3 Things You Should Know About Treating Paraneoplastic Lambert-Eaton Myasthenic Syndrome

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Initiate therapy for paraneoplastic LEMS with appropriate consideration for titration and monitoring

• Define best practices for multidisciplinary fast-track pathways with defined roles, referral service level agreements, and EMG access targets

RELEASE DATE: March 1, 2026

EXPIRATION DATE: March 1, 2027

Accreditation/Credit Designation

Physicians’ Education Resource^®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Physicians’ Education Resource^®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Catalyst Pharmaceuticals, Inc.

Off-Label Disclosure and Disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members, and do not reflect those of PER^® or any company that provided commercial support for this activity.

Instructions for Participation and How to Receive Credit

1. Read this activity in its entirety.

2. Go to https://www.gotoper.com/lems26sclc-postref to access and complete the posttest.

3. Answer the evaluation questions.

4. Request credit using the drop-down menu.

YOU MAY IMMEDIATELY DOWNLOAD YOUR CERTIFICATE.

About 50% to 60% of Lambert-Eaton myasthenic syndrome (LEMS) cases occur secondary to a malignancy, most commonly small cell lung cancer (SCLC), and 3% of patients with SCLC have LEMS.^1-3 Characterized by proximal muscle weakness, autonomic dysfunction, and areflexia,⁴ LEMS is driven by autoantibodies targeting voltage-gated calcium channels.⁵ Aminopyridines can provide symptomatic relief from SCLC-associated LEMS (SCLC-LEMS) and should be initiated as early as possible in conjunction with a neurologist. Here are 3 things you should know about treating SCLC-LEMS.

1) Amifampridine is an FDA-approved, National Comprehensive Cancer Network–recommended symptomatic treatment for SCLC-LEMS.

Neurology consultation and treatment with amifampridine (3,4-diaminopyridine), an oral medication that improves acetylcholine release through potassium channel blockade, should be considered for patients with SCLC-LEMS (Figure).^6,7 Amifampridine was approved by the FDA for use in adults with LEMS in 2018 based on data from the phase 3 LMS-002 trial (NCT01377922) and the confirmatory phase 3 LMS-003 trial (NCT02970162).^8,9

In the LMS-002 trial, 38 patients with LEMS received amifampridine during an initial 91-day screening and open-label run-in period prior to blinded randomization to continue amifampridine for 14 days vs placebo (7-day taper, 7-day placebo).⁸ The change in Quantitative Myasthenia Gravis score (QMG; a physician-rated categorical scale assessing muscle weakness) and Subject Global Impression score (SGI; a patient rating of their overall impression of the effects of the study treatment on their physical well-being) was measured between day 1 (baseline) and day 14 of the randomization period. The mean difference in QMG score (0.3 vs 2.2; mean difference, –1.7; 95% CI, –3.4 to –0.0; P = .0452) and SGI score (–0.7 vs –2.7; mean difference, 1.7; 95% CI, 0.7-3.0; P = .0028) both significantly favored amifampridine vs placebo, respectively.

The 26 participants in the LMS-003 blinded confirmatory trial had already been receiving open-label amifampridine at a stable dose for at least 1 week when they were randomly assigned to receive amifampridine (continuing at their usual dose) vs placebo on days 1 through 4.⁹ On day 4, a dose of blinded study medication was administered in the clinic, and efficacy assessments were then performed 45 minutes later. The least square mean difference from baseline (day 0) to day 4 SGI (−0.3 vs −2.9; 95% CI, 1.53-4.38; P = .0003) and QMG scores (0.7 vs 7.1; 95% Cl, −0.78 to −3.29; P = .0004) both significantly favored amifampridine vs placebo, respectively.

Several objective measures have also confirmed the efficacy of amifampridine vs placebo, including a Timed 25-foot Walk test (95% CI, 4.8-89.9; P =.0302) and a compound muscle action potential (95% CI, 0.5-2.6; P =.0065) measured on day 8 compared with baseline in LMS-002.⁸ Repetitive nerve stimulation test abnormalities, which are universal to all muscles in patients with LEMS, also normalize with amifampridine.¹⁰

2) Amifampridine does not interfere with testing for LEMS; it is generally well tolerated and can be uptitrated to improve efficacy.

Amifampridine treatment does not remove pathogenic LEMS autoantibodies and may therefore be initiated prior to or during the workup for LEMS to provide patients with symptomatic relief. The starting dose for amifampridine for adults is 15 to 30 mg per day taken in 3 to 5 divided doses.¹¹ The dose may be increased by 5 mg daily every 3 to 4 days according to efficacy and tolerability to a maximum single dose of 20 mg and a maximum total daily dose of 100 mg. Use of effective doses of dalfampridine (4-aminopyridine) was limited by generalized seizure activity caused by the drug.¹² Amifampridine has lower central nervous system penetration than dalfampridine, and there were no seizures reported in either the LMS-002 or LMS-003 studies.^8,9 However, seizures have been reported in patients taking high (100 mg daily) doses of amifampridine, and prior seizures are a contraindication to amifampridine per the FDA label.^13,14 Furthermore, patients with known seizure disorders or (active) brain metastases were excluded from the LMS-002 and LMS-003 studies.^8,9

“That particular question [of effect on time to initiation of LEMS treatment] has not been answered yet. But what we see is that the longer we wait to treat [LEMS], the worse condition the patients get to, and not all of it is reversible. So early treatment is key.” — Ruham Nasany, MD

The most common treatment-emergent adverse events reported from the 53 patients included in the run-in phase of LMS-002 were oral and digital paresthesias, headaches, nausea, and diarrhea (Table).⁸ There were no serious adverse events attributable to amifampridine in the LMS-002 or LMS-003 studies.^8,9 In LMS-003, serious adverse events of dry mouth, asthenia, and muscle weakness, all symptoms of untreated LEMS, were noted only in the placebo group.⁹

3) Treating SCLC should be prioritized to combat the pathogenic autoantibodies driving LEMS, as immune-based treatments to combat these antibodies have limited efficacy.

While control of the underlying SCLC is the therapeutic priority for patients with SCLC-LEMS, symptomatic management of LEMS with amifampridine should be pursued concurrently with tumor-directed therapy.¹⁵ Data for using immune suppression or immune modulation to treat LEMS have demonstrated limited efficacy. Furthermore, suppressing the immune system weakens a line of host defense against SCLC.

“Please treat the cancer. Treat the cancer with immunotherapy. There are no issues with that.… And if you recognize [LEMS], work with your neurology colleagues to start amifampridine.” — Ruham Nasany, MD

Intravenous immunoglobulin (IVIG) was investigated for the treatment of LEMS in a randomized, double-blind crossover trial of 9 patients who received a total dose of 2 g/kg IVIG vs placebo (equivalent volume of 0.3% albumin).¹⁶ Significant improvements in drinking time (P = .017), vital capacity (P = .028), and limb strength (P = .038) and a significant decline in serum calcium channel antibody titers (P = .028) were observed with IVIG vs placebo. Improvement in strength peaked at 2 to 4 weeks but declined by 8 weeks, and direct anti-idiotypic neutralization by immunoglobulin was not observed in vitro. These findings suggest that transient reduction of pathogenic autoantibodies by IVIG drives temporary improvement in symptomatic LEMS. Authors of a single-center chart review of 59 patients with LEMS reported that 46% and 23% of 13 patients who received IVIG experienced marked and moderate improvement, respectively, and that responses to IVIG were not sustained.¹⁷

This single-center chart review also reported on high-dose prednisone and plasmapheresis for the treatment of LEMS.¹⁷ Of the 23 patients treated with high-dose daily prednisone, 84% had mild to moderate improvement in strength, which was not sustained with drug tapering. The potential for adverse effects, particularly steroid-induced myopathy, also limits the use of steroids to treat LEMS. Fifteen patients underwent plasmapheresis, 1 of whom had marked but transient improvement in strength and 5 of whom had mild benefit. Improvement in LEMS symptoms with rituximab has been demonstrated in a very limited number of patients,but this drug can be considered when other interventions have failed.^18,19

Key References

8. Oh SJ, Shcherbakova N, Kostera-Pruszczyk A, et al; LEMS Study Group. Amifampridine phosphate (Firdapse) is effective and safe in a phase 3 clinical trial in LEMS. Muscle Nerve. 2016;53(5):717-725. doi:10.1002/mus.25070

9. Shieh P, Sharma K, Kohrman B, Oh SJ. Amifampridine phosphate (Firdapse) is effective in a confirmatory phase 3 clinical trial in LEMS. J Clin Neuromuscul Dis. 2019;20(3):111-119. doi:10.1097/cnd.0000000000000239

17. Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic syndrome (LEMS). Clinical and electrodiagnostic features and response to therapy in 59 patients. Ann N Y Acad Sci. 1998;841:823-826. doi:10.1111/j.1749-6632.1998.tb11024.x

For FULL References List, visit https://www.gotoper.com/lems26sclc-postref

CME Posttest Questions

1) A patient receiving therapy for newly diagnosed extensive-stage SCLC presents with muscle weakness. Antibody and electrodiagnostic testing confirm LEMS. What is the best option for this patient now?

A. Continue anticancer therapy, add amifampridine

B. Stop anticancer therapy, start amifampridine

C. Continue anticancer therapy, add pyridostigmine

2) Which of the following adverse events was most frequently observed in the phase 3 LMS-002 trial evaluating amifampridine in patients with LEMS?

A. Neutropenia

B. Oral/digital paresthesia

C. Pyrexia

D. Skin rash

Claim Your CME Credit at https://www.gotoper.com/lems26sclc-postref

To learn more about this topic, including information on diagnostic testing for LEMS, go to https://www.gotoper.com/lems26sclc-activity

CME Provider Contact Information

Physicians’ Education Resource^®, LLC
259 Prospect Plains Road, Building H, Cranbury, NJ 08512
onc-info@gotoper.com