SPECIAL FOCUS y The comprehensive clinical management of MM
Review
Management of bone disease in multiple myeloma Expert Review of Hematology Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Expert Rev. Hematol. 7(1), 113–125 (2014)
Evangelos Terpos*1, James Berenson2, Noopur Raje3 and G David Roodman4 1 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528 Athens, Greece 2 Institute for Myeloma and Bone Research, West Hollywood, CA, USA 3 Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, MA, USA 4 Indiana University School of Medicine, Indianapolis, IN, USA *Author for correspondence: Tel.: +30 213 216 2846 Fax: +30 210 338 1511 [email protected]
informahealthcare.com
Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal complications that cause significant morbidity and mortality. Currently, bisphosphonates (BPs) are the mainstay for the treatment of myeloma bone disease. Zoledronic acid which has been found to be superior to clodronate, both in terms of reduction of skeletalrelated events (SREs) and survival, and pamidronate are used for the management of myeloma-related bone disease. Patients with active disease (not in CR or VGPR) should receive BPs (especially zoledronic acid) even after two years of administration. Radiotherapy and surgical interventions can also be used for specific conditions, such as pathological fractures, spinal cord compression or uncontrolled pain. The better understanding of the biology of myeloma bone disease has led to the production of several novel agents, such as denosumab (targeting RANKL), sotatercept (activin-A antagonist) and romosozumab (targeting sclerostin) that appear very promising and have entered to clinical development. KEYWORDS: activin-A . bisphosphonates . bone disease . denosumab . RANKL . sclerostin . sotatercept . Wnt pathway
Multiple myeloma (MM) is an incurable hematological malignancy characterized by the accumulation of abnormal plasma cells in the bone marrow and the presence of lytic lesions and/or osteoporosis due to increased osteoclast activity, accompanied by suppressed osteoblast function. The clinical and economic impact of the associated bone pain, pathological fractures requiring surgery and/or radiation to bone, spinal cord compression and hypercalcemia can be devastating, with major effects on quality of life (QoL) and survival [1]. Factors produced by tumor cells stimulate osteoclasts to resorb bone and inhibit osteoblast activity. In turn, growth factors released by the increased bone resorptive process, also increase the growth of MM cells, creating a vicious cycle of tumor expansion and bone destruction. The biologic pathway of the RANK and RANKL and osteoprotegerin (OPG), which is the decoy receptor of RANKL, is of major importance for the increased osteoclast activity observed in MM [2]. Activin-A has also been implicated in MM bone disease through stimulating RANK expression and inducing osteoclastogenesis as well as inhibiting osteoblast differentiation [3–5]. Furthermore, the Wnt signaling inhibitors dickkopf-1 (DKK-1) and sclerostin, which are secreted by myeloma cells and increased in the serum of myeloma 10.1586/17474086.2013.874943
patients, block osteoblast differentiation and activity [6–8]. Since these molecules also interfere with tumor growth and survival, they provide possible targets for the development of novel drugs for the management of lytic disease in myeloma. The aim of this review is to summarize the established therapeutic management of myeloma bone disease and highlight the latest data on agents interfering with bone disease pathophysiology that will provide future interventions. Bisphosphonates: the mainstay of therapy of myeloma-related bone disease
Bisphosphonates (BPs) are pyrophosphate analogs that readily bind the exposed mineralized bone and are taken up by osteoclasts during bone resorption, inhibiting osteoclast recruitment and maturation, preventing the development of monocytes into osteoclasts, inducing osteoclast apoptosis and interrupting their attachment to the bone. All BPs have similar physicochemical properties; however, their antiresorbing activity is different. Their activity is drastically increased when an amino group is entered into the aliphatic carbon chain. Thus, pamidronate and alendronate are 100- and 700-fold more potent than etidronate, both in vitro and in vivo, while ibandronate and zoledronic acid show 10,000- to 100,000-fold
2014 Informa UK Ltd
ISSN 1747-4086
113
Review
Terpos, Berenson, Raje & Roodman
greater potency than etidronate. Oral clodronate, intravenous pamidronate and intravenous zoledronic acid have been licensed for the management of myeloma bone disease. Etidronate and ibandronate were found to be ineffective for the treatment of bone disease in myeloma patients [9,10].
Expert Review of Hematology Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Clodronate
Two major, placebo-controlled, randomized trials have been performed in MM. Lahtinen et al. reported reduction of the development of new osteolytic lesions by 50% in myeloma patients who received oral clodronate for 2 years that was independent of the presence of lytic lesions at baseline [11]. In the other study, although there was no difference in overall survival (OS) between clodronate and placebo patients, patients who received clodronate and did not have vertebral fractures at baseline appeared to have a survival advantage (59 vs 37 months). Both vertebral and nonvertebral fractures as well as the time to first non-vertebral fracture and severe hypercalcemia were reduced in the clodronate group after 1 year of follow-up, and at 2 years, the patients who received clodronate had better performance status and less myeloma-related pain than patients treated with placebo [12]. Pamidronate
Pamidronate is an aminobisphosphonate, which has been administered either orally or intravenously. In one trial, patients with advanced disease and at least one lytic lesion were randomized to placebo or intravenous pamidronate [13]. Administration of pamidronate resulted in a significant reduction in skeletal-related events (SREs; 24%) versus placebo (41%; p < 0.001). Patients receiving pamidronate also experienced reduced bone pain and no deterioration in QoL during the 2-year study. By contrast, administration of oral pamidronate failed to reduce SREs relative to placebo [14]. However, patients treated with oral pamidronate experienced fewer episodes of severe pain. The overall negative result of this study was attributed to the low absorption of orally administered BPs [14]. A recent study for patients with newly diagnosed MM demonstrated that pamidronate 30 mg monthly had comparable time with SREs and SRE-free survival time as compared with pamidronate 90 mg monthly. After a minimum of 3 years, patients receiving pamidronate 30 mg showed a trend toward lower risks of osteonecrosis of the jaw (ONJ) and nephrotoxicity compared with the higher dose. However, the study was not powered to show SRE differences between the two pamidronate dosages but only to show QoL differences [15]. Zoledronic acid
In a non-inferiority randomized Phase II trial published by Berenson et al., escalating doses of zoledronic acid were tested in comparison with 90 mg of pamidronate, in 280 patients, 108 of them affected by MM (the other had metastatic breast cancer to bone). Both zoledronic acid (at doses of 2 and 4 mg) and pamidronate significantly reduced SREs in contrast to 0.4 mg zoledronic acid [16]. This Phase II trial failed to show any superiority of zoledronic acid compared with pamidronate 114
in terms of SREs, but it was not powered to show differences between the groups. Bisphosphonates head to head
There are only two large randomized studies comparing two different BPs. A Phase III, randomized, double-blind, study was performed to compare the effects of zoledronic acid with pamidronate for patients with myeloma and lytic bone disease or with metastatic breast cancer to bone [17,18]. In the myeloma cohort, there was no difference between the two treatment arms regarding incidence and time to first SRE. However, N-terminal cross-linking telopeptide of collagen type I (NTX) levels, a sensitive marker of bone resorption, normalized more often in the zoledronic acid arm compared with pamidronatetreated patients. More recently, the Medical Research Council (MRC) of the UK compared zoledronic acid (4 mg intravenous every 3–4 weeks or at doses according to creatinine clearance [CrCl] rates) and oral clodronate (1600 mg orally daily) for patients with newly diagnosed, symptomatic MM, who were treated with antimyeloma therapy (n = 1960 evaluable for efficacy). Zoledronic acid reduced the incidence of SREs both in myeloma patients with or without bone lesions as assessed using conventional radiography, compared with clodronate [19,20]. After a median follow-up of 3.7 years, 35% of patients receiving clodronate had experienced SREs versus 27% of patients receiving zoledronic acid (p = 0.004). More importantly, zoledronic acid reduced mortality and extended median survival. Further, subset analysis showed this treatment extended survival by 10 months over clodronate for patients with osteolytic disease at diagnosis, whereas myeloma patients without bone disease at diagnosis as assessed using conventional radiography had no survival advantage with zoleronic acid [20]. These results confirm preclinical studies suggesting indirect and direct antimyeloma effects of zoledronic acid [21]. Possible mechanisms for the antimyeloma effects of zoledronic acid include direct cytotoxic effect on the tumor cells, the reduction of IL-6 secretion by bone marrow stromal cells, the expansion of gamma/delta T cells with possible anti-MM activity, anti-angiogenic effects and inhibitory effects in the adhesion molecules. In specific subsets of patients, other BPs have also been associated with improved survival: patients receiving second-line antimyeloma chemotherapy and treated with pamidronate experienced a borderline improvement in OS over placebo [13], whereas clodronate had an OS advantage in patients without vertebral fractures at presentation relative to placebo [12]. Nevertheless, a Cochrane Database meta-analysis showed that zoledronic acid was the only BP associated with superior OS compared with placebo (hazard ratio: 0.61; 95% CI: 0.28–0.98), but not compared with other BPs [22]. TABLE 1 depicts all major studies on BPs to date. Bisphosphonates adverse events
Even though BP therapy is generally well tolerated for patients with MM, clinicians should be alert to symptoms and signs suggesting adverse events (AEs), and patients and healthcare Expert Rev. Hematol. 7(1), (2014)
Management of bone disease in MM
Review
Table 1. Major studies of bisphosphonates therapy in multiple myeloma. BP
Dosage
MM, N†
Reduction of SREs‡
Survival benefit
Lahtinen et al. (1992)
CLO
2.4 g/day, p.o., for 2 year
350
Yes
NE
[11]
McCloskey et al. (2001)
CLO
1.6 g/day, p.o.
530
Yes
Subset§
[12]
Brincker et al. (1998)
PAM
300 mg/day, p.o.
300
No
No
[14]
Study (year)
Ref.
Expert Review of Hematology Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Placebo-controlled trials
{
Berenson et al. (1998)
PAM
90 mg, i.v., q4wk; 21 cyc
392
Yes
Subset
[13]
Menssen et al. (2002)
IBN
2 mg, i.v. q mo
198
No
No
[10]
PAM (90 mg)-controlled trials Gimsing et al. (2010)
PAM
30 vs 90 mg i.v. q4wk
504
Comparable
No change
[15]
Berenson et al. (2001)
ZOL
2 or 4 mg, i.v. q mo
108
Yes
NE
[16]
Rosen et al. (2001)
#
ZOL
4 or 8 mg, i.v. q mo
513
Yes
Subset
ZOL
4 mg, i.v. q3–4wk
1960
Yes
Yes
[17]
CLO (1.6 g)-controlled trial Morgan et al. (2010 & 2012)
[19,20]
†
Number of patients with MM. ‡ SREs include vertebral and non-vertebral fractures, need for radiation or surgery to bone and spinal cord compression. § In post hoc analysis, patients without vertebral fracture at study entry survived significantly longer on CLO (median survival 23 months) compared with placebo. { Survival in patients with more advanced disease was significantly increased in the PAM group (median survival 21 vs 14 months; p = 0.041 adjusted for baseline serum b2-microglobulin and Eastern Cooperative Oncology Group performance status). # Survival benefit with ZOL over PAM in a subgroup of patients who had elevated baseline bone-specific alkaline phosphatase levels. BP: Bisphosphonate; CLO: Clodronate; IBN: Ibandronate; MM: Multiple myeloma; NE: Non-evaluated; PAM: Pamidronate; SREs: Skeletal-related events; ZOL: Zoledronic acid. Adapted from [26].
professionals should be instructed on how to prevent and recognize AEs. These include inflammatory reactions at the injection site and acute-phase reactions after intravenous administration of aminobisphosphonates, gastrointestinal discomfort after oral administration, hypocalcemia and hypophosphatemia. Renal impairment and ONJ represent infrequent but potentially serious AEs with BP use. Hypocalcemia is usually relatively mild and asymptomatic among most patients with MM treated with BPs, although severe hypocalcemia has been observed. Patients should routinely receive calcium (600 mg/day) and vitamin D3 (400 IU/day) supplementation [23]. Vitamin D should be checked in all MM patients. If it is low, patients should take 50,000 IU, weekly, for 8 weeks and have their levels rechecked. Calcium supplementation should be used with caution for patients with renal insufficiency. Patients who develop hypercalcemia should have their vitamin D and calcium supplements discontinued. Intravenous BPs have the potential to cause acute or chronic renal dysfunction [13,17,19,24,25]. Approximately 12% of patients with MM, breast cancer, or other solid tumors showed renal deterioration (changes in serum creatinine) after 24 months of treatment, although in the MRC Myeloma IX trial [19] there was no difference regarding renal impairment between intravenous zoledronic acid and oral clodronate arms and the latter BP when administered orally has not been associated with nephrotoxicity. The nephrotoxicity of BPs is dependent on the dose, infusion time and the resulting maximum plasma concentration that affects the local intracellular BP concentration. All treated patients should have CrCl, serum electrolytes and informahealthcare.com
urinary albumin monitored. Current guideline recommendations state that the dosages of zoledronic acid and clodronate when administered intravenously should be reduced for patients who have preexisting renal impairment (CrCl 30–60 ml/min) but there are no clinical studies demonstrating the efficacy of this approach. For patients with CrCl between 30 and 60 ml/min, zoledronic acid dose should be adjusted. Zoledronic acid has not been studied for patients with severe renal impairment (CrCl
Review
Management of bone disease in multiple myeloma Expert Review of Hematology Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Expert Rev. Hematol. 7(1), 113–125 (2014)
Evangelos Terpos*1, James Berenson2, Noopur Raje3 and G David Roodman4 1 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528 Athens, Greece 2 Institute for Myeloma and Bone Research, West Hollywood, CA, USA 3 Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, MA, USA 4 Indiana University School of Medicine, Indianapolis, IN, USA *Author for correspondence: Tel.: +30 213 216 2846 Fax: +30 210 338 1511 [email protected]
informahealthcare.com
Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal complications that cause significant morbidity and mortality. Currently, bisphosphonates (BPs) are the mainstay for the treatment of myeloma bone disease. Zoledronic acid which has been found to be superior to clodronate, both in terms of reduction of skeletalrelated events (SREs) and survival, and pamidronate are used for the management of myeloma-related bone disease. Patients with active disease (not in CR or VGPR) should receive BPs (especially zoledronic acid) even after two years of administration. Radiotherapy and surgical interventions can also be used for specific conditions, such as pathological fractures, spinal cord compression or uncontrolled pain. The better understanding of the biology of myeloma bone disease has led to the production of several novel agents, such as denosumab (targeting RANKL), sotatercept (activin-A antagonist) and romosozumab (targeting sclerostin) that appear very promising and have entered to clinical development. KEYWORDS: activin-A . bisphosphonates . bone disease . denosumab . RANKL . sclerostin . sotatercept . Wnt pathway
Multiple myeloma (MM) is an incurable hematological malignancy characterized by the accumulation of abnormal plasma cells in the bone marrow and the presence of lytic lesions and/or osteoporosis due to increased osteoclast activity, accompanied by suppressed osteoblast function. The clinical and economic impact of the associated bone pain, pathological fractures requiring surgery and/or radiation to bone, spinal cord compression and hypercalcemia can be devastating, with major effects on quality of life (QoL) and survival [1]. Factors produced by tumor cells stimulate osteoclasts to resorb bone and inhibit osteoblast activity. In turn, growth factors released by the increased bone resorptive process, also increase the growth of MM cells, creating a vicious cycle of tumor expansion and bone destruction. The biologic pathway of the RANK and RANKL and osteoprotegerin (OPG), which is the decoy receptor of RANKL, is of major importance for the increased osteoclast activity observed in MM [2]. Activin-A has also been implicated in MM bone disease through stimulating RANK expression and inducing osteoclastogenesis as well as inhibiting osteoblast differentiation [3–5]. Furthermore, the Wnt signaling inhibitors dickkopf-1 (DKK-1) and sclerostin, which are secreted by myeloma cells and increased in the serum of myeloma 10.1586/17474086.2013.874943
patients, block osteoblast differentiation and activity [6–8]. Since these molecules also interfere with tumor growth and survival, they provide possible targets for the development of novel drugs for the management of lytic disease in myeloma. The aim of this review is to summarize the established therapeutic management of myeloma bone disease and highlight the latest data on agents interfering with bone disease pathophysiology that will provide future interventions. Bisphosphonates: the mainstay of therapy of myeloma-related bone disease
Bisphosphonates (BPs) are pyrophosphate analogs that readily bind the exposed mineralized bone and are taken up by osteoclasts during bone resorption, inhibiting osteoclast recruitment and maturation, preventing the development of monocytes into osteoclasts, inducing osteoclast apoptosis and interrupting their attachment to the bone. All BPs have similar physicochemical properties; however, their antiresorbing activity is different. Their activity is drastically increased when an amino group is entered into the aliphatic carbon chain. Thus, pamidronate and alendronate are 100- and 700-fold more potent than etidronate, both in vitro and in vivo, while ibandronate and zoledronic acid show 10,000- to 100,000-fold
2014 Informa UK Ltd
ISSN 1747-4086
113
Review
Terpos, Berenson, Raje & Roodman
greater potency than etidronate. Oral clodronate, intravenous pamidronate and intravenous zoledronic acid have been licensed for the management of myeloma bone disease. Etidronate and ibandronate were found to be ineffective for the treatment of bone disease in myeloma patients [9,10].
Expert Review of Hematology Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Clodronate
Two major, placebo-controlled, randomized trials have been performed in MM. Lahtinen et al. reported reduction of the development of new osteolytic lesions by 50% in myeloma patients who received oral clodronate for 2 years that was independent of the presence of lytic lesions at baseline [11]. In the other study, although there was no difference in overall survival (OS) between clodronate and placebo patients, patients who received clodronate and did not have vertebral fractures at baseline appeared to have a survival advantage (59 vs 37 months). Both vertebral and nonvertebral fractures as well as the time to first non-vertebral fracture and severe hypercalcemia were reduced in the clodronate group after 1 year of follow-up, and at 2 years, the patients who received clodronate had better performance status and less myeloma-related pain than patients treated with placebo [12]. Pamidronate
Pamidronate is an aminobisphosphonate, which has been administered either orally or intravenously. In one trial, patients with advanced disease and at least one lytic lesion were randomized to placebo or intravenous pamidronate [13]. Administration of pamidronate resulted in a significant reduction in skeletal-related events (SREs; 24%) versus placebo (41%; p < 0.001). Patients receiving pamidronate also experienced reduced bone pain and no deterioration in QoL during the 2-year study. By contrast, administration of oral pamidronate failed to reduce SREs relative to placebo [14]. However, patients treated with oral pamidronate experienced fewer episodes of severe pain. The overall negative result of this study was attributed to the low absorption of orally administered BPs [14]. A recent study for patients with newly diagnosed MM demonstrated that pamidronate 30 mg monthly had comparable time with SREs and SRE-free survival time as compared with pamidronate 90 mg monthly. After a minimum of 3 years, patients receiving pamidronate 30 mg showed a trend toward lower risks of osteonecrosis of the jaw (ONJ) and nephrotoxicity compared with the higher dose. However, the study was not powered to show SRE differences between the two pamidronate dosages but only to show QoL differences [15]. Zoledronic acid
In a non-inferiority randomized Phase II trial published by Berenson et al., escalating doses of zoledronic acid were tested in comparison with 90 mg of pamidronate, in 280 patients, 108 of them affected by MM (the other had metastatic breast cancer to bone). Both zoledronic acid (at doses of 2 and 4 mg) and pamidronate significantly reduced SREs in contrast to 0.4 mg zoledronic acid [16]. This Phase II trial failed to show any superiority of zoledronic acid compared with pamidronate 114
in terms of SREs, but it was not powered to show differences between the groups. Bisphosphonates head to head
There are only two large randomized studies comparing two different BPs. A Phase III, randomized, double-blind, study was performed to compare the effects of zoledronic acid with pamidronate for patients with myeloma and lytic bone disease or with metastatic breast cancer to bone [17,18]. In the myeloma cohort, there was no difference between the two treatment arms regarding incidence and time to first SRE. However, N-terminal cross-linking telopeptide of collagen type I (NTX) levels, a sensitive marker of bone resorption, normalized more often in the zoledronic acid arm compared with pamidronatetreated patients. More recently, the Medical Research Council (MRC) of the UK compared zoledronic acid (4 mg intravenous every 3–4 weeks or at doses according to creatinine clearance [CrCl] rates) and oral clodronate (1600 mg orally daily) for patients with newly diagnosed, symptomatic MM, who were treated with antimyeloma therapy (n = 1960 evaluable for efficacy). Zoledronic acid reduced the incidence of SREs both in myeloma patients with or without bone lesions as assessed using conventional radiography, compared with clodronate [19,20]. After a median follow-up of 3.7 years, 35% of patients receiving clodronate had experienced SREs versus 27% of patients receiving zoledronic acid (p = 0.004). More importantly, zoledronic acid reduced mortality and extended median survival. Further, subset analysis showed this treatment extended survival by 10 months over clodronate for patients with osteolytic disease at diagnosis, whereas myeloma patients without bone disease at diagnosis as assessed using conventional radiography had no survival advantage with zoleronic acid [20]. These results confirm preclinical studies suggesting indirect and direct antimyeloma effects of zoledronic acid [21]. Possible mechanisms for the antimyeloma effects of zoledronic acid include direct cytotoxic effect on the tumor cells, the reduction of IL-6 secretion by bone marrow stromal cells, the expansion of gamma/delta T cells with possible anti-MM activity, anti-angiogenic effects and inhibitory effects in the adhesion molecules. In specific subsets of patients, other BPs have also been associated with improved survival: patients receiving second-line antimyeloma chemotherapy and treated with pamidronate experienced a borderline improvement in OS over placebo [13], whereas clodronate had an OS advantage in patients without vertebral fractures at presentation relative to placebo [12]. Nevertheless, a Cochrane Database meta-analysis showed that zoledronic acid was the only BP associated with superior OS compared with placebo (hazard ratio: 0.61; 95% CI: 0.28–0.98), but not compared with other BPs [22]. TABLE 1 depicts all major studies on BPs to date. Bisphosphonates adverse events
Even though BP therapy is generally well tolerated for patients with MM, clinicians should be alert to symptoms and signs suggesting adverse events (AEs), and patients and healthcare Expert Rev. Hematol. 7(1), (2014)
Management of bone disease in MM
Review
Table 1. Major studies of bisphosphonates therapy in multiple myeloma. BP
Dosage
MM, N†
Reduction of SREs‡
Survival benefit
Lahtinen et al. (1992)
CLO
2.4 g/day, p.o., for 2 year
350
Yes
NE
[11]
McCloskey et al. (2001)
CLO
1.6 g/day, p.o.
530
Yes
Subset§
[12]
Brincker et al. (1998)
PAM
300 mg/day, p.o.
300
No
No
[14]
Study (year)
Ref.
Expert Review of Hematology Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Placebo-controlled trials
{
Berenson et al. (1998)
PAM
90 mg, i.v., q4wk; 21 cyc
392
Yes
Subset
[13]
Menssen et al. (2002)
IBN
2 mg, i.v. q mo
198
No
No
[10]
PAM (90 mg)-controlled trials Gimsing et al. (2010)
PAM
30 vs 90 mg i.v. q4wk
504
Comparable
No change
[15]
Berenson et al. (2001)
ZOL
2 or 4 mg, i.v. q mo
108
Yes
NE
[16]
Rosen et al. (2001)
#
ZOL
4 or 8 mg, i.v. q mo
513
Yes
Subset
ZOL
4 mg, i.v. q3–4wk
1960
Yes
Yes
[17]
CLO (1.6 g)-controlled trial Morgan et al. (2010 & 2012)
[19,20]
†
Number of patients with MM. ‡ SREs include vertebral and non-vertebral fractures, need for radiation or surgery to bone and spinal cord compression. § In post hoc analysis, patients without vertebral fracture at study entry survived significantly longer on CLO (median survival 23 months) compared with placebo. { Survival in patients with more advanced disease was significantly increased in the PAM group (median survival 21 vs 14 months; p = 0.041 adjusted for baseline serum b2-microglobulin and Eastern Cooperative Oncology Group performance status). # Survival benefit with ZOL over PAM in a subgroup of patients who had elevated baseline bone-specific alkaline phosphatase levels. BP: Bisphosphonate; CLO: Clodronate; IBN: Ibandronate; MM: Multiple myeloma; NE: Non-evaluated; PAM: Pamidronate; SREs: Skeletal-related events; ZOL: Zoledronic acid. Adapted from [26].
professionals should be instructed on how to prevent and recognize AEs. These include inflammatory reactions at the injection site and acute-phase reactions after intravenous administration of aminobisphosphonates, gastrointestinal discomfort after oral administration, hypocalcemia and hypophosphatemia. Renal impairment and ONJ represent infrequent but potentially serious AEs with BP use. Hypocalcemia is usually relatively mild and asymptomatic among most patients with MM treated with BPs, although severe hypocalcemia has been observed. Patients should routinely receive calcium (600 mg/day) and vitamin D3 (400 IU/day) supplementation [23]. Vitamin D should be checked in all MM patients. If it is low, patients should take 50,000 IU, weekly, for 8 weeks and have their levels rechecked. Calcium supplementation should be used with caution for patients with renal insufficiency. Patients who develop hypercalcemia should have their vitamin D and calcium supplements discontinued. Intravenous BPs have the potential to cause acute or chronic renal dysfunction [13,17,19,24,25]. Approximately 12% of patients with MM, breast cancer, or other solid tumors showed renal deterioration (changes in serum creatinine) after 24 months of treatment, although in the MRC Myeloma IX trial [19] there was no difference regarding renal impairment between intravenous zoledronic acid and oral clodronate arms and the latter BP when administered orally has not been associated with nephrotoxicity. The nephrotoxicity of BPs is dependent on the dose, infusion time and the resulting maximum plasma concentration that affects the local intracellular BP concentration. All treated patients should have CrCl, serum electrolytes and informahealthcare.com
urinary albumin monitored. Current guideline recommendations state that the dosages of zoledronic acid and clodronate when administered intravenously should be reduced for patients who have preexisting renal impairment (CrCl 30–60 ml/min) but there are no clinical studies demonstrating the efficacy of this approach. For patients with CrCl between 30 and 60 ml/min, zoledronic acid dose should be adjusted. Zoledronic acid has not been studied for patients with severe renal impairment (CrCl
