MULTIPLE MYELOMA WITH ADVANCED BONE DISEASE AND LOW TUMOR BURDEN– DIFFERENT CLINICAL PRESENTATION BUT SIMILAR OUTCOME AFTER BORTEZOMIB-BASED THERAPY AND RADIOTHERAPY
SUMMARY – There is a small but well recognized group of patients with multiple myeloma (MM), characterized by multiple bone lesions and low tumor burden, the so-called macrofocal form of MM (MF-MM). The aim of the study was to analyze the incidence, clinical manifestation, thera- peutic outcome and prognosis of patients with MF-MM treated with bortezomib-based therapy and radiotherapy, in comparison to classic MM. There were 148 MM patients treated with bortezomib- based regimens, with 15 (10.1%) of them meeting the criteria for MF-MM. Comparative analysis involved disease- and therapy-related variables and markers of bone metabolism in MF-MM and classic MM groups. Event-free survival (EFS) and median survival (MS) were analyzed. Patients in MF-MM and classic MM groups had similar mean age and sex distribution. Patients with MF-MM had advanced myeloma bone disease (MBD), significantly lower clonal plasma cell infiltration in bone marrow, and lower paraprotein level. These patients were predominantly in an early International Staging System stage, showed non-secretory and light-chain variants, and significant association with extramedullary plasmacytomas. EFS was 20 months in MF-MM group versus 13 months in classic MM group (nonsignificant difference). MS was 42 months in both MF-MM and classic MM groups. MF-MM presents with imbalance of the minimal tumor burden and massive bone involvement. Along with advanced skeletal manifestations, these patients showed features of preserved bone mar- row and no end-organ damages. Following bortezomib-based therapy and radiotherapy, the EFS and MS did not differ between MF-MM and classic MM groups.
Introduction
Generalized bone lesions affect clinical evolution of multiple myeloma (MM), create difficulties in de- fining the stage of the disease, its therapeutic outcome does not always follow the outcome of medullary disease, and myeloma bone disease (MBD) disables pa- tients and deteriorates their prognosis. Usually, severe MBD reflects an advanced MM with high percentage of bone marrow plasma cell infiltration, high level of serum/urine paraprotein and end-organ damages.A small proportion of MM patients present with multiple, generalized bone lesions and low tumor bur- den, i.e. low percentage of monoclonal plasma cells in bone marrow and low production of paraprotein or non-secretory variants. This group is called by some authors multifocal form of MM (MF-MM). The same term was used in our analysis. There are limited data in the literature on therapeutic options, outcome, moni- toring of therapeutic response, prognostic factors and survival of these patients.The aim of the study was to analyze the incidence, clinical manifestation, therapeutic outcome and prog- nosis of patients with MF-MM treated with bortezo- mib-based therapy and radiotherapy in comparison to classic MM.During the period from January 2008 till June 2014, 148 patients with MM treated with bortezo- mib-based regimens were retrospectively studied. Their mean age was 60.16±9.43 years and the male to female ratio was 1.05:1. The criteria for MF-MM were: MBD grade 2 and 3; clonal plasma cell infiltra- tion in bone marrow less than 20%; and paraprotein in serum <25g/L, paraprotein in urine <1.0 g/24 h by protein electrophoresis/immune fixation. Fifteen of 148 (10.1%) patients fulfilled the criteria for MF-MM (Table 1).
Clinical stage was defined according to the International Staging System (ISS). Bone lesions were assessed by conventional x-ray of axial skeleton or computed tomography (CT) scan and magnetic reso- nance imaging (MRI) at the sites of interest. MBD was graded in four grades: 0 – no lytic bone lesions or osteoporosis; 1 – osteolytic lesions at <3 sites +/- os- teoporosis; 2 – multiple bone lesions at >3 sites and/or pathologic fractures; and 3 – multiple lytic lesions and destructions of skeletal segments. All 148 patients were treated with bortezomib-based regimens in 21- day cycles. Bortezomib (Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, Cambridge, Massachusetts, USA) was administered in a dose of1.3 mg/m2 on days 1, 4, 8 and 11, and was combined with dexamethasone (VelDex) in 31 (20.9%), with cy- clophosphamide (CyBorD) in 54 (36.5%) and with anthracycline (PAD) in 14 (9.5%) patients. Bortezo- mib regimen was administered as first line therapy in 53 (36.1%), as second line therapy in 51 (34.7%) and as >second line therapy in 43 (29.1%) patients. Five (33.33%) patients underwent high-dose therapy with melphalan 200 mg/m2 with autologous stem-cell transplantation. Radiotherapy of lytic bone lesions, pathologic factures and soft tissue plasmacytomas was incorporated in therapeutic regimen when indicated. Patients underwent radiotherapy on a linear accelerator Siemens Mevatron Primus.
Two main schemes of irradiation were used: 2×8.5 Gy with an interval of 72 hours and 5×4 Gy. Three patients received irradiation at one of the affected sites with 1 fraction of 8 Gy as a single dose. Comparative analysis of the disease and therapy related variables and markers of bone metabo- lism (serum Ca and alkaline phosphatase, AP) was performed in patients with MF-MM and classic MM. As patients with MF-MM represent a unique prob- lem in terms of therapeutic response because many of them lack a detectable monoclonal protein in serum and/or urine and myeloma cell infiltration in bone marrow is initially low, the event free survival (EFS) and median survival (MS) were assessed for analysis of outcome. Therapeutic response of MBD was assessed by the dynamics of bone pain, dynamics in the size of bone lesions and changes in the level of serum Ca and AP. Statistical analysis was performed by use of SPSSv. 18.0, using descriptive analysis, analysis of variation and analysis of alternatives, and independent samples T-test for independent samples. The method of Ka- plan-Maier with log rank test was used for analysis of EFS and MS.
Results
Patients in the MF-MM and classic MM groups had similar mean age (60.6±7.32 vs. 60.11±9.67 years) and similar sex distribution (Table 2).Clinical characteristics of MF-MM patients in comparison to classic MMBy the principle of selection, in comparison with classic MM patients, all patients with MF-MM had MM = multiple myeloma; MF-MM = macrofocal MM; Hb = he- moglobin; LDH = lactate dehydrogenase; AP = alkaline phospha- tase; β2M = beta2-microglobulin; NS = nonsignificantadvanced MBD, i.e. grade 2 and grade 3 was recorded in 5 (100%) and 54 (40.9%) patients, respectively (p<0.001); MF-MM patients also had significantly lower clonal plasma cell infiltration in bone marrow and lower level of paraprotein in serum and/or urine. These patients were predominantly in an early ISS stage and showed a significant predominance of non- secretory and light-chain variants (Figs. 1 and 2). In the group of MF-MM, there were no patients with severe anemia, while the share of patients with renal failure, hypoalbuminemia and elevated beta2-micro- globulin (β2M; >3.5 mg/L) was significantly lower. MF-MM was significantly associated with extramed- ullary plasmacytomas (Table 2). The levels of hemo- globin and albumin were also significantly higher, while β2M and creatinine were significantly lower than in classic MM (Table 3). There was no between- group difference in the levels of Ca and AP.
The mean number of bortezomib cycles was 6.07±1.06 in MF-MM and 6.73±0.49 in classic MM group (NS). Patients with MF-MM were irradiated significantly more frequently than those with classic MM (14 (93.3%) vs. 65 (49.9%); p<0.001) and MF-MM had a significantly higher mean number of irra- diations (2.53±0.34 vs. 0.56±0.54; p<0.001). Therapy alleviated bone pain in all patients, and in 9/15 patients complete resolution of symptoms occurred. In 3 patients, reduction in the size of bone lesions was ob- served. Extramedullary formations were reduced in all patients, and in 11/15 patients they completely disap- peared (fibrous tissue on enhanced CT scan). After therapy, a significant increase in the level of AP and decrease in the levels of Ca, LDH and β2M was re- corded (Table 4). There was a trend of longer EFS of 20 months (95% confidence interval (95% CI): 18.152-21.848) in MF-MM group versus 13 months (95% CI: 10.213-15.787) in classic MM group but the differ- ence was not statistically significant (Fig. 3). MS was 42 months in both MF-MM and classic MM groups: MF-MM 95% CI: 18.38-65.62 and classic MM 95%CI: 37.04-46.96.There was no significant difference in hematologic and non-hematologic toxicity between the two groups, MM = multiple myeloma; MF-MM = macrofocal MM; Hb = he- moglobin; LDH = lactate dehydrogenase; β2M = beta2-microglob- ulin; AP = alkaline phosphatase; NS = nonsignificantalthough patients with MF-MM had undergone more irradiation (Table 5). The most common side effect was peripheral polyneuropathy: 5 (33.3%) versus 46 (35.9%) in the MF-MM and classic MM group, re- spectively. There were no patients with polyeuropathy grade 3 and 4. Discussion Intensive bone resorption is the earliest event in the evolution of MM1, while the increased number of osteoclasts/mm2 per trabecular bone surface is the most solid marker of monoclonal gammopathy of undeter- mined significance (MGUS) transformation into ac- tive MM2. Nowadays, the pathogenic mechanisms of bone resorption are a subject of profound research. Both the osteolytic lesions at the sites of plasma cell infiltration and distant humoral demineralization of bone are a result of the action of osteolytic cytokines secreted or induced by myeloma cells. A great number of osteolytic substances or ‘osteoclast activating factors’ have been discussed in the literature, e.g., tumor necro- sis factor α (TNF-α), TNF-β, interleukin 1b (IL-1b), IL-6, IL-10, IL-11, hepatocyte growth factor (HGF), matrix metalloproteinases (MMP) 2, 7, 9, and macro- phage inflammatory protein (MIP-1α, MIP-1β)3. Nowadays, the critical role of the osteoprotegerin/re- ceptor activator of NF-jB ligand (OPG/RANKL) sys- tem in bone remodeling in physiologic and pathologic conditions and in MM has been proven in many pre- clinical settings and in myeloma patients. The balance of the system is shifted towards RANKL overexpres- sion and OPG suppression resulting in increased bone resorption and decreased bone formation. The role of Dickkopf protein-1 (DKK-1) as an inhibitor of osteo- blast function is also important4-7. The negative quanti- tative balance of bone remodeling is a result of en- hanced osteoclast function and suppressed osteoblast function reflected by the level of bone-specific AP. Until the era of novel agents, almost all drugs attacked the factors responsible for osteoclast activation, and no drug stimulated osteoblast function. With the intro- duction of bortezomib in clinical practice, it was prov- en that proteasome inhibition not only suppresses bone resorption but also affects positively osteoblast function8. There are data on a decrease of the markers of bone resorption and increase of the markers of bone synthesis in MM after treatment with bortezomib9. Patients with MF-MM present a specific feature, imbalance of the minimal tumor burden on the one hand, and massive bone involvement, i.e. multiple os- teolytic lesions, fractures, and destructions of skeletal segments on the other hand. A parallel to light-chain (AL) amyloidosis is possible: in AL amyloidosis, low plasma cell tumor mass produces light chains with prominent tissue tropism; in MF-MM form, a higher expression of osteolytic cytokines with high bone im- pact is suspected. Although MF-MM form is rare, it poses significant difficulties in diagnosis, staging, prognostic assessment and therapy of patients. These patients share some common characteristics such as low tumor burden, i.e. low percentage of clonal plasma cells in bone marrow, and low production of serum and/or urine paraprotein, with a predominance of the non-secretory and light-chain variants. Minimal sup- pression of hematopoiesis and low M-grade with rare immune paresis is reflected by the unusual normal lev- els of hemoglobin10, platelets and β2M, and preserved renal function. The most prominent feature of MF- MM is massive involvement of skeleton and frequent associations with soft tissue plasmacytomas11. There are contradictory data concerning the outcome of these patients. Smith et al. report that patients with non-secretory MM and multiple lytic bone lesions have a significantly shorter MS of 21 months versus 42 months12. In a retrospective study, Dimopoulous et al. found the incidence of MF-MM of 10/56 in young MM patients for a 20-year period, therapeutic re- sponse rate of 55%, and unreached MS. According to the authors, these patients had low tumor burden and better outcome with calculated MS of 8 years13. Kumar et al. describe atypical presentations of non-secretory MM and their frequent association with multiple bone lesions and plasmacytomas. They proved similar outcome and prognosis in these patients after autolo- gous stem cell transplantation compared to the classic MM form11. Our patients shared the presenting fea- tures reported by most of the authors with identical MS in the two groups after therapy with bortezomib- based regimens and radiotherapy. The trend of longer PFS in our analysis may have been a reflection of the late diagnosis of relapse due to the absence or low grade M-component. The dynamics of the bone me- tabolism markers of Ca and AP after therapy with bortezomib-based regimens plus radiotherapy reflect- ed improved osteoblast and osteoclast function. While the rapid therapeutic response and improvement in the markers of MM activity are typical after bortezo- mib therapy, there are few data on the reduction in the size of ostelytic bone lesions and increase in the bone fraction of AP. Zangari et al. found a 25% increase of AP level above the baseline, which correlated with high CR + PR rates and longer time to progression14. Heider et al. demonstrated significant elevation of os- teocalcin and bone fraction of AP in parallel to reduc- tion of collagen cross-links15. The mechanisms of im- provement of bone lesions once they occur are still under investigation. Nowadays, the role of MRI and positron emission tomography-CT (PET-CT) in the assessment of MF-MM is proven as they differentiate plasma cell infiltration of bone marrow, osteolytic bone lesions and soft tissue plasmacytomas. These are the recommended methods for monitoring therapeutic response, with exceptional significance in non-secreto ry MM, soft tissue plasmacytomas, as well as in the MF-MM group.Myeloma tumor mass, transformed bone marrow microenvironment, multiple cell populations of osteo- clasts, osteoblasts, osteocytes, stromal cells, endothelial cells, cell-to-cell interactions and humoral factors are being attacked with ‘novel’ agents. Hopefully, it is a matter of near future to disrupt Bortezomib the ‘vicious circle’ of MM, i.e. as MM is more active, bone resorption is more intensive, and vice versa.