Introduction
The introduction of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies has changed the treatment paradigm of multiple myeloma. With the advent of these new therapeutic options, life expectancy has substantially increased for myeloma patients which has led to an increased number of patients with triple-class refractory disease. Also, a large majority of these patients are elderly with poor tolerability to conventional chemotherapy and multiple comorbidities. Thus, there remains an unmet need for effective novel therapies with good tolerability and safety profile. CARTs and anti-BCMA bispecific antibodies are the most recent additions to the myeloma landscape. Elranatamab is the most used bispecific in the Indian setting. However, it has only been used on a clinical trial basis, and real-world data especially in the Indian setting is missing. Here, we present our experience with three cases of multi relapsed/refractory multiple myeloma on elranatamab monotherapy.
Case 1
We present the case of a 63 years old diabetic male diagnosed with multiple myeloma (IgG lambda type, R-ISS:II) with 13q del in February 2020 and received VTD regimen. He underwent an autologous stem cell transplant in December 2020 followed by thalidomide maintenance therapy. He relapsed in December 2021 and was started on carfilzomib-based salvage therapy. The patient responded initially followed by biochemical relapse, following which he was started on daratumumab based regimen in September 2022. The patient received 7 cycles of daratumumab based regimen in total followed by relapse (Serum free light chain assay (SFLC)−5.5/78.8–0.07, Serum protein electrophoresis (SPEP)−0.3 gm/dl). Bone marrow aspirate showed 60% plasma cells suggestive of frank relapse.
Given triple refractory disease, the patient was started on elranatamab monotherapy on 22 August 2023. Baseline IgG levels, cytomegalovirus (CMV) serostatus, and viral markers were checked. Given baseline hypogammaglobulinemia (S.IgG-282 mg/dl), the patient was given intravenous immunoglobulin (IVIG) infusion before the first dose of elranatamab and it was checked every 3 weeks (half life of IVIG is 14–21days) in view of high risk of infections in the treated population. The patient experienced Grade I CRS which was managed with supportive care. The patient experienced grade III thrombocytopenia and grade IV neutropenia after the first dose around day 4 following which counts recovered spontaneously. There was no recurrence of Grade III-IV cytopenias. There was no neurotoxicity observed. Post cycle 1, SPEP showed no M spike with monoclonal band detected on immunofixation electrophoresis and the SFLC ratio normalized (1.29/1.58–0.816) suggestive of a very good partial response (urine M-protein was not evaluated). The patient was started on cycle 2 however only two doses could be given due to CMV reactivation (CMV PCR-5594 copies), he was started on gancyclovir therapy. Post cycle 2, despite treatment interruption, the patient maintained his VGPR status (M spike not detected, SFLC ratio −1.10/<2.98). He is currently on his third cycle and is tolerating treatment well.
Case 2
This is a case of a female in her 60 s with no previous co-morbidities diagnosed with multiple myeloma (IgG Lambda type, ISS II, R-ISS II) in 2015. At baseline, the patient had extramedullary disease with a vertebral mass causing extradural compression of the spinal cord and cauda equina nerve roots at L1-L3 vertebral level requiring kyphoplasty and radiotherapy to the spine. The FISH analysis didn't show any high-risk cytogenetic abnormalities. She received VTD regimen and underwent an autologous stem cell transplant in September 2015. She was on oral thalidomide maintenance till Feb 18 to which she was intolerant, hence she was shifted to lenalidomide maintenance following which she again relapsed in Feb 2019. She received carfilzomib-based salvage therapy (KPD), followed by pomalidomide maintenance. She again relapsed in March 2022 and received daratumumab –based (D-KCd) salvage therapy. She received 6 cycles of daratumumab based salvage therapy and again relapsed in July 23(M-spike-1.97 gm/dl, k/l-25/531–0.04). The patient was also on anti-tubercular therapy for disseminated tuberculosis since March 2023.
Given triple-class refractory disease, she was started on elranatamab monotherapy in August 2023. Baseline CMV serostatus and IgG levels were checked which were followed serially. The patient experienced grade II CRS (ASTCT grading) [ 1 ] which was managed with IV fluids and supportive care. There was no neurotoxicity observed. There were no cytopenias leading to treatment delay. Post first cycle, disease evaluation was done which showed an M spike of 2.20 gm/dl and an SFLC ratio of 1.85/392.61–0.005. Although there was a reduction in lambda light chain levels, M-spike had marginally increased which was contrary to the expected results. It could also be explained by the fact that all bispecifics are humanized IgG4 monoclonal antibodies, that can be detected on protein electrophoresis which might have led to a marginal increase in M protein levels. Only two doses could be given during cycle 2 due to respiratory syncytial virus (RSV) URI and ATT-induced hepatitis. Post cycle 2, M-spike was 2.02 gm/dl and the SFLC ratio was <2.3/102.5 suggestive of marginal response (MR). The patient is currently receiving cycle 3 and tolerating it well. She did not experience any CMV reactivation.
Case 3
The patient is a male in his 40 s with no previous comorbidities, diagnosed with multiple myeloma (IgG kappa type, ISS-III, RISS-III) in September 2015. Bone marrow aspirate showed 75% plasma cells. He received VTD regimen, however, the patient had progressive disease, so he was started on cyclophosphamide based (CRd) regimen followed by an autologous stem cell transplant in Feb 2016. He was on bortezomib-lenalidomide maintenance after the transplant. He relapsed in December 2022 and received daratumumab-based salvage (D-KPD) therapy(patient was unwilling for second transplant at this time), however had clinical progression with a right femoral plasmacytoma requiring a surgical intervention in March 2023.
The patient was started on elranatamab monotherapy in March 2023. Baseline investigations showed an SFLC ratio of 0.3 (kappa/lambda:4.5/14.8) with undetectable M-spike. Whole body PET-CT showed multiple FDG avid lytic lesions in the axial and appendicular skeleton. Post cycle 1, the patient had an M-spike of 0.4 gm/dl and an SFLC ratio of 0.96 (kappa/lambda: 1.49/1.54). The patient was started on cycle 2, however could receive only two doses due to CMV reactivation with colitis. Post cycle 2, SPEP showed no M spike with a monoclonal band detected on serum immunofixation electrophoresis and the SFLC ratio was normal (31/05/23) s/o VGPR. The patient again experienced CMV reactivation in June 2023 which was managed with IV gancyclovir. Given recurrent CMV reactivation, the patient was started on oral valgancyclovir prophylaxis and continued on elranatamab monotherapy. The patient also had hypogammaglobulinemia which was managed with IVIG replacement. The patient did not experience any cytopenias or neurotoxicity till cycle 6. The patient is currently receiving the 7th cycle.
After a week of the first dose of cycle 7, the patient presented with left-sided lower motor neuron type facial palsy with a prior history of viral upper respiratory tract infection 2–3 days ago. MRI (magnetic resonance imaging) brain did not show any significant intracranial abnormality. Cerebrospinal fluid analysis showed occasional mature leucocytes with a WBC count of 2–3/cumm with normal glucose and protein levels. Multiplex PCR panel for meningitis was negative. Blood cytomegalovirus (CMV) PCR showed 2401 copies/ml. He was started on intravenous gancyclovir therapy. However, there was no improvement, the patient developed intermittent spikes of high-grade fever and left-sided focal seizures with hemiplegia. Given the high suspicion of viral encephalitis, a repeat MRI brain and cerebrospinal fluid analysis was performed which was normal. Repeat meningitis multiplex PCR panel was also negative. In view of negative MRI and cerebrospinal fluid findings for any infective etiology, diagnosis of grade IV ICANS (immune cell effector associated neurotoxicity syndrome) vs drug-induced encephalopathy was opined. In view of poor GCS (Glasgow coma scale) and imminent risk of aspiration pneumonitis, endotracheal intubation was performed and patient was put on mechanical ventilation. The patient was initiated on dexamethasone and anakinra based treatment, however, there was progressive deterioration and he continued to have seizures despite >3 anti-epileptics. Despite all efforts, there was no improvement and the patient ultimately succumbed to it.
Discussion
B-cell maturation antigen is highly expressed on mature B cells and is critical for the survival and proliferation of plasma cells. It has emerged as a novel target for anti-myeloma therapies in the form of bispecific cell engagers (Teclistamab,Elranatamab), antibody-drug conjugates (Belantamab mafodotin), and chimeric antigen receptor (CAR) T-cell therapies (Ide-cel,Cilta-cel). Elranatamab is one such BCMA targeting T-cell engager bi-specific antibody that received accelerated FDA approval for the treatment of relapsed/refractory multiple myeloma who have received at least four prior lines of therapy including a proteasome inhibitor, immunomodulatory agent, and monoclonal antibody. The phase II MagnetisMM-3 trial showed a promising efficacy with an ORR of 61% with a CR rate of >35%. With a median follow-up of 14.7 months, the median PFS was not reached and the 15-month PFS rate was 50.9% [ 2 ].
Cytokine release syndrome was observed in 56.3% of patients on step-up dose with all events being grade 1 or 2. No grade 3 or higher events were reported in the trial. Similarly, two of our patients experienced (Case 1&2) CRS which was grade I and II, respectively with no grade 3 or 4 events. The median time to onset of CRS was reported 2 days of which 98.8% events occurred during the first three doses. Case1 & 2 also experienced grade I-II CRS events within 2 days of the first step-up dose while later doses were tolerated well. 15.1% of patients were reported to have more than 1 CRS event while none of our patients experienced more than one event. Tocilizumab and corticosteroids were not used in both our patients, they responded well to supportive care. ICANS grade 1 or 2 was observed in 3.4% of patients while none of our patients experienced neurotoxicity at the onset.
The incidence of infectious complications was reported to be around 69.9% of which COVID-19-related infection was the most common coinciding with the ongoing pandemic. In our experience, two of the patients experienced CMV reactivation(cases 1&3) and one had RSV URI (case 2). Also, one patient (case 3) had recurrent episodes of CMV reactivation with colitis leading to treatment interruption and delay, therefore he was kept on oral valgancyclovir prophylaxis. The increased risk of viral infections or reactivations is well explained by the T cell engager activity which depletes the T cell repertoire and adds to the already existing myeloma-induced immunosuppression.
Only one of our patients (case 1) experienced neutropenia during the first cycle which recovered spontaneously not requiring G-CSF support or treatment interruption. This is a major advantage in comparison to the currently approved treatments which cause cytopenias further increasing the risk of infectious complications [ 3 ].
All three of our patients had an ECOG performance status of 1 or 2 with none of them having high-risk cytogenetics. Case 3 had extramedullary disease in the form of a right thigh mass (biopsy-proven plasmacytoma with plasmablastic features) at relapse, requiring surgical intervention. All three of our patients had triple-class refractory disease. Two of our patients had a very good partial response to elranatamab monotherapy while one had a partial response. The median time of response was 4 weeks. Thus, elranatamab monotherapy can induce early responses, even in this difficult-to-treat subgroup of triple-class refractory patients with extramedullary disease.
In the study, 80% of patients who switched to biweekly dosing maintained or improved their response at least 6 months after the switch. Only one of our patients (Case 3) has recently been switched to biweekly dosing (Cycle 7). The responses may also deepen with the subsequent cycles which yet remains to be seen.
The rate of hematological adverse events has been reported as 17.1%, among which neutropenia (15.4%) is the most common leading to treatment interruption. In contrast, none of our patients had treatment delay due to neutropenia, while case 3 had treatment interruption during the second cycle due to thrombocytopenia and was started on TPO-RA support. Upon rechallenge, she tolerated the treatment well and was continued on further cycles.
The most common non-hematological adverse event leading to treatment interruption was infections in the phase II trial(50.4%) of which COVID-19-related infection was the most frequent, coincidental with the ongoing pandemic. COVID-19-related infection was not seen among our patients however one of our patients (case 2) had RSV-related infection. In the phase II study, 98.6% of patients had immune paresis at the baseline with 43.1% of patients requiring immunoglobulin replacement during the study. While case 1 had hypogammaglobulinemia at the start of therapy and IVIG replacement was initiated, the other two patients required IVIG replacement during treatment. All three of our patients received antiviral, antifungal, and Pneumocystis jiroveci prophylaxis while anti-bacterial prophylaxis was not given. Case 2 received levofloxacin as a part of her ATT regimen.
The most common neurological events reported were muscle spasms and peripheral sensory neuropathy (7.3% each). One (Case 2) of our patients had grade I peripheral sensory neuropathy with no motor dysfunction. No incidence of cranial nerve palsy was reported in the trial, while one of our patients (Case 3) developed a left-sided LMN (lower motor neuron) type of facial palsy with left-sided hemiplegia and partial seizures with secondary generalization. No intracranial abnormality was seen on magnetic resonance imaging. Cerebrospinal fluid (CSF) was acellular and negative for any malignant cells. Viral multiplex PCR was also negative.
Initially, BCMA was thought to be expressed exclusively in hematopoietic tissue, preferentially expressed by mature B lymphocytes and plasma cells, in greater quantities on malignant plasma cells [ 4 ]. However, it has expression in neural tissue as well, the highest being in basal ganglia in comparison to other neural tissue. This can explain the off-target neurotoxicity observed with anti-BCMA therapies [ 5 ]. Neurotoxicity has been observed in 18% of patients in the trial of 128 patients with relapsed/refractory multiple myeloma who received ide-cel. The most common neuro-toxicity observed was confusion and encephalopathy, with hemiparesis observed in a few patients [ 6 ]. In the trial of 97 patients with cilta-cel (CARTITUDE-1), neurotoxicity was observed in 21% of patients. The neurotoxicity was believed to be ICANS-related in 16 patients whereas in the other 12 patients, there were other events observed such as movement disorders, nerve palsy, and peripheral motor neuropathy which were considered distinct [ 7 ].
Similarly, ICANS-related and other neurotoxicity has been observed in anti-BCMA bispecific trials as well, though detailed investigations and presentation for the same are not available, precluding the understanding of the mechanism. In the initial stages, the phase 2 trial of elranatamab was halted due to reports of peripheral neuropathy in the phase 1 trial [ 8 ]. The package insert of elranatamab also clearly states a 15% risk of encephalopathy and a 13% risk of peripheral motor neuropathy observed in the patients. However, some of these toxicities are distinct from those, classically described for ICANS with a later time of onset and different set of symptoms. The detailed symptomatology and investigation for these have not been described in the trials, thus a greater understanding of these “distinct” neurotoxicities observed with anti-BCMA therapies is needed [ 9 ].
Conclusion
Elranatamab monotherapy could prove to be an efficacious option for the treatment of relapsed /refractory multiple myeloma patients with triple-class refractory disease who have limited therapeutic options. However, patients need to be screened for infectious complications with appropriate prophylaxis and immunoglobulin replacement, if required. A high suspicion is required for the neurological complications of the drug and a longitudinal neuro-cognitive screening is required for the patients.
CRediT authorship contribution statement
Disha Kakkar: Writing – original draft, Investigation, Data curation. Aakanksha Singh: Writing – review & editing. Reshmi Harikumar Pillai: Data curation. Tribikram Panda: Writing – review & editing. Roy J Palatty: Formal analysis. Rohan Halder: Writing – review & editing. Narendra Agrawal: Writing – review & editing, Visualization, Supervision, Resources. Dinesh Bhurani: Supervision, Resources, Investigation, Conceptualization.
Declaration of competing interest
Nil
Acknowledgments
Acknowledgement
I would like to thank all my seniors, colleagues and juniors for their contributions in the study.
Informed consent
Informed consent was obtained from all individual participants included in the study
Competing Interests and Funding
Nil
Compliance with Ethical Standards
This is an observational study. The Institutional Ethics Committee has confirmed that no ethical approval is required.
Informed consent was obtained from all individual participants included in the study.
The participant has consented to the submission of the case report to the journal.
Footnotes
All authors contributed to the study conception. Data collection were performed by Disha Kakkar, Aakanksha Singh, Reshmi Harikumar Pillai, Tribikram Panda, Roy J Palatty. The first draft of the manuscript was written by Disha Kakkar and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
References
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