SLONM with MGUS: Long Term Follow-Up After Melphalan and SCT

SLONM with MGUS: Long Term Follow-Up After Melphalan and SCT

SLONM with MGUS: long term follow-up after melphalan and SCT21 November 2018

Appendix e-2: Case descriptions

Case 11 / The first patient has been reported by Voermans et al. in 2008: this 40-year old male patient with MGUS IgG type kappa responded well to HDM and autologous SCT (HDM-SCT) during a follow-up of 15 months. During the subsequent 18 months, muscle strength further improved up to independent functioning and full-time work. Two subsequent vastus lateralis muscle biopsies (taken 6 and 18 months post-treatment) showed signs of chronic myopathy, but no nemaline rods anymore (Figure 1).
The M-protein reoccurred in blood three years after treatment (age 43). This was followed by decrease of muscle function nine months later. Nemaline rods reappeared in the fourth muscle biopsy taken four years after the first biopsy (Figure 1).
He was again treated with HDM-SCT. His M-protein decreased from 3 g/L to detectable but unquantifiable. Five months later (age 44), lenalidomide 10 mg per day for 21 days on 28 day cycles was started and the M-protein became only detectable with immunofixation. However, because no further improvement was noted the lenalidomide was stopped five months later. Muscle function also improved after the second treatment: neck flexion and extension 4; grip strength 5, biceps brachii 2, brachioradialis 3, tricpes 3, ioliopsoas 2, quadricpes femoris 3+. He was able to walk on this toes, and to a lesser extent on this heels. The Trendelenburg test remained positive. The functional recovery was impressive. Seven years after the first treatment he was independent in daily functioning, able to work fulltime and traines daily with his physical therapist. His M-protein is still detectable in the serum with immunofixation but stable and the patient is without any treatment at the moment.
After 1st graft:
Clinical response: II
Hematological response: CR / PD after 3 years and 9 months
After 2nd graft:
Clinical response: I.
Hematological response: VGPR
Case 2 / This male patient presented at the age of 59 with gradual decrease of muscle strength and atrophy of proximal arms and legs. Initially, this resulted in difficulties walking stairs and lifting heavy objects. Gradually, hip girdle weakness increased with a waddling gait. At the age of 61, walking distance was limited to 50 m. Both chewing and swallowing had become more difficult with regular aspiration. He had no orthopnea and no cardiac symptoms. The family history was negative for neuromuscular disorders.
Physical examination revealed mild bulbar dysarthria and dysphagia and facial weakness. The sternocleidomastoid and trapezius muscles had normal strength. Muscles of the shoulder girdle were severely atrophic and weak: deltoid 2, serratus anterior 2, subscapular 4, biceps 3. Hipflexion and abduction were also weak: 3. Quadriceps was 2 and hamstrings 4. Muscle strength in distal limbs, hand and feet was normal. Sensation was normal, reflexes were low, and no fasciculations were observed.
His blood test had shown the presence of a M-protein (IgG type lambda, unquantifiable) at first analysis. The first quadriceps muscle biopsy (age 60) revealed predominantly neurogenic features with normal Gomori staining. A second deltoid muscle biopsy, performed eight months later, revealed severe myopathic changes, with disruption of the myofibrillar structure and abundance of nemaline rods. Then SLONM associated with MGUS was diagnosed.
He was referred for HDM-SCT (age of 61). He did not reach hematological complete remission, and therefore the therapy was continued with lenalidomide and dexamethasone (the latter only for six months). With this therapy hematological complete remission was achieved and the dose of lenalidomide was decreased to 5 mg. This resulted in an initial stabilization of his condition, followed by a gradual improvement. A repeat muscle biopsy of the quadriceps muscle one year after the treatment showed stabilization of the histopathological changes with persistence of rods.
Currently, three and a half years after treatment, he walks independently inside and uses a stick when walking outside. He can walk the stairs independently, with the use of the railing. He is able to walk for almost one hour, and is able to drive a car and ride a bicycle. Speech and swallowing are normal. He is working fulltime in an administrative function. Shoulder abduction and leg muscle strength have improved (deltoid 2 with increased range of motion, proximal leg muscle strength 4; distal 5).
Clinical response:I.
Hematological response: CR.
Case 3 / Patient 3 had also always been very active physically. At the age of 47, she remarked a positive Trendelenburg and impairment of walking (upstairs). A spinal stenosis was suspected and she was operated, without improvement. Her symptoms gradually increased. She started using an electronic bike, a wheelchair, and a walker. At the age of 50, she could only walk supported for 50 m. The strength in her arms gradually decreased, with increasing limitations in daily activities. Swallowing had become more difficult but speech was normal. She had no myalgia, no cardiac complaints, and no orthopnea.
Physical examination at the age of 50 showed mild facial weakness (incomplete eye closure and touting of lips), severe shoulder girdle weakness (2) and atrophy with scapula alata. Muscle strength was reduced in her upper arms (4) and normal in her hands. Neck flexion and extension were also weak (3). Hip flexion (2), and knee extension and flexion (3) were weak also. Distal strength and sensation were normal, reflexes were low, and no fasciculations were observed.
An M-protein was first detected at the age of 47 (IgG type lambda 3.3 g/L). Electromyography showed myopathic changes predominantly in proximal muscles with spontaneous activity in axial muscles. A first quadriceps muscle biopsy performed (age 49) showed mixed myopathic and neurogenic features, some cores, and extensive mitochondrial changes (ragged-red fibers and COX negative fibers). Biochemical analysis of the muscle biopsy was normal and no mitochondrial DNA defects were detected in blood. A second quadriceps muscle biopsy performed six months later showed again extensive myopathic changes with abundance of rods in the Gomori staining. SLONM with MGUS was diagnosed and she was treated with HDM-SCT (age 50). Lenalidomide and dexamethasone were added because of a residual IgG lambda peak on immunofixation after transplant.
Follow-up two years after treatment showed partial improvement. She functioned independently at home and used a cane while going outdoors. Swallowing was normal. Muscle strength had improved to: neck extension (4), shoulder abduction (2), infra- and supraspinatus (3), and knee extension (5) and flexion (4). She continued to improve functionally and walks independently three years after treatment.
Clinical response: I.
Hematological response: VGPR.
Case 42 / The fourth patient, a woman aged now 73 years, has been reported by Benveniste et al. in 2008. Just before HDM-SCT, the patient presented with head drop and was wheelchair bound, unable to walk unaided and stand up from a chair; and maximal arm abduction was 30°. A monoclonal immunoglobulin IgG type lambda was detected 2.6 g/L.
Total duration of follow-up after HDM-SCT has been eight years, with a very good response to initial treatment resulting in nearly normal functioning. Now she walks 10 m in 12 seconds without assistance, uses a cane only for walking outside, can arise from the chair 18 times with mild leaning on knees; arm elevation is normal, arm antepulsion at 90° is maintained 1 minutes 20 seconds, and the head is held vertical without any difficulty. Rising from the floor has remained difficult. No monoclonal IgG is detectable by immunofixation and patient is in hematological complete remission.
Clinical response: I.
Hematological response: CR.
Case 5 / This 73-year old female patient presented with pelvic femoral weakness at the age of 60. The disease worsened with neck weakness and increasing weakness of lower limbs requiring a cane at age of 64 years. Soon, she became wheel chair bound for going outside. In addition, proximal upper limbs were affected since the age of 65 years.
Characteristic rods were found on the third biopsy at age of 65 (Figure 1), prompting to detect a monoclonal IgG type kappa in the serum (2.6 g/L). Bone marrow aspiration showing 8% of dystrophic plasma cells, and the diagnosis of SLONM with MGUS was retained.
Various therapies including oral dexamethasone, melphalan, cyclosphosphamide, azathioprine, plasma exchanges (from 66 to 68 years) resulted in a stabilization of the motor capacities during 3 years. At age of 71 years, motor function decreased significantly and she could only walk for 30 steps with a walker. The monoclonal IgG kappa peak was 2.6 g/L. The patient received HDM-SCT at the age of 71 years. After the graft, which did not affect the M-protein level, limb and axial weakness worsened despite a treatment with lenalidomide and dexamethasone. The deterioration accelerated in the subsequent years. She was bedridden, with dropped head, unable and arm abduction limited at 30° at age 76. The M-protein increased to 5.8 g/L, bone marrow aspiration showed 2% of dystrophic plasma cells, and she died a few months later.
The long course before deterioration might suggest a genetic cause of the nemaline myopathy. However, this was deemed unlikely due to normal CK levels, and normal protein expression studied by immunostaining (dystrophin, sarcoglycans, dysferlin, caveolin, merosin, telethonine, and merosine). Most likely, the various therapies including oral dexamethasone, melphalan, cyclosphosphamide, azathioprine, plasma-exchanges (from 66 to 68 years) resulted in a stabilization of the motor capacities during 3 years.
Clinical response: IV.
Hematological response: SD.
Case 6 / In this 46-year-old female, weakness appeared at age 39, with a very rapid course affecting neck (head drop) and proximal limb muscles requiring a wheelchair when going outside three years later. The diagnosis of SLONM was particularly difficult: the first three biopsies showed no rods, but nonspecific myopathic changes (1st and 2nd) and dermatomyositis like changes with perifascicular atrophy, several perivascular inflammatory cells and C5b9 deposits on capillaries (3rd).
Prednisolone, methotrexate, rituximab, and intravenous immunoglobulins were given without any benefit. Characteristic rods were evidenced only in the fourth biopsy performed at age 44 years. A monoclonal IgG type lambda was detected (M-protein only detectable on electrophoresis, the peak being not quantifiable) early in the disease, but this was not related to the myopathy since rods were absent on the first three biopsies. The M-protein was again unquantifiable at the moment of the HDM-SCT, performed at the age of 44 years. Just before the SCT, she was fully wheelchair bound. Shoulder abduction was 0°. Ten months after the graft, she has achieved a complete haematological response and the clinical appeared mildly improved: she was able to stand up with help, to walk independently 10 m and to get up from the chair with help. Abduction of arms was 60°. The head drop persisted.
Two years after the graft, the patient presented a severe uterine bleeding requiring hysterectomy. Simultaneously weakness of limbs and neck worsened rapidly, with loss of ambulation. Her M-protein increased to 17.8 g/L, and a second HDM-SCT was performed at age of 46 years. The immediate post-SCT period was particularly difficult due to severeaspiration pneumonia, requiring intensive care treatment including tracheostomy and gastrostomy. Three months after the graft, the patient began to recover. Eight months after the SCT, the progression is highly significant: arm elevation increased from 0° to 40°, she has no more distal upper and lower limbs weakness,sitting position isheld without assistance, her voice normalized,and she showed a partial recovery in oral feeding and spontaneous ventilation. The patient is still wheelchair dependent, with persistent head drop. -bound, and a distal upper limb improvement is found. The M-protein decreased to 5.6g/l.
After 1st graft:
Clinical response: II
Hematological response: CR / PD after 2 years
After 2nd graft:
Clinical response: I
Hematological response: PR
Case 73 / The case of this previously healthy 54-year-old man was reported in 2009. He presented with a 2-year history of progressive painless difficulties in walking and climbing stairs, with a subacute worsening within the last 3 months prior to diagnosis. Walking was waddling and limited to 20 meters, and his wife had to support him in daily activities. At the nadir of his condition, he could neither raise his head nor sit and stand. He then also experienced mild bulbar dysarthria and dysphagia with facial weakness. Muscles of the shoulder girdle were mildly atrophic and weak: deltoid 2, biceps 3. Hipflexion and adduction were also weak (2). Quadriceps was atrophic at 3, and hamstrings 4. Distal muscles had normal strength, sensation was normal, and there was a generalized hyporeflexia. In the following weeks, the patient became restricted to a wheelchair and developed dyspnea.
Needle electromyography was compatible with a myopathy in proximal muscles with no spontaneous activity at rest. Deltoid muscle biopsy showed scattered atrophic fibers, with small fuschinophilic corpuscles on trichome stain and nemaline rods on electron microscopy. Work-up revealed IgG type kappa (11 g/L) without signs of multiple myeloma or HIV infection. The bone marrow biopsy showed 5% (up to maximum 10%) plasma cell infiltration.
The patient received HDM-SCT. Improvement, as documented by clinical scores, began progressively 1 month after SCT. Three years later, at the time of publication, he could walk and stand alone, and was able to raise his arms overhead, was independent in daily activities. Hematologically, he had a CR with a no M-protein detectable. He was examined annually for both hematological and neurological evaluations. Six and half years later, some difficulties in climbing stairs remained with muscle weakness in the hip flexion and adduction at 3. He reported a gradual improvement in daily activities such cooking or unrestricted walking on level ground.
Clinical response: I.
Hematological response: CR.
Case 8 / This 40-year old female suffered from pain at the left groin, then the lower back and the left calf at age 36. At age 37, walking, climbing stairs, getting up from a squatting position, and swallowing solids became impaired. The neurological examination showed mild atrophy of shoulder girdle muscles with some scapular winging and lumbar hyperlordosis. Gait was waddling with a positive Gowers sign. Mild facial weakness was noted together with marked proximal muscle weakness (deltoid (3), infraspinatus (4 R,2 L), iliopsoas (3), gluteus maximus (2), hamstrings (4). Serum CK was normal at 133 IU/L. EMG showed an excess of polyphasic motor unit potentials in proximal muscles. Muscle CT scan and a right deltoid muscle biopsy were normal, including immunohistochemical and immunoblotting studies for muscular dystrophies. Acid alpha-glucosidase activity was normal. Cardiac and respiratory functions were normal. FSHD was excluded. At age 38, muscle weakness had increased and she could not walk more than a few 100 meters. The weight loss from 50 to 43 kg and oropharyngeal dysphagia necessitates a percutaneous endoscopic gastrostomy.
Serum CK remained normal at 45 UI/L. Vital capacity was reduced (54% of the predicted value) and a follow-up muscle CT scan revealed marked wasting of paraspinal and limb girdle muscles. A second muscle biopsy of the left vastus lateralis muscle led to the discovery of numerous rod bodies. As at that time a monoclonal IgG kappa band (0.24 g/L) was found, and SLONM with MGUS was diagnosed. Immunohistochemistry showed deposition of IgG and kappa chains at the sarcolemma of all muscle fibers. Bone marrow biopsy and bone scintigraphy were unremarkable and treatment with methylprednisolone and plasma exchange was started. However, muscle weakness progressed (neck flexor muscles 4, neck extensor muscles 2, deltoid 0/5, biceps 4, triceps 3, iliopsoas 1, quadriceps and gluteus medius 2, gluteus maximus 0, adductors and hamstrings 3) and at age 39 she was weelchair-bound.
Two years after coming to medical attention, autologous STC following HDM (140 mg/m2) was performed. Five months later, the gastrostomy was removed as swallowing had normalized. Seven months after HDM-SCT, the vital capacity had improved to 77% of the predicted value and the monoclonal component had become undetectable. Motor recovery was noted with normal facial and neck flexor muscle strength. Twelve months after HDM-SCT, the patient walked a few meters with a walker.
Clinical response: I.
Hematological response: CR.

References

1.Voermans NC, Minnema M, Lammens M, et al. Sporadic late-onset nemaline myopathy effectively treated by melphalan and stem cell transplant. Neurology 2008;71:532-534.

2.Benveniste O, Laforet P, Dubourg O, et al. Stem cell transplantation in a patient with late-onset nemaline myopathy and gammopathy. Neurology 2008;71:531-532.

3.Novy J, Rosselet A, Spertini O, Lobrinus JA, Pabst T, Kuntzer T. Chemotherapy is successful in sporadic late onset nemaline myopathy (SLONM) with monoclonal gammopathy. Muscle & nerve 2010;41:286-287.

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