Multiple myeloma (MM) is a mature B-cell neoplasm characterized by the presence of clonal plasma cells in bone marrow. Extramedullary MM is associated with aggressive disease and poor prognosis owing to its increased proliferation and therapeutic resistance (1). Although the emergence of monoclonal antibodies (mAbs), such as daratumumab, elotuzumab, and isatuximab, has dramatically improved the prognosis of MM, the optimal sequence of treatment regimens remains controversial (2).

Daratumumab, an anti-CD38 antibody, reduces the number of natural killer (NK) cells, requiring more than six months for recovery (3). Another monoclonal antibody, elotuzumab, is an anti-signaling lymphocytic activation molecule family member 7 (SLAMF7) antibody that activates NK cells (4,5). Several studies have shown that pre-treatment with daratumumab attenuates the effectiveness of elotuzumab (6,7). To date, there have been no reports discussing the use of different mAbs for MM associated with extramedullary disease. Herein, we report a unique case of daratumumab-resistant MM with extramedullary disease that was successfully treated with elotuzumab, pomalidomide, and dexamethasone (EPd).

A 66-year-old Japanese male with a history of hypertension, dyslipidemia, and type 2 diabetes was referred to our hospital for multiple osteolytic tumors of the skull, ribs, and ilium. Laboratory tests revealed anemia (hemoglobin, 12.1 g/dl) and increased immunoglobulin G (IgG, 2,866 mg/dl). Serum levels of β₂ microglobulin and lactate dehydrogenase (LDH) were 3.4 mg/l and 182 U/l, respectively. Immunoelectrophoresis demonstrated the presence of monoclonal component IgG κ-type. Urinary Bence Jones protein was not detected. Serum free light chain κ level was 12.2 mg/l; λ level, 3.1 mg/l; and κ/λ ratio, 3.94. Bone marrow aspirate showed 52% infiltration of monoclonal plasma cells. Cytogenetic analysis revealed a normal male karyotype (Fig. 1A) and fluorescence in situ hybridization (FISH) was negative for del(17p), t(4;14) (Fig. 1B). FISH for t(14;16) was also negative, but gain/amp(1q21) was not tested. The patient was diagnosed with stage II MM according to the Revised International Staging System (8).

Treatment with four cycles of bortezomib, lenalidomide, and dexamethasone, followed by autologous stem cell transplantation resulted in a very good partial response according to the 2016 International Myeloma Working Group uniform response criteria (9). Thereafter, maintenance therapy was continued with lenalidomide and dexamethasone. Thirty-four months later, although the IgG level was well controlled (548 mg/dl), anterior thoracic pain developed. Computed tomography (CT) revealed new osteolytic lesions in the sternum; therefore, the treatment was changed to daratumumab, bortezomib, and dexamethasone (DBd) at 16 mg/kg on days 1, 8, and 15; 1.3 mg per square of body-surface area twice weekly for two weeks; and 20 mg on the day of and the day after bortezomib, respectively (10), resulting in alleviation of his pain and tumor shrinkage.

Fifteen months after the initiation of DBd, severe right-sided chest pain developed, and the IgG level was elevated to 2,266 mg/dl. The lymphocyte count was elevated to 3,072/µl (Fig. 2). Lymphocytes were morphologically normal, while neither lymphocytes subset analysis nor NK cell activity was performed. Serum β₂ microglobulin and κ/λ ratio were 4.5 mg/dl and 0.80, respectively. Chest radiography revealed a massive tumor occupying the apex of the right lung (Fig. 1C). A chest CT scan showed a bulky tumor arising from the right rib, extending to the right thorax, and pleural dissemination with lymph node metastasis to the right axilla and mediastinum (Fig. 1D). Neither bone marrow examination including FISH analysis nor biopsy of extramedullary mass was performed due to the patient's refusal. Upon clinical relapse of MM with extramedullary disease, the treatment was changed to EPd (elotuzumab, 10 mg/kg on days 1, 8, 15 and 22 during cycles 1 and 2, and 20 mg/kg on day 1 of each cycle thereafter; pomalidomide, 4 mg per day on days 1 through 21; dexamethasone, 40 mg once weekly) (11), which resulted in expeditious resolution of the chest pain. Notably, chest radiography on day 13 of treatment revealed marked regression of the tumor in the right apex (Fig. 1E), and serum IgG levels rapidly decreased to 492 mg/dl (Fig. 2). Three months after the initiation of EPd, a subsequent CT scan demonstrated disappearance of the disease (Fig. 1F).

Even in the era of monoclonal antibodies and proteasome inhibitors, the prognosis in MM with extramedullary disease still remains poor (12,13). In a retrospective study assessing elotuzumab-based regimens for the treatment of extramedullary MM, progression-free survival and overall survival were short (3.8 and 12.9 months, respectively) (14). Here, we present the first case of DBd-resistant MM with extramedullary disease that was successfully treated with EPd.

The mechanism of action of elotuzumab depends on the action of NK cells. Elotuzumab binds to SLAMF7, which is expressed at high levels in both MM and NK cells, and exerts cytotoxic effects by activating NK cells and antibody-dependent cellular cytotoxicity (ADCC) (4,5). In contrast, daratumumab, an anti-CD38 antibody, reduces the NK cell count in peripheral blood mononuclear cells by binding to CD38 expressed on NK cells (15). It takes six months for NK cells to recover in number after cessation of daratumumab infusion (3). These results suggest that continuous elotuzumab may have weakened effects when used following treatment with daratumumab.

Hoylman et al (6) compared clinical outcomes in patients who received either daratumumab before elotuzumab (dara-first) or elotzumab before daratumumab (elo-first) and demonstrated that the response rate to elotuzumab was diminished in the dara-first group, with a significantly longer cumulative progression free survival in the elo-first group. In randomized phase III studies, daratumumab was more effective against relapsed/refractory MM when administered with fewer prior lines of therapy (10,16–18). Furthermore, in transplant-ineligible newly diagnosed MM, the ALCYONE and MAIA studies showed that treatment with daratumumab as a front-line therapy produced superior outcomes (19–22). Based on these results, daratumumab is likely to be administered before elotuzumab, and an approach that allows retention of elotuzumab's efficacy is required.

Disease burden, NK cell count, and SLAMF7 expression in myeloma cells have been suggested as biomarkers of elotuzumab response (23). However, these markers are not readily measurable in clinical settings. Recently, a simpler clinical index has been reported to predict response to elotuzumab treatment. This report showed that the median time to next treatment was significantly longer in patients with higher lymphocyte counts (>1,400/µl), non-deviated κ/λ ratio (0.1–10), lower β₂ microglobulin (<5.5 mg/l), and no prior daratumumab use (7). In the present case, although elotuzumab was administered immediately after daratumumab treatment, the patient responded well. Interestingly, in the present case, the lymphocyte counts during DBd gradually increased to a level at which elotuzumab was sufficiently effective (Fig. 2). Although the NK cell fraction was not measured in the present case, the increase in lymphocytes during DBd may reflect the existence of abundant NK cells. Furthermore, in a mouse model, DBd treatment enhanced the cytotoxicity of expanded NK cells by upregulating the expression of NK cell-activating ligands, downregulating the expression of NK cell-inhibitory ligands, and promoting ADCC (24). The augmentation of NK cell cytotoxicity by DBd may also contribute to the enhanced therapeutic effect of EPd. On the other hand, elotuzumab has been shown to inhibit myeloma cell growth in vivo through antibody-dependent cellular phagocytosis by macrophages (25,26). This mechanism of action of elotuzumab may have contributed to the dramatic response seen in our case.

Overall, the findings in our case suggest that EPd might be a promising strategy for the treatment of patients with relapsed extramedullary MM while on daratumumab treatment. Further studies are required to select a more appropriate sequence of treatment for these patients.