, he developed xerostomia, xeroderma, anorexia, new-onset blurred vision, new-onset vertigo, and deterioration of his longstanding peripheral neuropathy. He was assessed by otolaryngology, ophthalmology, and neurology, and no obvious underlying etiology was established. His fundoscopy and otoscopy results were unremarkable. MRI of the brain and C-spine disclosed nonspecific heterogeneous marrow signals that were in the clivus and multifocal marrow replacement most prominent at C7. Because of limited treatment options, therapy was continued with dose adjustment to 0.4 mg/kg every 4 weeks (from 0.8 mg/kg every 2 weeks) with pomalidomide. His vertigo and blurred vision resolved, and his talquetamab dose was uptitrated back to 0.8 mg/kg every 4 weeks when he began to relapse, and his new-onset dizziness recurred while his longstanding peripheral neuropathy remained at its pretalquetamab baseline. He has begun physical therapy for postural stability.

Case 3 is a 67-year-old woman with penta-exposed free-λ MM. She was admitted for talquetamab step-up dosing, developed grade 1 CRS, and received tocilizumab. During her third cycle, she presented to the emergency department with 2 days of difficulty in walking, weakness, and new-onset vertigo. She underwent an MRI of the brain which did not reveal any acute intracranial disease. Her talquetamab dose was reduced from 0.8 mg/kg every 2 weeks to 0.4 mg/kg every 2 weeks with near-complete resolution of her symptoms. She has started taking meclizine as needed for her residual, episodic vertigo that does not limit her ambulation.

Case 4 is a 61-year-old man with triple-exposed IgA-κ MM with relapse with plasma cell leukemia. He was admitted for talquetamab step-up dosing, developed grade 1 CRS, and received tocilizumab. After completing the step-up dosing, he was discharged but presented to the emergency department after 2 weeks with 3 days of worsening new-onset vertigo, new-onset blurred vision, and severe ataxia that restricted his ambulation. He was initially thought to have delayed immune effector cell–associated neurotoxicity syndrome and improved with steroids, then proceeded with talquetamab. MRI of the brain was notable for areas of signal changes in marrow-containing structures. With cycle 4, his vertigo recurred; his talquetamab dose was reduced from 0.8 mg/kg every 2 weeks to 0.4 mg/kg every 4 weeks, and his symptoms improved.

Case 5 is a 74-year-old woman with penta-exposed free-λ MM. During her bridging to idecabtagene vicleucel, she received 3 doses of talquetamab step-up dosing. She achieved complete remission with resolution of her vertigo but had progression of disease after 11 months and was admitted for talquetamab step-up dosing, developed grade 1 CRS, and received tocilizumab. Her MM was refractory to talquetamab, so pomalidomide was added with initiation of cycle 2. She achieved partial remission, but with cycle 7 developed vertigo, new-onset weakness, and ataxia, and her talquetamab was held. She was hospitalized for an unwitnessed fall, and MRI result was negative for acute intracranial pathology, although a new 4-mm extra-axial mass along the left side of the falx was identified without edema or mass effect. Her vertigo and weakness have improved, but she remains ataxic and engages with physical therapy for postural stability. She remains off treatment having achieved partial chemical response.

It is unclear why this constellation of vertiginous and ataxic symptoms appears in a small subset of patients receiving talquetamab, but other side effects are thought to be related to on-target, off-tumor effects. Expression of GPRC5D mRNA is low or absent in most tissues,5, 6, 7 and in murine models, GPRC5B (rather than GPRC5D) appears to be much more highly expressed in pontine nuclei^8,9 (supplemental Table 1). Most patients, including those in prior case series, received prior anti–B-cell maturation antigen therapy including ciltacabtagene autoleucel; in our assessment, this is not likely to be associated with vestibular toxicity due to the talquetamab dose-dependent effects that improved on withdrawal that we observed. These patients were monitored over multiple lines of therapy and did not have preexisting or myeloma-related vestibular symptoms before starting talquetamab (supplemental Table 2). We also considered whether these symptoms could be paraneoplastic, because truncal ataxia can be a rare presenting symptom of Lambert-Eaton myasthenic syndrome, itself rarely associated with MM.^10,11 However, none of our patients developed any other characteristic symptoms of Lambert-Eaton myasthenic syndrome or any other paraneoplastic disorder.

We found that de-escalation of therapy can lead to improvement of vestibular symptoms and in some instances can also result in complete resolution (Table 2). Case 2 was particularly interesting as his now-onset dizziness recurred when rechallenged with full-dose talquetamab. Dose reduction or cessation was an individual decision made with each patient. One patient received meclizine; none received steroids or IV immunoglobulin, which could be considered for symptomatic relief in the absence of viable alternatives. We reviewed our treatment population and estimated an incidence of 15% to 20% on talquetamab monotherapy, but as case 5 suggests, it can take several cycles to become evident, and follow-up is needed to uncover the true incidence.

Table 2.

Each of our 5 patients reported symptom improvement, including vestibular symptom improvement, with either dose reduction, frequency reduction, or withdrawal of talquetamab therapy

Age (y)/sex	CAR-T	Initial dose (all q14d), mg/kg	Total dose, mg/kg	Dose adjusted	Outcome	Time to onset, wk	Time to attenuation, wk
69/F	No	0.8	2.07	Stopped	Resolved	4	2
68/M	BCMA	0.8	6.07	Reduced	Improved	16	2∗
67/F	BCMA	0.8	2.87	Reduced	Improved	12	2
61/M	No	0.8	4.47	Reduced	Improved	2	4
74/M	BCMA	0.8	10.87	Stopped	Improved	28	8†

We posit that this is related to centrally acting on-target, off-tumor effects. “Time to onset” was the time between the first talquetamab dose and the first vestibular symptoms. “Time to attenuation” was the time between the last talquetamab dose or reduction of talquetamab dose and resolution or improvement of vestibular symptoms.

BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T cells; F, female; ICANS, immune effector cell–associated neurotoxicity syndrome; M, male; q14d, every 14 days.

^∗This patient had longstanding peripheral neuropathy and reported on clinic visit 2 weeks after reducing his talquetamab dose that his symptoms felt at baseline without the new-onset dizziness he had reported on the higher dose.

^†This patient experienced ataxia, blurred vision, and vertigo, which improved with steroids for what was thought to be ICANS, recurred with further talquetamab, and improved after dose reduction.

Conflict-of-interest disclosure: D.S. reports honoraria from GSK, Bristol Myers Squibb (BMS), Takeda, Janssen, and Merck; speakers bureau participation for GSK and BMS; current equity holdings in private company and stock options in a privately held company COTA Healthcare; and membership on board of directors or advisory committees for Celularity. N.B. reports consultancy for, and research funding from, Amgen, Janssen, Karyopharm, Merck, BMS, and Sanofi. H.P. reports consultancy for, and honoraria from, Janssen. The remaining authors declare no competing financial interests.