Bone Marrow Transplantation (2018) 53:895–899

https://doi.org/10.1038/s41409-017-0080-6

CORRESPONDENCE

Chemotherapy with stem cell transplantation is more effective than

immunotherapy in sporadic late onset nemaline myopathy with
monoclonal gammopathy
1
Rouslan Kotchetkov ●
Anna Dyszkiewicz-Korpanty2,3 Vishal Kukreti4
●

Received: 27 November 2017 / Revised: 5 December 2017 / Accepted: 10 December 2017 / Published online: 24 January 2018
© The Author(s) 2018. This article is published with open access

Sporadic late onset nemaline myopathy (SLONM) is a rare rare nature of the disease, the best treatment modality is
proximal myopathy with an insidious onset and slow pro- unknown.
gression. Patients present initially with a proximal limb A 64-year-old male without a background history of
weakness. Most commonly dyspnea, dysphagia, facial musculoskeletal disease presented with 1 year of pro-
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muscle weakness, and cardiomyopathy develop with dis- gressive generalized muscle weakness, difficulties with
ease progression. If not treated, SLONM could result in ambulating and holding his posture. He subsequently
40% mortality within the first 12 months. In approximately developed dysphagia and dyspnea. On exam he could walk
half of the reported cases SLONM is associated with plasma with support only, was in a mild respiratory distress, and
cell disorders, mostly monoclonal gammopathy of unknown had marked proximal weakness in the upper and lower
significance (MGUS) and anecdotally with multiple mye- extremities with visible muscle atrophy. His blood work
loma and light chain deposition disease [1–3]. SLONM was unremarkable, except for the presence of immu-
associated with a monoclonal gammopathy (SLONM + noglobulin G (IgG) lambda monoclonal (M) protein of
MGUS) has an aggressive course of the disease, more 2.7 g/L. Bone marrow biopsy showed 5% plasma cells
severe weakness, earlier development of dysphagia and with no light chain restriction. Further work up for an
dyspnea, and overall carries an unfavourable prognosis [1, underlying HIV or malignancy was negative. He had car-
2]. Two approaches are used to treat SLONM + MGUS: (1) diomyopathy with global systolic dysfunction (left ven-
immunosuppressive therapy (steroids, steroid-sparing tricular ejection fraction decreased to 20%). Creatinine
agents, intravenous immunoglobulins (IVIG), and plasma- kinase level was normal. Muscle biopsy showed variable
pheresis/plasma exchange) or (2) chemotherapy followed size skeletal muscle with scattered small basophilic
by autologous stem cell transplantation (ASCT). Due to the angulated fibers associated with mild endomysial hemo-
lysis. Some of the muscle fibers showed dense sarco-
plasmic aggregates. Electron microscopy revealed skeletal
muscles with extensive myofibrillar disarray and abundant
cytoplasmic nemaline rods. No rod-like inclusions were
* Rouslan Kotchetkov
kotchetkovr@rvh.on.ca
found in nuclei. Diagnostic work up did not identify any
hereditary causes. The patient was diagnosed with a
1
Division of Hematology-Oncology, Simcoe Muskoka Regional SLONM + MGUS and subsequently started systemic
Cancer Program, Royal Victoria Health Center, 201 Georgian chemotherapy with cyclophosphamide, bortezomib, dex-
Drive, Barrie, ON L4M 6M2, Canada
amethasone. After six cycles of this regimen he underwent
2
Laboratory Medicine Program, Toronto General Hospital, conditioning with high-dose melphalan (200 mg/m2) fol-
University Health Network, University of Toronto, 200 Elizabeth
lowed by ASCT. Clinical improvement started 6 weeks
St., Toronto, ON M5G 2C4, Canada
3
after the initiation of chemotherapy and was more pro-
Division of Medical Oncology and Hematology, Department of
nounced a month after the ASCT. Twelve months fol-
Medicine, Princess Margaret Cancer Center, Toronto, ON, Canada
4
lowing the ASCT the patient was able to walk over 5 km
Division of Medical Oncology and Hematology, Department of
daily, swim, and was autonomous in daily activities. Left
Medicine, Princess Margaret Cancer Centre, University Health
Network, University of Toronto, 610 University Avenue, ventricular ejection fraction improved to 55%. He has no
Toronto, ON M5G 2M9, Canada measurable M-protein. He was last seen in a follow-up at
896 R. Kotchetkov et al.

38 months post-transplant and has remained in complete POEMS (polyneuropathy, organomegaly, endocrinopathy
clinical and hematological remission. /edema, M-protein, skin abnormalities) syndrome [4]. Tis-
We reviewed the literature and identified 14 SLONM + sue damage may occur via several mechanisms. In immu-
MGUS patients treated with an immune-based approach noglobulin light chain amyloidosis amyloid depositions
(Table 1) and 14 patients with chemotherapy + ASCT produced by monoclonal plasma cells result in cellular
(Table 2). Overall, in both groups there was a male pre- injury, tissue damage, and organ dysfunction [5]. Direct
dominance, 1.5:1 and 3.5:1, respectively, with a median age cytotoxicity of immunoglobin light chains has also been
of 49 years. All patients had a small monoclonal M-protein, demonstrated in cases of cardiac amyloid [6]. In POEMS
and all MGUS cases were exclusively IgG, with kappa to syndrome, it is not the aggregation and deposition of the
lambda distribution 1.1:1. Among 14 patients who were monoclonal antibodies in affected tissue but rather the
treated with immune-based therapy some degree of antibody activity toward autogenous antigens along with the
improvement was achieved in 7 (50%) patients. Three effects of vascular endothelial growth factor (VEGF) and
patients were reported to have a significant clinical possibly other humoral mediators overproduction is con-
improvement. Of those, two declined ASCT and were sidered causative [12]. However, both of these entities
successfully treated with immunotherapy. In both patients improve when the clone of plasma cells is eradicated [7, 8].
improvement of neurological symptoms correlating with a Based on these observations Voermans and colleagues
resolution of monoclonal protein was reported (Table 1 [1]). suggested that high-dose melphalan + ASCT should be the
One patient who received IVIG monthly over 3 years first-line therapy for SLONM + MGUS [4]. A recent review
reported almost complete resolution of weakness (Table 1 also confirmed the efficacy of ASCT for the therapy of
[2]). In two other patients who were treated with combined SLONM and considered SLONM + MGUS as a treatable
immunosuppression, a moderate improvement was disease with therapy directed toward plasma cell clone,
achieved (Table 1 [3, 4]). Two other patients who received including chemotherapy and ASCT [2]. Taking into account
combined therapy with steroids, plasma exchange, and the pathophysiology of the disease, response to che-
steroid-sparing immunosuppressants had only a mild neu- motherapy, which correlates with M-protein values, we
rological improvement (Table 1 [5, 6]). Only the patient propose to approach SLONM + MGUS as a plasma cell
treated with a combination of prednisone and cytarabine for dyscrasia, rather than dysimmune disease. Given the low
2.5 years has achieved stable disease (Table 1 [7]). Six efficacy of steroids and immunosuppressants and the rapid
patients (42%) treated with either prednisone and IVIG course of the disease we recommend the use chemotherapy
monotherapy, or prednisone and immunosuppressants pro- and ASCT with a goal to eradicate malignant plasma cells
gressed (Table 1 [8–11]). clone, similar to other plasma cell neoplasms.
In contrast, when considering our experience along with Over the past few years significant advances have
the experiences reported in the literature, the treatment with become available for treating plasma cell dyscrasias. The
ASCT resulted in significant improvement of neurological advances of therapy in multiple myeloma suggest that novel
symptoms in 14/15 (93%) patients (Table 2). Among eight agents, such as proteasome inhibitors and immunomodula-
patients reported by Voermans et al. [4] seven achieved a tors, might be an effective therapy of SLONM + MGUS
sustainable good/moderate response, with six very good even without consolidative ASCT. A recent report also
partial or complete hematological responses, and one partial showed an efficacy of lenalidomide + dexamethasone
response. One patient showed no clinical or hematological combination in a 54-year-old female patient with SLONM
response and died from a progressive disease. Six cases, associated with multiple myeloma. In this patient clinical
similarly to our case, showed a significant improvement of improvement was already reported after 3 months of ther-
neurological symptoms, including a complete recovery in apy [3]. These new data are of a particular importance for
three patients (Table 2, [2–7]). The majority of clinical and patients with comorbidities who are not eligible for ASCT.
hematological responses were long-lasting, with a follow- As recently reported by Belhomme et al. [9], a patient with
up of up to 96 months (mean 18 months, range a severe left ventricular dysfunction possibly due to MGUS
5–96 months). Clinical response correlated with hematolo- related myopathy showed a significant improvement after
gical response and all patients had no measurable M-protein treatment with four cycles of cyclophosphamide, bortezo-
during the reported follow-up period. mib, dexamethasone without consolidation with ASCT.
Even though the nature of the relationship between SLONM + MGUS is a rare disease and our analysis is
SLONM and monoclonal gammopathy is not completely limited by its retrospective nature and a small number of
clarified, several observations suggested a direct association published case series. More data are needed to determine the
between the presence of M-protein and the disorder. It was optimal management of SLONM + MGUS. Based on our
proposed to classify SLONM + MGUS as a plasma cell experience and the literature review we conclude that che-
dyscrasia with toxic M-protein, similar to amyloidosis or motherapy followed by consolidative ASCT is more
Table 1 Patients treated with immune-based approach
Ref No. of Age, gender Type of M-protein Initial therapy Subsequent Therapy Best clinical response Best hematol Time to Duration of
patients MGUS height therapy duration (mo) response best response follow-up
(mo) (mo)

1. 2 39 F; 51 M IgG kappa N/A PP + IVIG Pulse MP 12 Significant improvement Ig level 12 156

normalized
2. 1 61 M IgG kappa N/R IVIG 50 g × 4 days No 40 Almost complete N/R 24 40
monthly; titrated to resolution of weakness
150 g/month (5/5) MRC scale
3. 1 46 M IgG kappa N/R IVIG 0.4 g/kg × MP 1 g IV then 12 Improvement: MRC N/R 12 12
5 days monthly MMF scale 3–5/5
4. 1 52 F IgG kappa N/R PP MP + N/R Moderate improvement Reduced M- N/R N/R
azathioprine in muscle strength protein level
5. 1 31 F IgG 15.4 g/L (γ- Plasma exchange ×32 Prednisone, CP 36 Mild improvement Gamma- 36 36
lambda globlin on globulin ↓to 6
SPEP) g/L
6. 1 63 M IgG kappa small Prednisone 50 mg/day, IVIG monthly 6 Slow, modest N/A N/A 6
& lambda MMF 2000 mg/day
7. 1 45 M Ig kappa N/A Prednisone 60 mg/day IVIG course × 30 Stable N/A N/A 54
2.5 y
Chemotherapy with stem cell transplantation is more effective than . . .

+ ARA-C 200 mg/

day × 1.5 y
8. 3 43,58,69 all All Ig N/R Prednisone 35, 60, & None 2, 9, 11 No response All died N/A N/A 12
males kappa 80 mg/day
9. 1 49 M IgG N/R IVIG 0.4 g/kg q None 6 No response No response No 6
lambda 6 weeks
10. 1 45 M IgG N/R Prednisone CP, IVIG, N/R Without benefits N/R N/A 21
lambda rituximab
11. 1 37 M IgG N/R Prednisone 100 mg None 18 Progressed N/R N/A 54
lambda alternate days
PP plasmapheresis, MP methylprednisolone, N/R not reported, MGUS monoclonal gammopathy of unknown significance, MRC Medical Research Council, CR complete response, Ig
immunoglobulin, IVIG intravenous immunoglobulin, CP cyclophosphamide, MMF mycophenolate mofetil, N/A not available, ARA-C cytarabine. See Refs. [1, 10–17]
897
 898

Table 2 Patients treated with chemotherapy + ASCT

Ref No. of Age, gender Type of M-spike Initial therapy Induction ASCT type; Best clinical Best hemat Time to best Duration of
patients MGUS height chemotherapy melphalan response response response follow-up
(g/L) dose mg/m2 (mo) (mo)

1. 8 Mean = 49.5 All IgG: 4.57 [UQ- IVIG, rituximab, None 6 single 2 I in 7, II in 2; IV CR-4, VGPR-2, N/R 28 [8–96]
[38–66], 3 M, kappa-4; 11.0] prednisone, plasma tandem; N/R in 1 (MRC) PR-1, PD-1
5F lambda-4 exchange
2. 1 27 M IgG lambda 0.66 IVIG: 0.4 g/kg × None Single, 200 Significant CR 18 24
5 days + MP improvement
1 g × 3 days
3. 1 47 M IgG kappa 0.5 Melphalan B+D Tandem, N/R Improvement CR post 2nd 14 14
+ LCDD ASCT&CyBorD
4. 1 38 F IgG kappa N/R N/R N/R Single, 140 Significant CR After 2mo N/A
improvement
5. 1 54 M IgG 11 None None Single, 200 Complete resolution CR 12 12
6. 1 63 M IgG lambda 2 None None Single, 140 Complete resolution CR 24 24
7. 1 44 M IgG kappa 0.4 None None Single, 200 Significant clinical M-spike UQ 5 5
response (MRC
scale)
8. 1 64 M IgG lambda 2.7 None CyBorD x6 Single, 200 Complete resolution CR 12 38
UQ unquantifiable, MP methylprednisolone, B+D, Bortezomib+Dexamethasone, N/R not reported, MGUS monoclonal gammopathy of unknown significance, MRC Medical Research Council,
CR complete response, IgG immunoglobulin G, IVIg IV immunoglobulin, PE plasma exchange, CR complete response, VGPR very good partial response, PR partial response, PD progressive
disease, CyBorD cyclophosphamide/bortezomib/ dexamethasone. See Refs. [4, 18–23] (Kotchetkov et al. unpublished, 2018).
R. Kotchetkov et al.
Chemotherapy with stem cell transplantation is more effective than . . . 899

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