A 61-year-old man with underlying hypertension and anxiety disorder presented with backache and left lower chest pain since end of year 2020 and later was diagnosed with MM with left T8-T11 paravertebral plasmacytoma in March 2021. There was no bone marrow examination because patient refused. CT-guided biopsy of left lower thoracic paravertebral mass showed plasmacytoma with lambda light chain restriction (Figure 1). MRI thoracic spine showed left T8-T11 posterior mediastinal soft tissue mass, with a size of 6.8 x 3.8 x 10.0 cm, with intraspinal extension and infiltration into left posteromedial segment of 10th and 11th rib (Supplementary Data (available here)). Serum protein electrophoresis (SPE) and immunofixation (IF) showed IgA lambda of 10 g/L without immunoparesis, while urine protein electrophoresis (UPE) and IF did not show evidence of paraprotein. Serum free light chain (sFLC) showed reduced kappa:lambda ratio of 0.10 (13.2 mg/L:132.7 mg/dL). Other investigations were normal:beta2-microglobulin 1.7 mg/L, albumin 42 g/L, Hb 15.7 g/dL, TWC 4.547 x 109/L, PLT 219.9 x 109/L, creatinine 83 micromol/L, eGFR 87 mL/min/1.73 m2, corrected Ca 2.37 mmol/L, and LDH 172 micro/L within normal range.
Patient developed major depressive disorder since the diagnosis of MM on top of the preexisting anxiety disorder. Despite psychological therapy, both conditions waxed and waned following the condition of MM. Hence, throughout the follow-up, it is difficult to manage this patient, especially on the evaluation of certain subjective symptoms.
Dexamethasone was started at the end of March 2021 while waiting for the results of the investigations above. Bortezomib-dexamethasone plus zoledronic acid (VD + Z) was started in the middle of April 2021 instead of the usual triplet with addition of cyclophosphamide, thalidomide, or lenalidomide (R) due to patient's concern on potential adverse effect of all drugs and to keep the number of drug minimum with intention to increase to triplet once proven he was tolerable to VD + Z. In early May 2021, MRI thoracic spine showed progression of the paravertebral plasmacytoma, with a size of 8.2 x 5.8 x 15 cm, without significant change in the involvement at T9/10 and T10/11 foramina and intraspinal extension (Supplementary Data). In the middle of May 2021, local radiotherapy to the left paraspinal plasmacytoma, 30 Gy in10 fractions, was completed, while systemic MM treatment was changed to RVD + Z. Retrospective investigation of the initial paravertebral plasmacytoma sample revealed that about 30% of the tumour cells showed aberrant nuclear p53 protein expression (Figure 1), positivity for fluorescent in situ hybridisation (FISH) TP53 deletion (nuc ish (DLEU x 2,TP53 x 1)(200)) (Figure 1), and positivity for FISH IGH rearrangement (nuc ish (IGH x 3,BCL x 2)(51/200)) (Figure 1).
After 2nd cycle of RVD + Z at the end of June 2021, patient achieved at least a partial response (PR). SPE showed IgA lambda of <1 g/L. UPE showed a faint band at fast moving gamma region. sFLC showed normal ratio of 1.04 (18.8 mg/L:18.0 mg/L). MRI and PETCT showed reduction of the paravertebral mass (Supplementary Data).
After 4th cycle of RVD + Z in the middle of August 2021, patient achieved a very good PR (VGPR) or near complete response (CR). SPE and IF were negative, while UPE showed a faint restriction band at fast moving gamma region for which IF did not reveal any abnormality. sFLC showed normal ratio of 1.22 (15.4 mg/L:12.6 mg/L). MRI and PETCT showed further reduction of the paravertebral mass (Supplementary Data).
The patient was a heavy smoker. During treatment of MM, imaging showed occurrence of lung changes which were progressive (Supplementary Data). He was investigated and treated as smear-negative pulmonary tuberculosis (PTB) due to clinical suspicion and endemicity of PTB in the region. Anti-TB was started in August 2021, while MM treatment was changed to lenalidomide maintenance. The lung changes improved with anti-TB (Supplementary Data).
In November 2021, SPE/IF, UPE/IF, and sFLC remained negative and PETCT showed stable left paraspinal mass. His anti-TB was continued until the diagnosis of leptomeningeal myelomatosis in February 2022.
His backache and peripheral sensory neuropathy worsened around December 2021. He was diagnosed with sciatica due to nerve root compression and received a steroid injection to left L4/4 facet joint at the end of December 2021, but the injection did not improve his condition. Lenalidomide maintenance was off in the middle of January because worsening drug-induced peripheral neuropathy was suspected while anti-TB, which could also cause drug-induced peripheral neuropathy, was continued to ascertain the main causative agent and in view of the importance of complete anti-TB regimen. However, symptoms were not improved and motor weakness at right wrist and fingers appeared in February 2022. MRI brain and whole spine in the middle of February 2022 showed multiple nodular lesions at leptomeningeal at the cerebrum, cerebellum, spinal cord, cauda equina, and bilateral internal auditory canals (Supplementary Data). CSF analysis showed protein 1.83 g/L, glucose 3.3 mmol/L, cell count 113 x 106/L with all mononuclear cells, cytology of abundant large atypical plasmacytoid cells in loose clusters along with singly dispersed cells, and immunophenotyping of lambda-restricted plasma cells (Figure2). SPE showed reappearance of M-protein <1 g/L. He was treated as MM-CNS at relapse/progression in this case given the tempo of the worsening CNS symptoms which appeared more than a year after initial diagnosis of MM, although MM-CNS at diagnosis could not be confidently ruled out because no CNS assessment was done.
After the diagnosis of leptomeningeal myelomatosis, he received intravenous methylprednisolone 1 g daily for three days which improved the symptoms partially. He decided to take traditional treatment, which did not improve the symptoms further instead the symptoms started to worsen after a week. At the end of March 2022, he and his family members agreed for chemotherapy. Before the start of chemotherapy, he was wheelchair and bed bound with lower limbs' power of grade 3 at the right and 4 at the left and upper limbs' power of 3-4 at the right and 4-5 at the left. Finger-nose test was positive. He was delirious and had visual and auditory hallucination. MRI showed worsening of leptomeningeal lesions (Figure 3). Dara-PVPD (daratumumab, pomalidomide, vincristine, procarbazine, and dexamethasone) was started. His condition was rapidly improved. He was able to stand and walk with walking frame after two cycles of treatment. At the time of writing, he completed the 4th cycle in the middle of May 2022. Between the 2nd and 3rd cycle, he developed an abscess at left gluteal ischial tuberosity region which resolved with antibiotic and local surgical drainage but resulted a week delay to the commencement of the 3rdcycle. The peripheral sensory neuropathy worsened from fingertips to whole palms and soles after the 2nd cycle needing dose modification. The detail of Dara-PVPD given from the 1st to 4th cycle is shown in Supplementary Data.
He achieved a VGPR3 after the 4th cycle. CSF analysis in the middle of the 4th cycle showed protein 0.58 g/L, glucose 3.2 mmol/L, cell count 6 x 106/L, cytology of low cellularity with no malignant cell seen, and immunophenotyping of no evidence of clonal plasma cells and myeloma involvement. MRI showed disappearance of leptomeningeal lesion in the cerebrum, cerebellum, spinal cord, and cauda equina, except PR at left internal auditory canal and left external capsule (Supplementary Data).
He completed 6th cycle in the middle of June 2022. Assessment post-6th cycle showed further CNS improvement:CR with CSF and other MRI lesions except stable external capsule lesion as compared to MRI post-4th cycle. At the time of writing, he was undergoing peripheral blood haematopoietic stem cell collection and planned for thiotepa-based autologous haematopoietic stem cell transplantation in the middle of July 2022.