Skeletal-Related Events In Patients With Multiple Myeloma In The Era Of Novel Agents: Low Incidence Of Pathological Fractures After Treatment

Abstract Skeletal-related events (SREs) which include pathological fractures, spinal cord compression (SCC) and a need for radiotherapy or surgery to bone are frequent complications of multiple myeloma (MM). Although, the frequency and characteristics of SREs in MM patients who received conventional chemotherapy (CC) or thalidomide-based regimens along with bisphosphonates (BPs) have been described, there are no data available in the era of proteasome inhibitors or novel IMiDs. Thus, we retrospectively evaluated the records of 400 consecutive patients with symptomatic MM (207M/193F, median age: 63 years) who were diagnosed, treated and followed in a single center. All patients had a whole body skeletal survey using conventional radiography at diagnosis and then at the time of relapse or whenever clinically indicated, while MRI of the spine and pelvis at diagnosis was available for 223 patients. Furthermore, we tested 125 patients for SNPs in genes that are involved in the biology of bone destruction: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). At diagnosis, the skeletal survey detected osteolytic disease in 284 (71%) patients. In MRI, 34.5% of the patients had focal, 40.5% diffuse, 21% normal, and 4% a variegated pattern of marrow involvement. SREs were observed in 167 (41.7%) patients at diagnosis: 104 (26%) patients presented with pathological fractures (87 with vertebral fractures, 18 with rib fractures and 17 with fractures of the long bones; 22 patients had both vertebral and long bone or rib fractures), while 22 (5.5%) patients required surgery to bone, 21 (5.2%) radiotherapy and 20 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (49.5% vs. 24%, p<0.001) or abnormal MRI pattern (49.7% vs. 23.3%, p=0.001). However, we noted that approximately 1/4 patients without lytic lesions in plain X-rays or with normal MRI pattern presented with a SRE at diagnosis. Patients homozygous for RANKL polymorphism had lower incidence of osteolysis at diagnosis (14/28, 50%) versus all others (76%, p=0.009), suggesting that this polymorphism may protect bone loss in MM, as it has been suggested for normal population. Frontline therapy with IMiD-based regimens was given in 172 (43%) patients, while 80 (20%) patients received bortezomib-based regimens, 111 (27.7%) both IMiD and bortezomib (VTD or VRD) and 37 (9.2%) patients CC. BPs were given in all but 86 patients (21.5%) at diagnosis, mainly due to renal insufficiency; however, almost 60% of them (n=51) received BPs later in the course of their therapy. The vast majority (91%) of patients received zoledronic acid (ZA). Due to renal impairment, ZA was discontinued in 6 patients, while the dose was reduced in 44. During first line treatment, 7 (1.75%) patients developed a SRE: 2 on bortezomib- and 5 on IMiD-based regimens. The rate of SREs was higher in patients who did not receive upfront BPs (4.7% vs. 1%; p=0.021). The median follow-up was 39 months. At the time of first relapse (data available for 176 patients), 3 patients presented with fractures and 35 patients required local radiotherapy to bone (SRE incidence: 21.6%). Patients who had received only bortezomib-based regimens (VD or VCD, n=20) had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173); the 3 patients with fractures had received MPT (n=2) or RD (n=1). In total, during the course of their disease, 52.8% of the patients presented with at least one SRE. Presentation with SREs at diagnosis did not predispose for SREs during the disease course, regardless of anti-myeloma treatment, possibly due to the low number of fractures and the higher number of radiation needed after frontline therapy. In summary, our data from the first systematic report on the incidence and characteristics of SREs in the era of novel agents indicate that SREs remain a significant complication in MM. Importantly, despite high response rates after first line therapy more than 20% of patients required radiotherapy at the time of relapse. The fracture rate was very low during first line therapy and at first relapse probably due to the extensive use of potent BPs and bortezomib, which has bone anabolic effects. The use of modern imaging techniques (i.e. PET/CT or LDWBCT) that can detect bone masses earlier and lead to earlier initiation of treatment may reduce the SRE incidence in the near future. Disclosures: No relevant conflicts of interest to declare.

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Natural History of Skeletal Related Events in Patients with Multiple Myeloma Who Received First- and Second- Line Therapy with Novel Agents: Results from a Single Center Analysis in 620 Patients

Blood ◽

10.1182/blood-2019-123606 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4326-4326

Author(s):

Evangelos Terpos ◽

Nikolaos Kanellias ◽

Eftathios Kastritis ◽

Maria Gavriatopoulou ◽

Vassilis Koutoulidis ◽

...

Keyword(s):

Research Funding ◽

Novel Agents ◽

Long Bone ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Skeletal Related Events ◽

First Relapse

Introduction: Skeletal-related events (SREs) that include pathological fractures, spinal cord compression (SCC) and need for radiotherapy or surgery to the bone are frequent complications of multiple myeloma (MM). Although the incidence of SREs at diagnosis is well-documented, there is limited information for the natural history of SREs during treatment with novel agents. Thus, we evaluated the SRE rate in MM patients who received frontline and second line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies and explored possible correlations with disease or genetic features and type of treatment. Methods: MM patients who received frontline therapy in our center (Department of Clinical Therapeutics, University of Athens, Greece), between 2007-2017, were included in this analysis. Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and then at the time of relapse or whenever clinically indicated. Magnetic Resonance Imaging (MRI) of the spine and pelvis at diagnosis was recorded when available. SNPs in genes that are involved in bone destruction in osteoporosis were also evaluated: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). Results: In total, 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. At diagnosis, osteolytic disease was present in 408 (66%) patients. MRI was available in 390 patients: 149 (38%) patients had focal, 139 (36%) diffuse, 81 (21%) normal and 21 (5%) variegated pattern of marrow involvement. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures (183 with vertebral fractures, 18 with rib fractures and 15 with long bone fractures; 32 patients had both vertebral and long bone or rib fractures), while 34 (5.5%) patients needed surgery to bone, 45 (7.2%) radiotherapy and 31 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (76.4% vs. 12.4%, p<0.0001) or abnormal MRI pattern (49% vs. 11.3%, p<0.0001) at diagnosis. No correlation was found between the presence of SREs at diagnosis and a specific SNP of those studied. Frontline therapy with IMiD-based regimens was given in 38% of patients; 27% patients received bortezomib-based regimens and 28% both IMiD and bortezomib-based therapies (VTD or VRD); 7% received only conventional chemo. Bisphosphonates (BPs) were given to 465 patients (75%) at diagnosis; the vast majority (91%) received zoledronic acid. The remaining 155 patients did not receive upfront BPs, mainly due to renal insufficiency. During first line treatment, 39 (6.3%) patients developed a SRE: 25/341 (7.3%) on bortezomib- (including combos with an IMiD) and 14/235 (6%) on IMiD-based regimens. At the time of first relapse, 4.5% of patients presented with new fractures and 12% required local radiotherapy to bone (SRE rate: 16.5%). The rate of SREs at first progression was much higher in patients who did not receive upfront BPs (92.3% vs. 7.7%). There was no difference in the incidence of SREs at first relapse between patients who received PI- vs. non-PI-based regimens as first line therapy (54.2% vs. 45.8%, p=0.544). During second line therapy, 12.2% of patients developed a SRE, with no difference regarding the second line therapy (PI- or IMiD-based regimens). In total, 126 (20.3%) patients developed at least one SRE, during the course of the first and second line of therapy; this was more common in those who presented with an SRE at diagnosis (33% vs 12%; p<0.03). Conclusions: Our data, which constitutes one of the few systematic reports on the incidence and characteristics of SREs in the era of novel agents, indicate that SREs remain a significant complication in MM. Despite high response rates after first line therapy and the broad use of BPs, more than 20% of patients develop a new SRE during the first and second line treatment or at the time of first relapse. Importantly, patients who do not receive BPs due to renal impairment develop very frequently SREs, suggesting an unmet need in this setting. More effective frontline therapies or more potent bone-targeted agents (denosumab or anti-sclerostin drugs) may manage to further reduce the SREs rate in MM patients, especially in those who cannot receive BPs. Disclosures Terpos: Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Kastritis:Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Gavriatopoulou:Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Dimopoulos:Sanofi Oncology: Research Funding.

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Deletion 17p in Unselected Newly Diagnosed Symptomatic Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.5081.5081 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5081-5081

Author(s):

Efstathios Kastritis ◽

Evangelos Terpos ◽

Maria Gkotzamanidou ◽

Maria Roussou ◽

Maria Gavriatopoulou ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Elevated Serum ◽

Initial Therapy ◽

Novel Agents ◽

Newly Diagnosed ◽

First Line ◽

Poor Outcome ◽

First Line Therapy ◽

Line Therapy

Abstract Abstract 5081 Multiple myeloma is characterized by significant genetic heterogeneity. Cytogenetic abnormalities are almost always present and specific cytogenetic features may be associated with poor outcome. Deletion of the short arm of the chromosome 17, involving the p53 locus, has been associated with poor outcome of the disease and the frequency of this abnormality increases in more advanced phases of the disease. Novel drugs may overcome, to a certain degree, the poor prognosis that is associated with certain cytogenetic abnormalities, but recent data indicate that neither bortezomib nor thalidomide or lenalidomide may overcome the deleterious effect of del17p either in newly diagnosed or in patients with relapsed disease. These data come from selected patients who have been treated within the context of clinical trials, most of which included intensified treatment such as single or double transplants. In order to assess the prognostic importance of del 17p in unselected patients with multiple myeloma, most of which received upfront novel agents, we analyzed 168 consecutive previously untreated patients, who were treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece) who had available data on del17p, assessed by standard FISH methodology. Some of these patients were included in clinical trials, however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also included in the analysis, thus, being more representative of the general myeloma population. IMWG criteria were used for the assessment of response, progression-free (PFS) and overall survival (OS). Twenty-five (15%) of patients had del17p detected at initial diagnosis. The baseline clinical characteristics and conventional prognostic factors of patients with and without del17p were not significantly different. First line therapy was based on novel agents (thalidomide, bortezomib or lenalidomide) in 91% of patients and was similar for patients with or without del17p (p=0.887). Response to first line therapy was also similar (83% for those with del 17p versus 78% for those without, p=0.529). The quality of responses (CR, VGPR & PR) was also similar. Sixty percent of patients with a del17p and 39% of those without del17p have relapsed or progressed after initial therapy. The median progression free survival for patients with and without del17p was 18.5 versus 22.5 months respectively (p=0.065). In multivariate analysis, del17p was associated independently with shorter PFS (HR: 1.77, 95% CI: 1.021–3.07, p=0.042). Other factor that were independently associated with shorter PFS included age>65 years (p<0.001), ISS stage (p=0.028), low platelet counts (<130×109/L; p=0.032) and elevated serum LDH ≥300 IU/L (p<0.001). The median survival was significantly shorter for patients with del17p (29.5 versus 51 months, p=0.007). When we adjusted for other prognostic factors, including treatment with novel versus conventional agents, then the presence of del17 was independently associated with shorter survival (HR: 2.29, 95% CI: 1.15–4.6, p=0.019). Other factors associated with shorter survival included age >65 years (p=0.005), ISS-3 disease (p=0.038), low platelet counts (<130×109/L; p=0.005) and elevated serum LDH ≥300 IU/L (p=0.001). Importantly, median survival after first disease relapse for patients with del17p was 14 months while for patients without del17p was 42 months (p=0.01), despite the fact that in almost all patients novel agents were used as salvage treatment. In conclusion del17p remains an independent prognostic factor associated with poor survival in unselected patients with newly diagnosed MM, even when novel agents are used as initial therapy. Patients with del17p have very poor outcome after relapse, even with the use of novel agents as salvage therapy. Our data indicate that novel treatment and innovative strategies should be considered for these patients and that patients with del17p should be considered for participation in clinical trials of novel agents as soon as they relapse, since currently available treatment options offer limited benefit in these high risk patients. Disclosures: No relevant conflicts of interest to declare.

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Bortezomib in first-line therapy is associated with falls in older adults with multiple myeloma

Journal of Geriatric Oncology ◽

10.1016/j.jgo.2021.02.009 ◽

2021 ◽

Author(s):

Kelly L. Schoenbeck ◽

Mark A. Fiala ◽

Tanya M. Wildes

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Falls In Older Adults

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Analysis of Falls in Older Adults with Multiple Myeloma Undergoing First-Line Therapy

Blood ◽

10.1182/blood-2019-129611 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5886-5886

Author(s):

Kelly L. Schoenbeck ◽

Tanya M. Wildes ◽

Mark A. Fiala

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Peripheral Neuropathy ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Increased Risk ◽

Risk Of Falls ◽

Falls In Older Adults ◽

First Line Treatment

Background: Patients with multiple myeloma are frequently treated with bortezomib, a proteasome inhibitor, which is associated with treatment-related peripheral neuropathy. Older adults are at increased risk of falls compared to the general population, often leading to associated morbidity and mortality. While an association between peripheral neuropathy and falls in older adults is well-established, the relationship between bortezomib and falls in older multiple myeloma patients is unknown. Our primary aim was to determine if older patients with multiple myeloma treated with bortezomib as first-line therapy had an increased incidence of falls within the first 12 months after starting treatment. Our secondary aim was to assess the overall survival of patients who fell compared to those who did not among patients who lived more than 12 months after initiating treatment. Methods: We analyzed the SEER-Medicare database for all patients 65 years old or older diagnosed with multiple myeloma between 2007 and 2013 and were enrolled in fee-for-service Medicare part A, B and D plans. The patients' corresponding Medicare claims data were analyzed through 2014 for myeloma treatments, fall claims, and covariates of interest. The primary outcome was accidental falls (E880-E888) occurring between 14 days to 12 months after starting multiple myeloma treatment. First-line therapy was defined as any anti-myeloma treatment administered within 14 days of starting multiple myeloma treatment, with bortezomib treatment being the focal independent variable. Cox regression was performed to determine the relative risk of having a fall after controlling for other covariates. Patients who started bortezomib after first-line therapy were censored at time of bortezomib commencement. The survival analysis included only patients who survived more than 12 months of starting treatment to allow landmark analysis of falls in the first year. Results: Of 4,084 older adults with new multiple myeloma diagnoses undergoing first-line therapy, the median age was 75 (range 65-97) with 51% males. Bortezomib was used in first-line therapy for 2,052 (50%) patients, of which 157 (8%) patients experienced a fall within 12 months after starting treatment compared to 102 (5%) of patients not receiving bortezomib (p < 0.001). Bortezomib was associated with a 28% increase risk of falls (HR 1.29; 95% CI 1.00-1.65; p = 0.047). In multivariate analysis, bortezomib was not associated with an increased incidence of falls after controlling for age, gender, race, proxies for Charlson Comorbidity Index (CCI) and poor performance status, pre-existing peripheral neuropathy, falls within the 12 months prior to starting first-line myeloma treatment, depression, polypharmacy, and first-line treatment with lenalidomide (Table 1). Advancing age, history of fall(s), depression, and polypharmacy (defined as more than 10 unique prescription medications at initiation of first-line treatment), were all associated with an increased risk of falls, consistent with prior literature. In a landmark analysis of those who survived 12 months following the start of treatment, a fall was associated with a 26% increased risk of hazard for death (aHR 1.26; 95% CI 1.02-1.56; p = 0.033) after controlling for other covariates. The median OS of those with a fall was 35.7 months (95% CI 29.1-48.4) compared to 49.1 months (95% CI 47.1-52.8) for those without (p < 0.0001). Conclusion: In older adults with multiple myeloma, treatment with bortezomib was not associated with increased risk of a patient having a diagnostic code for falls. However, experiencing a fall within the year after starting treatment was associated with decreased overall survival. Limitations of the study include that the incidence of falls is likely underestimated in billing data, given prior data from our group showing a rate of self-reported falls of 26% in the year after diagnosis. Additional research, including prospective trials involving fall assessments, should be considered in older patients with multiple myeloma. Disclosures Wildes: Janssen: Research Funding; Carevive: Consultancy. Fiala:Incyte: Research Funding.

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Efficiency of lenalidomide, bortezomib and prednisone (RVP) in patients with newly diagnosed multiple myeloma

Oncohematology ◽

10.17650/1818-8346-2019-14-1-14-19 ◽

2019 ◽

Vol 14 (1) ◽

pp. 14-19 ◽

Cited By ~ 1

Author(s):

K. A. Belousov ◽

T. A. Mitina ◽

Yu. Yu. Chuksina ◽

A. K. Golenkov ◽

E. V. Kataeva ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Objective Response ◽

Hematological Toxicity ◽

Efficacy And Safety ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Objective: to study the efficacy and safety of the antitumor RVP program (lenalidomide, bortezomib, prednisone) as a first-line therapy in patients with multiple myeloma (MM). Materials and methods. A prospective study involved 39 patients with MM (15 women, 24 men), median age 61 years (30–76 years). All patients had Durie–Salmon stage III disease. According to the paraprotein isotype variant, 19 patients (48.7 %) had Gk myeloma, 8 (20.5 %) had Gλ, 4 (10.2 %) – Ak, 1 – Aλ, 1 – Dk, 1 – paraproteinemia Bens-Jones k and 1 – Bens-Jones λ, 2 – Dλ, and 2 patients – nonsecreting MM. The average level of plasma cells in the bone marrow was 31.7 % (0.8–80.0 %). In 14 (35.8 %) patients there were plasmacytomas of various localization (spine, cranial bones, clavicle, pleura). Nine (23.0 %) patients had renal failure, requiring the start of renal replacement therapy. The average Karnovsky index in the study group was 50 %. All patients received RVP therapy (lenalidomide 25 mg in 1–14 days, bortezomib 1.3 mg subcutaneously in 1, 4, 8, 11 days, prednisolone 60 mg/m2; the interval between courses was 42 days) as the first line therapy. Evaluation of therapy efficacy, characterized by overall survival, objective response rates (the number of complete, very good partial and partial remissions) was performed after 6 treatment courses. Results. The median follow-up was 15 months; the median of overall survival was not achieved. Objective antitumor response achieved in 29 (74.3 %) patients, including complete remissions in 3 (7.6 %), very good partial remissions – in 7 (17.9 %), partial remissions – in 19 (48.7 %) patients. In 2 out of 9 patients who received renal replacement therapy, independence from dialysis therapy was achieved. Cases of III–IV stage hematological and non-hematological toxicity in the study were not noted. Conclusion. The antitumor RVP program showed high efficacy and safety as a first-line therapy in a non-selective group of patients, including those with a complicated MM course.

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The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL)

Blood ◽

10.1182/blood-2004-08-3231 ◽

2005 ◽

Vol 105 (7) ◽

pp. 2949-2951 ◽

Cited By ~ 144

Author(s):

Giovanni Palladini ◽

Vittorio Perfetti ◽

Stefano Perlini ◽

Laura Obici ◽

Francesca Lavatelli ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Primary Amyloidosis ◽

Line Treatment ◽

Second Line ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Symptomatic Bradycardia ◽

Intermediate Dose

AbstractBased on the efficacy of thalidomide in multiple myeloma and on its synergy with dexamethasone on myeloma plasma cells, we evaluated the combination of thalidomide (100 mg/d, with 100-mg increments every 2 weeks, up to 400 mg) and dexamethasone (20 mg on days 1-4) every 21 days in 31 patients with primary amyloidosis (AL) whose disease was refractory to or had relapsed after first-line therapy. Eleven (35%) patients tolerated the 400 mg/d thalidomide dose. Overall, 15 (48%) patients achieved hematologic response, with 6 (19%) complete remissions and 8 (26%) organ responses. Median time to response was 3.6 months (range, 2.5-8.0 months). Treatment-related toxicity was frequent (65%), and symptomatic bradycardia was a common (26%) adverse reaction. The combination of thalidomide and dexamethasone is rapidly effective and may represent a valuable second-line treatment for AL.

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