A novel combination of bortezomib, lenalidomide, and clarithromycin produced stringent complete response in refractory multiple myeloma complicated with diabetes mellitus – clinical significance and possible mechanisms: a case report

Our patient was a 68-year-old Japanese woman (48 kg/151 cm) with a 7-year history of DM. She had a past history of receiving a radical mastectomy for right mammary cancer in the department of surgery of our hospital at the age of 65. Her postoperative course was uneventful. After the operation, she received chemotherapies (trastuzumab, paclitaxel, and tegafur-uracil) until the end of December 2014, and later she was followed without treatment on an out-patient basis. In March 2015, she showed progressive unexplained anemia. On 4 June 2015, she was admitted to the surgical department of our hospital at the age of 68 because of anemia, abdominal pain, paralytic ileus, generalized neuralgia-like pains, and bilateral shoulder joint swellings and pains. On 13 June 2015, she was referred and admitted to the hematologic division for further evaluation.

Physical examinations on admission were as follows. Her temperature was 36.5 °C, her pulse was 88, and her blood pressure was 130 systolic and 85 diastolic. Her right mamma was completely removed with a remaining operation scar. She appeared chronically ill and could not turn over due to generalized neuralgia-like pains and severe right shoulder pains. Her skin showed pallor and palpebral conjunctivae were anemic. Her abdomen was distended, tympanitic, and diffusely tender without peristalsis, indicating paralytic ileus. Superficial lymph nodes were impalpable.

Laboratory data on admission were as follows. A complete blood cell count showed moderate anemia (red blood cell count, 2.31 × 10¹²/L; hemoglobin 7.4 g/dL), slightly increased leukocytes (white blood cell count, 9.5 × 10⁹/L with 67.5% neutrophils, 17.5% lymphocytes, and 13% monocytes, 2% eosinophils) and normal platelet count (301 × 10⁹/L). Elevated levels of serum free light chain-λ (FLC-λ; more than 3200 mg/L; normal range (nr.), 4.44~26.18 mg/L), β₂-microglobulin (BMG; 6.5 mg/L; nr. 0.9~1.9 mg/L), soluble-interleukin (IL)-2 receptors (1300 U/mL; nr. 124~466 U/mL), ferritin (955.6 ng/mL; nr. 3.6~114 pg/mL), CRP (1.74 mg/dL; nr. 0~0.26 mg/dL), D-dimer (8.69 μg/mL; nr. < 0.72 μg/mL), and fibrin degradation product (FDP; 20.1 μg/mL; nr. < 5 μg/mL), N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 pg/mL; nr. ≤ 125 pg/mL), CA19-9 (42 U/mL; nr. ≤ 37 U/mL), sialyl-Le^x-i (SLX; 42.8 U/mL; nr. ≤ 38 U/mL), glycated hemoglobin (HbA1c; 6.7%; nr. 4.54~6.25%) and uric acid (7.2 mg/dL; nr. 2.5~7.0 mg/dL), and depressed levels of immunoglobulin (Ig) G (341 mg/dL; nr. 870~1700 mg/dL), IgA (15 mg/dL; nr. 110~410 mg/dL), IgM (10 mg/dL; nr. 46~260 mg/dL), IgD (<1.0 mg/dL; nr. ≤ 12.6 mg/dL), total protein (6.4 g/dL; nr. 6.7~8.3 g/dL), albumin (3.8 g/dL; nr. 3.9~4.9 g/dL), zinc turbidity test (ZTT; 1 KU; nr. 4~12 KU), serum Fe (50 μg/dL; nr. 54~181 μg/dL) and total cholesterol (106 mg/dL; nr. 130~219 mg/dL) were observed. Values of carcinoembryonic antigen (CEA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), amylase, blood urea nitrogen (BUN), creatinine, and electrolytes were within normal range. Titers of rheumatoid arthritis particle agglutination, anti-nuclear antibody, anti-microsome antibody, and anti-thyroglobulin antibody were within normal range. Her urine showed proteinuria (7.4 g/day). Lambda-type BJ protein was detected in her urine by immunofixation electrophoresis. Bone scintiscan using ^99mTc-hydroxymethylene diphosphonate (HMDP) revealed multiple uptakes of radioisotope in generalized bones, particularly in vertebrae and shoulder joints. Chest and abdominal computed tomography scans revealed massive soft tissue masses around bilateral shoulder joints suggestive of amyloid light-chain (AL) deposition (shoulder-pad sign), paralytic ileus, small multiple mesenteric lymph nodes, small amount of ascites, slight right hydronephrosis, and slight splenomegaly. Skull X-ray films showed sporadic punched out lesions.

An iliac bone marrow (BM) puncture performed on 16 June 2015 showed that her BM was infiltrated by atypical medium-sized and large-sized myeloma cells with basophilic cytoplasm and fine chromatin networks with occasional nucleoli. Binuclear and trinuclear myeloma cells were frequently seen (Fig. 1). Myeloma cells accounted for 70.8% of total nucleated cells on smear preparation. On immunohistochemical examination, they were exclusively positive for light chain λ.

A chromosomal analysis of the BM cells revealed complex hyperdiploidies (Fig. 2). Thus, a diagnosis of BJ-λ type MM (Durie and Salmon, stage IIIA; International Staging System, stage III; Southwest Oncology Group, stage III) was made.

In the hematologic division of our hospital, most of the patients with MM are vulnerable older people with severe complications. Thus, the dose of Len is minimized to 10 mg/day in those patients to avoid the adverse effects, such as leukopenia, thrombocytopenia, toxicoderma, deep venous thrombosis, neuropathy, a high fever associated with elevated CRP (that is, transient inflammatory reaction), and so on. In fact, 10 mg of Len was found to be effective enough for treating MM with reduced adverse effects, and allowing for safe repetitions of treatments [6]. Moreover, doses of Bor and Dex are also reduced to improve tolerability and to optimize efficacy as suggested by Palumbo et al. [7].

The whole clinical course (Fig. 3), the detailed clinical course (Fig. 4), and regimens used during the whole clinical course are listed in Table 1. At first, three cycles of ① vincristine, adriamycin, and Dex (VAD) therapy were carried out. This treatment was fairly effective; levels of FLC-λ and BMG were depressed to 1140 μg/L from more than 3200 μg/L and to 2.2 mg/L from 6.5 mg/L, respectively. Bilateral shoulder joint pains and paralytic ileus were rapidly improved. She was released from confinement to bed and able to walk 3 weeks after starting the first cycle of VAD therapy. Although this regimen proved to be effective for relieving her symptoms, levels of FLC-λ still remained high (1140 mg/L). As shown in Table 1 and Fig. 3, regimens ①~⑫ were consecutively carried out. In general, the regimens including Dex caused severe hyperglycemia which required insulin therapy, and most of them, except regimen ③ in which CAM (400 mg/day for 3 weeks) was combined with Len and Dex, could not be efficiently repeated due to DM aggravation or inefficacy of the regimens. Of all the regimens, regimen ⑨ (short dosing-period [sdp] Bor-Dex-CAM⁸⁰⁰), and the regimen ⑪/⑫ (sdpB^{(Reduced dose [Rd]} R^{Minimized dose [Md]-}CAM⁸⁰⁰) proved to be very effective. Levels of FLC-λ were drastically depressed to a normal range by regimens ⑨ and ⑪ (Fig. 4). However, the former could not be repeated because of the aggravation of DM, leading to deterioration of the general condition of our patient. On the other hand, regimen ⑪ could be safely repeated without fearing DM aggravation; the levels of FLC-λ were brought down to a normal range (12.9 mg/L) with normal κ/λ ratio (1.024) after four cycles of this regimen (Table 1). Myeloma cells disappeared from her BM (Figs. 3 and 4) and BJ proteins disappeared from her serum and urine. Two color flow cytometric analysis of the BM showed absence of clonal plasma cells (PCs). In addition, levels of serum IgG, IgA, and IgM elevated to normal levels. Thus, our patient was proved to be in sCR according to the updated criteria of International Myeloma Working Group (IMWG) [8]. In May 2017, urticaria started to appear after subcutaneous (sc) injections of Bor. Thus, the administration of Bor was reduced to once a week from twice a week (regimen ⑫: sdpB^RedR^Md-CAM⁸⁰⁰) and intravenous administration of hydrocortisone 100 mg, prior to each Bor injection, was started to prevent urticaria. Regimen ⑫ was safely repeated without fearing DM aggravation as well as urticaria. Levels of FLC-λ remained within normal range, and our patient is in good condition as of November 2017.