A systematic review and meta-analysis of interventional studies of bisphosphonates and denosumab in multiple myeloma and future perspectives.

Introduction

Multiple myeloma (MM) is a malignant disease of the haemopoietic system, characterized by plasma cell proliferation contained mainly in the bone marrow, but can also be present in the peripheral circulation, as solitary plasmacytoma. It is a heterogenous condition, that can vary from monoclonal gammopathy of unknown significance to plasma cell leukemia[ 1 , 2 ]. It mainly affects people who are between their sixth and seventh decade of life, although 37% of cases involve younger people. It is rarely encountered in groups younger than 30 years old[ 1 ]–[ 3 ]. Skeletal involvement is disease-defining and correlates with disease progression, tumor burden and prognosis[ 4 ]. It is estimated that 85% of asymptomatic patients with MM have osteopenia to some extent[ 3 ]. MM bone lesions are purely lytic and rarely heal, even in patients in complete remission. They affect predominantly areas of bone marrow (vertebral bodies, ribs, skull), but can also occur in any other bone causing significant pain and manifesting from radiographic lytic areas to pathologic fractures or spinal cord compression[ 5 ].

MM-induced bone disease interferes with normal bone remodeling, causing excessive differentiation and activation of osteoclasts (OCL), thus turning the balance towards bone resorption[ 6 ]. Interaction between MM cells and bone mesenchymal cells (BMSc) leads to expression of receptor activator of nuclear factor Kappa-b ligand (RANKL) from osteoblasts, which stimulates OCL differentiation and activation[ 7 ]. Myeloma cells produce cytokines that stimulate stromal and T cells, to form osteoclastogenic activating factors, such as RANKL, MIP-1a, Interleukin-3 (IL-3), IL-6 and tumor necrosis factor-a (TNF-a), which also inhibit the production of osteoprotegerin (OPG), a decoy protein that binds RANKL and deactivates it. The activated OCL further enhance myeloma cell activity, by producing IL-6, osteopontin, annexin II etc.[ 5 , 8 , 9 ]. The RANKL/OPG ratio demonstrates the metabolic activity in the marrow microenvironment and in myeloma patients it is skewed towards bone resorption, favoring RANKL[ 9 ]. It is noteworthy that patients with high RANKL/OPG ratio have inferior survival[ 10 ].

Bisphosphonates (BPs) are a diverse group of molecules that inhibit osteoclast activity by binding to hydroxyapatite crystals. After their absorption to bone surface and internalization by OCL, they interfere with their function and cause apoptosis[ 11 , 12 ]. Bisphosphonates are classified according to whether they are nitrogen containing or not, which correlates with their potency. First generation non-nitrogen BPs are etidronate (ETI) and clodronate (CLOD), second generation nitrogen-containing are pamidronate (PAM) and ibandronate (IBA) and third generation nitrogen-containing are zoledronic acid (ZOL). Nitrogen-containing BPs are 10-10,000 times more potent than non-nitrogen, regarding anti-resorption ability[ 12 ]–[ 14 ]. They can be administered either intravenously (IV) or orally (PO), but they are poorly absorbed from the gastrointestinal tract and therefore require very careful administration to maximize absorption[ 15 , 16 ]. Based on in vitro data ETI is regarded the least potent and ZOL the most potent BP[ 14 , 17 ]. Side effects that have been recorded from their use, include esophageal irritation/ulceration[ 18 ], renal function impairment, hypocalcemia and the more rare but severe osteonecrosis of the jaw (ONJ)[ 19 ]–[ 21 ]. For their anti-resorptive action they have become important adjuvant agents to the treatment of malignancies that cause bone destruction such as MM, among others.

Denosumab (DENOS) is a human monoclonal antibody that specifically binds with RANKL, thus preventing the last from linking with RANK receptor in OCLs. It mimics the properties of OPG and inhibits OCL activation, contributing to the prevention of bone resorption[ 22 ]. It is widely used in fracture prevention in postmenopausal women with high fracture risk and in 2018 its indications were expanded in patients with multiple myeloma, as it proved to be bioequivalent to zoledronic acid in delaying first on study skeletal related event[ 23 ].

The aim of the present systematic review is to highlight the use of BPs and DENOS in the treatment of MM, as demonstrated by interventional studies from 1980 up to date, report the benefits and potential harms that arise from their use and demonstrate ongoing research. Furthermore, a meta-analysis of studies comparing denosumab with bisphosphonates is performed, to demonstrate whether the novel denosumab is superior to bisphosphonates in the treatment of multiple myeloma.

Methods

The methods and the results of this review have been carried out in accordance with the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)[ 24 ]. The study protocol has been published in The International Prospective Register of Systematic Reviews (PROSPERO) under the unique ID CRD42021287267[ 25 ]. Amendments to the original protocol include a meta-analysis of the studies that compare DENOS to ZOL.

Search strategy

A systematic search of the literature was conducted in the databases of National Library of Medicine-Pubmed, Scopus, Web of Science and Clinicaltrials.gov for relevant studies. The references from relevant reviews on the subject were also screened. We used keywords through evaluation of Medical Subject Headings (MeSH) which were: bisphosphonates, diphosphonates, zoledronic, pamidronate, alendronate, risedronate, etidronate, denosumab, multiple myeloma, plasma cell myeloma and limited our search criteria to include clinical trials and randomized controlled trials (RCTs) in humans were that was applicable. The search was concluded in September 2021. Detailed search strategy per database is included in the Appendix.

Selection criteria

Inclusion criteria consisted of interventional studies (clinical trials, RCTs) that compared bisphosphonates versus placebo (PLC)/no treatment (NT)/other bisphosphonates/denosumab, in multiple myeloma patients, who were receiving standard chemotherapy treatment or not, according to their disease stage. Eligible studies should include at least one outcome of interest. The outcomes evaluated were overall survival (OS), disease progression (DP) or progression free survival (PFS), skeletal related events (SREs), bone pain, ONJ and renal toxicity (RT). Studies that included patients with MM and other metastatic tumors in the population were also included and when subgroup data were available, only the MM patient subgroup was considered. Regarding large RCTs with multiple publications, all studies reporting different outcomes that came from the same sample were included.

Exclusion criteria consisted of observational studies, case reports, case series, Phase I/II pharmacokinetic and dose-determination studies, in vitro studies, animal studies, studies with no full text available or studies where the full text could not be retrieved even after communication with the authors, articles with no full text published in English, studies that were not conducted in the population of interest but in humans with other types of tumors with metastatic bone disease and studies that did not include even one of the outcomes of interest.

Types of participants and interventions

Participants who were diagnosed with MM, as this was defined by researchers in each study. Participants from asymptomatic to advanced MM were included. The intervention group consisted of patients treated with bisphosphonates or denosumab and the control group of patients that received placebo, no treatment or other bisphosphonate type.

Types of Outcomes

Primary outcomes

Disease progression - As it was defined by the authors of each study. There were no uniform criteria in all included studies. Some assessed DP using the International Response criteria[ 26 ] and others by clinical, radiographic and/or biochemical evaluation. In some studies DP was reported as progression free survival, as time to disease progression (TTDP) or as time to first skeletal related event (TTSRE).

Overall survival -In terms of mortality

Skeletal related events - As they were defined by the authors of each study. This could include participants experiencing new osteolytic lesions, pathological vertebral or non-vertebral fractures, loss of vertebral height, spinal cord compression or hypercalcemia.

Secondary outcomes

Reduction in bone pain – Multiple scales were used in the assessment of bone pain in the studies included, as reported by the authors. Some authors used the Brief Pain Inventory[ 27 ], the 100 mm Visual Analogue Scale[ 28 ], questionnaires regarding pain intensity, analgesic use, days of absence from work or hospitalization days, or scales intended to provide scoring on pain frequency, intensity and type of analgesic required.

Number of participants with osteonecrosis of the jaw

Renal toxicity, Grade III/IV (National Cancer Institute common toxicity criteria) events[ 29 ].

Study selection

Two reviewers (VC and GK) independently conducted the literature search, according to the pre-specified criteria. Duplicate results were removed manually at the initial stage and the rest of the results were screened for eligibility by Title & Abstract. In the final stage, the full text of the remaining studies was assessed for inclusion. When it was not possible to find full text of a study, the authors were contacted. Studies approved by at least one of the reviewers was considered eligible. Whenever there was dispute a third author, DK, resolved the issue.

Data Extraction

Data extraction was performed by VC and GK and then approved by DK. For all studies we extracted the following data: the name of the first author, year of publication, type/name of study, the population characteristics (disease stage, age), number of participants, intervention drug, comparator drug, dosage, route and frequency of administration of drugs, treatment duration and follow-up duration.

Data analysis

Data were imported in Excel spreadsheet, Microsoft Office 365. Results were reported as hazard ratio (HR), odds ratio (OR), risk ratio (RR) or descriptively with percentages or number of events and the attributed p-value, were that was available. A meta-analysis of studies comparing DENOS versus (vs.) ZOL was conducted, using Review Manager 5.4 software[ 30 ]. Level of significance was set at p <0.05.

Risk of bias assessment

To assess the risk of bias (methodological quality) of each study included in the review, we used the revised Cochrane risk-of-bias tool for randomized trials (RoB2)[ 31 ]. A fixed set of domains of bias (bias arising from randomization process, bias from deviations to the intended interventions, bias from missing data, bias from measurement of the outcome, bias from selection of the reported result) focusing on different aspects of trial design, conduct, and reporting were assessed. Two independent reviewers (VC and GK) evaluated the included articles, and any discrepancies were resolved through discussion.

Results

Search results

Our original search yielded 993 results. Ninety-nine full text studies were screened after duplicates and studies from Title & Abstract were removed. The final number of studies that were eligible for qualitative synthesis after full text assessment were 43. Detailed diagram of the process with reasons for exclusion is illustrated in Figure 1 and the list of excluded studies after full text was sought is included in the Appendix.

Study Characteristics

The total number of included studies were thirty-seven[ 10 , 32 ]–[ 64 , 65 ], as six[ 66 ]–[ 71 ] were multiple publications of large RCTs with subgroup analysis. There were nine studies comparing ZOL with PLC, NT or only chemotherapy(CHEMO)[ 51 , 52 , 56 , 58 , 60 , 62 , 63 , 72 , 73 ], nine comparing PAM versus(vs) PLC/NT/CHEMO[ 38 , 39 , 41 , 42 , 45 , 46 , 48 , 50 , 54 ], seven CLOD vs PLC/NT/CHEMO[ 32 , 34 ]–[ 37 , 40 , 43 ], one IBA[ 44 ] and one ETI vs PLC. Regarding head to head comparisons between bisphosphonates, or denosumab with bisphosphonate, there was one large study, the Medical Research Council Myeloma IX study with its extension phase and another publication regarding adverse events of interest, comparing ZOL with CLOD[ 53 , 57 , 59 ], one study with the extension phase by Rosen et al. comparing PAM vs ZOL[ 47 ] and another comparing different doses of ZOL with PAM[ 65 ], one for PAM vs IBA[ 74 ] and two large studies regarding DENOS vs ZOL[ 55 , 64 ] and an included third publication[ 61 ] for the myeloma subset of patients from the study of Henry et al. 2011. Details of the characteristics of the main studies are presented in Table 1 and studies regarding subgroups are presented in Table 2 .

As far as population characteristics is concerned, 5 studies included participants with MM and other metastatic solid tumors with bone involvement, namely breast, prostate cancer, and others[ 47 , 49 , 55 , 63 , 65 ]. The rest of the studies had participants with MM only, in various stages. Eleven studies had MM participants in stages II or III, according to the International Staging System (ISS)[ 4 ] or Durie Salmon Staging System[ 75 ], five with patients with asymptomatic or smoldering myeloma and the rest recruited people in all the stages ( Table 1 ).

Administration of ZOL was 4 mg intravenous (IV)/every 4 weeks in most studies. Two studies[ 63 , 72 ] compared ZOL administration every 4 vs 12 weeks. CLOD was given orally(PO) in most studies, with prevalent dose of 1600 mg/daily. Lastly, the prevalent dose of PAM was 90 mg IV/every 4 weeks ( Table 1 ).

Risk of Bias Assessment

The results from the risk of bias assessment of the included studies are presented in Figure 2 . Twenty-nine studies were assessed. There were some concerns arising from the randomization process because detailed information about how the randomization was done, was not provided in some studies and some concerns regarding the blinding of personnel. Four studies[ 53 , 54 , 60 , 63 ] were open label and in most cases the efficacy and safety analysis included most of the randomized population. Lastly, in most of the studies there was no problem with protocol deviations or selection bias.

Outcome measures

Primary outcomes: Disease progression, overall survival and skeletal related events

CLOD vs PLC/ZOL

Studies regarding the use of CLOD date from 1980 to 2013, with the most recent being a large multicenter RCT, the Medical Research Council Myeloma IX study, with 1960 total number of participants[ 53 ] with follow up ranging from 3.7 years in the original study, to 5.9 years in the extension phase[ 57 ]. In this study CLOD was compared to ZOL and patients were further stratified to intensive and non-intensive pathway, according to intensity of induction to chemotherapy, and received two different chemotherapy combinations in each pathway. ZOL was superior to CLOD in increasing overall PFS by 2 months, (HR 0.88;95% CI,0.80–0.98), but when the same outcome was assessed separate for the intensive and non-intensive pathway, it did not reach statistical significance (HR 0.90;95% CI, 0.78–1.05 and HR 0.87;95% CI, 0.74–1.01 respectively). Overall survival was 44.5 months for CLOD and 50 months for ZOL, which was significant (HR 0.84;95% CI, 0.74–0.96). 27% of patients in the ZOL group had a SRE before disease progression, compared to 35% (p=0.0004)[ 53 ]. Overall ZOL reduced SREs compared to CLOD, in patients receiving bisphosphonates for more than 2 years (p=0.0102), regardless of other treatment regiments[ 69 ]. In the extended follow up, results demonstrated a significant increase in PFS as well as OS (HR 0.89;95% CI, 0.80–0.98 and HR 0.86;95% CI,0.77– 0.97 respectively), increasing OS by 5.5 months. Subgroup analysis of transplant eligible patients in the Myeloma IX study demonstrated that ZOL was not superior to CLOD in OS for patients with complete response (CR) to therapy, but significantly improved OS in patients with partial response (PR) (HR 0.53 [95% CI, 0.32-0.86]). ZOL was marginally better than CLOD in reducing SREs only in patients with very good partial response (VGPR) (HR 0.74;95% CI, 0.52-1.05) and not in those with CR[ 68 ].

There were two more large RCTs, one from the Finnish Leukemia Group[ 34 ] and the VIth MRC Multiple Myeloma Trial[ 40 ], recruiting a total number of 871 participants, comparing CLOD with placebo (PLC). In those studies, there was no significant difference in OS, with a follow up, up to 8 years. CLOD was effective in preventing bone progression and reduced osteolytic lesions significantly (p=0.026), but no difference was noted between groups regarding vertebral and non-vertebral fractures. There was low dropout rate after randomization in both studies, but in the study from the Finnish Leukemia Study Group, there was significant difference in age between the CLOD and PLC groups, with the population in the PLC being older. Riccardi et al.[ 36 ] and Heim et al.[ 37 ] also demonstrated significant improvement in bone progression with CLOD, as well as survival. Finally, the study of Delmas et al. [[ 58 ]] reported less osteolytic lesions compared to PLC at 6 and 12 months but had very few participants. Details are presented in Tables 3 , 4 , 5 .

PAM vs PLC/NT/CHEMO/ZOL/IBA

PAM versus PLC/NT or only CHEMO demonstrated no significant difference in OS. In four studies SREs were reduced significantly[ 38 , 41 , 46 , 54 ] but the same was not evident in the studies of Brincker et al., Attal et al. and Kraj et al.[ 39 , 48 , 50 ] ( Table 3 ). It is to be noted that of the studies that demonstrated significant reduction in SREs with PAM administration, 2 had patients in early disease stages (DS IA or IIA and ISS I)[ 46 , 54 ] and only the study of Berenson et al. was in patients with advanced myeloma[ 38 , 41 ]. Contrary to that, the studies of Kraj et al. and Attal et al., included patients with advanced disease stage and in Brincker et al., most patients had vertebral collapse at study entry, suggesting a low beneficial effect in the more advanced stages of myeloma ( Table 1 ).

When compared to ZOL, there was no difference in reducing SREs in the study of Rosen et al. for the MM subgroup[ 47 ] and the same was demonstrated in DP when compared to IBA[ 10 ]. In the study of Berenson et al. 2000, there was no difference in SREs between groups of ZOL 2 mg and 4 mg and PAM, but there was significant difference between o.4mg ZOL and PAM[ 65 ] ( Table 4 ).

ZOL vs PLC/NT/DENOS

The efficacy of ZOL was assessed in studies, from 2000-2018, with comparisons versus PLC, NT, only CHEMO, CLOD, PAM AND DENOS ( Table 1 ). In asymptomatic MM patients, ZOL showed no superiority versus NT in PFS at 5 years. It reduced SREs (OR 2.9;95% CI, 1.04-8.06) but with a wide confidence interval[ 52 ]. When thalidomide (THAL) was added, in the same population type, their combination was significantly better at PFS and time to disease progression (TTDP) than ZOL alone, with a median PFS of 2.4 years compared to 1.2 years in the ZOL group alone[ 56 ]. OS and PFS was improved significantly in patients with symptomatic and advanced disease, and SREs were reduced in the ZOL group[ 51 , 58 ]. For patients with biochemical relapses, progressive bone disease occurred in 16% versus 41% (p<0.0005) for ZOL and NT respectively. Survival did not reach statistical significance (73% vs 46%, p=0.161 for ZOL vs NT) in the overall assessment but for patients with lytic lesions at study entry the survival rates were significantly better for the ZOL group ( Table 3 )[ 60 ] Administration of ZOL with longer interval had the same efficacy in reducing SREs[ 63 , 72 ]. Long-term treatment with ZOL, 4 years compared to 2 years, reduced SREs (p<0.001) but not OS or PFS[ 62 ] ( Table 3 , 4 , 5 ).

Lastly, we retrieved 2 trials comparing ZOL with DENOS[ 55 , 64 ], with 3494 participants, of which 1898 were MM patients alone[ 61 , 64 ]. The study of Raje et al. had 2 more publications[ 66 , 67 ] as did the study from Henry et al.,[ 61 , 76 ] one including only the MM subset of patients ( Table 2 ). The meta-analysis demonstrated non-inferiority of DENOS compared to ZOL in all the outcomes of interest ( Table 6 ). There was low heterogeneity of studies regarding OS and SREs (I 2 43% and 0% respectively) but in PFS heterogeneity was higher (I 2 68%) probably due to the study of Henry et al., that included patients mostly with metastatic solid tumors with bone involvement except breast and prostate cancer and high dropout rate. Forest plots of the meta-analysis are presented in Figures 3 , 4 , 5 .

In the large trial of Raje et al.[ 64 ], PFS significantly increased for the DENOS group by 10.5 months versus the ZOL group [HR0.82(0.68,0.99)]. In a subgroup analysis of Asian patients that participated in the same study, 38.8% of patients on DENOS had first on study SRE, versus 50.5%, but it did not reach statistical significance[ 66 ]. The group that benefited the most from DENOS regarding PFS, were patients <70 years old and those with intent for autologous stem cell transplantation[ 67 ]. There was significant participant withdrawal (80%) in the trial of Henry et al., which reduced the sample size from 1776 to 358. There were differences between groups, regarding patient characteristics in the latter study, as demonstrated by Raje et al.[ 61 ]. More patients with poor renal function were treated with DENOS and patients taking ZOL, had stem cell therapy and immunomodulation therapy more frequent, which may have affected time to disease progression.

Secondary Outcomes: Bone Pain, Osteonecrosis of the Jaw, Renal Toxicity

Bone Pain

Results from CLOD versus PLC/CHEMO studies, indicated a significant reduction in pain and analgesic use, in patients receiving CLOD from baseline, as well as compared to PLC[ 32 , 34 , 35 , 37 , 40 ]. In the study of Lahtinen et al., no significant difference in pain reduction was evident between groups, but the number of patients with no pain at 2 years was reduced significantly in both groups, with more patients feeling no pain in the CLOD group (53.6% and 44.6% for CLOD and PLC respectively[ 34 ]. In the VI th Medical Research Council Myeloma Study[ 40 ], which had the largest sample, at 2 years, 10.9% of patients in the CLOD group were having back pain compared to 19.9% in the PLC group, which was significant ( Table 7 ).

In the studies of Berenson et al.[ 38 ], Brincker et al.[ 39 ] and Terpos et al.[ 42 ] PAM was successful in reducing bone pain and analgesic use compared to PLC or CHEMO only. On the other hand, Kraj et al.[ 48 ] demonstrated a reduction in pain from PAM administration the first 9 months compared to CHEMO only and no difference after 9 months. Even though the study had only 46 participants the treatment duration was 66 months, with a long follow up period. Administration of ZOL 4 mg/IV, showed greater mean pain reduction than other dose regiments (0.4 mg and 2 mg) and PAM, after 10 months of treatment. Statistically significant levels were reached only between ZOL 4 mg and ZOL 0.4 mg and not among other group comparisons[ 65 ]. There were similar pain reduction scores when ZOL was given every 12 weeks compared to every 4 weeks[ 63 ]. Patients recruited in a single arm trial for ZOL, experienced significant pain reduction from baseline in at least 4 out of 6 visits[ 49 ]. When DENOS was compared to ZOL, one study[ 76 ] demonstrated superiority in reducing bone pain (in favor of DENOS), but had 80% participant withdrawal, while in another large trial[ 64 ], the same result was not reproduced, with both drugs showing similar effectiveness. Patients with osteolytic lesions receiving IBA had significant pain reduction from baseline, but there was no difference in between group comparisons[ 44 ]. ETI did not demonstrate pain reduction effects[ 33 ].

Osteonecrosis of the jaw

In patients that were treated with PAM, the rate of ONJ was very small. In the study of Attal et al.[ 50 ] only 2 of 397 participants developed ONJ after 26 months of treatment. CLOD when compared to ZOL, in the Medical Research Council Myeloma IX study, had significantly lower incidence of ONJ, in the short and long-term follow up (0.5% versus 3.7% respectively)[ 53 , 59 ]. The incidence of ONJ in patients treated with ZOL was generally less than 4%. There were two studies that reported 0 and 1 patient, but the duration of therapy was short[ 49 , 52 ]. Surprisingly, Aviles et al. 2013[ 58 ] reported no patient with ONJ after 2 years of ZOL administration, with a follow up ranging from 3-8 years. In two large studies comparing ZOL with DENOS there was no difference in the incidence of ONJ, which had a range of 1.3-3% and 1.1-4% respectively[ 55 , 64 ] but that percentage was higher in the subgroup analysis of Asian population 66 from the study of Raje et al.[ 64 ]. In the latter, there was 6.9% vs 5.4% of ONJ incidence between DENOS and ZOL respectively, which did not have significant difference between groups ( Table 7 ).

Renal Toxicity

In the studies with CLOD versus PLC or CHEMO only, there were no serious events of renal toxicity between groups ( Table 7 ). In the Myeloma IX study, events of acute renal failure were similar for CLOD and ZOL, with no significant difference in the short and long-term follow up ( Table 7 ).

PAM was generally well tolerated and there was no significant toxicity compared to PLC/NT/CHEMO. ZOL, in the 4 mg dose, every 4 weeks, when compared to PAM had similar safety profile but the 8 mg dose had significant difference in renal toxicity vs PAM, therefore causing the investigators to alter ZOL dosing of that group to lower dose[ 47 ]. ZOL was generally well tolerated, with low incidence of renal toxicity, but Vogel et al.[ 49 ] reported 17 patients with treatment discontinuation due to rise in serum creatinine ( Table 7 ). When compared to DENOS, there was higher percentage of patients with adverse events regarding renal function, and that was more pronounced in participants with baseline lower creatinine clearance ( Table 7 ). Overall ZOL had a good safety profile, when the dosage was adjusted for creatinine clearance[ 55 , 64 ].

Discussion

In MM patients, progression to bone disease is of pivotal importance that affects morbidity. Most patients will eventually develop skeletal lesions (80-90%), due to the imbalance between bone apposition and resorption, that follows when MM tumor burden exceeds 50% in a local area. Histologic studies have demonstrated that there is increased OCL activity adjacent to MM cells[ 77 ]. MIP-1a is a chemokine produced by MM cells, which help them adhere to bone marrow BMSc and stimulate production of RANKL, TNF and vascular endothelial growth factor. This in consequence, causes proliferation and differentiation of OCLs, which leads to increased local bone resorption and the creation of lytic lesions[ 78 ].

Bisphosphonates’ main target is to reduce proliferation of OCLs and induce apoptosis and for that reason they play an important role in the treatment of MM[ 14 ].

Results from the study of Lahtinen et al.[ 34 ] first demonstrated that there was a beneficial effect of oral CLOD in reducing osteolytic lesions and delaying bone disease progression in MM patients. That result was also evident in the study of Berenson et al.[ 41 ], regarding IV PAM. When ZOL became available, clinical trials comparing it to PAM demonstrated similar safety profile and slightly better efficacy in reducing SREs and bone pain[ 47 , 65 ]. In the Myeloma IX study[ 53 ], ZOL proved to be superior to CLOD in increasing OS by 5.5 months and reducing SREs. Even though it had higher incidence of ONJ, that percentage was less than 5%. Renal toxicity was slightly higher for ZOL but there was no significant difference. In the future study of Himelstein et al.[ 63 ], it was shown that IV 4 mg ZOL administration every 12 weeks had the same efficacy, with reduced incidence of ONJ and renal function impairment, compared to every 4 weeks. Treatment with ZOL has been proven safe and effective for 2 years. The extended follow up of the Myeloma IX study showed low incidence of adverse events and the Z-MARK study, that included patients with 1-2 years of prior bisphosphonate use, extended the safe use of ZOL up to 4 years, in 3-month intervals.

A Mixed Treatment Comparison that compared the efficacy of ZOL, PAM, CLOD and IBA in reducing SREs concluded that ZOL was superior to other BPs. ZOL had 1.43 incidence rate, while PAM had 1.64 and CLOD 1.90. The excess rates of PAM and CLOD versus ZOL in the incidence of SREs were 15% and 33% respectively[ 79 ].

In a more recent Cochrane review and meta-analysis[ 80 ] bisphosphonates were effective in reducing SREs and pathologic vertebral fractures (moderate quality of evidence). OS was improved with ZOL but not PFS. Regarding ONJ, there was no significant difference in the incidence between BP type and evidence for lesser bone pain was of low quality.

There was no uniform scale used to assess bone pain between studies. The Brief Pain Inventory[ 27 ] was applied in three[ 63 , 65 , 76 ], World Health Organization scoring scale[ 81 ] in two[ 35 , 37 ] and the 100-mm Visual Analogue Scale[ 82 ] in one[ 49 ]. The rest of the studies used questionnaires regarding pain frequency and severity, analgesic type and consumption and descriptive scales to rate pain intensity ( Table 7 ). That diversity in the tools of pain evaluation and in some cases the use of non-validated instruments, is a methodological limitation which contributes to the low quality of evidence on the matter.

Renal function deterioration is the most important complication associated with IV BP infusion. In a retrospective study, McDermott et al. demonstrated that important predictive factors for renal impairment, in patients treated with ZOL, were patient age, myeloma disease, nonsteroidal anti-inflammatory drugs, cumulative doses of BPs and cisplatin therapy[ 83 ]. Caution is warranted with PAM as well, but generally doses up to 90 mg every 4 weeks are well tolerated[ 84 ]. In a recent retrospective study, there was 8% incidence of acute kidney injury in patients with pre-existing renal impairment compared to others with normal renal function[ 85 ]. Oral BPs are not associated with significant nephrotoxicity[ 84 ].

All three bisphosphonate types have their contribution in MM treatment, but recommendations differ between various countries. American Society of Clinical Oncology (ASCO) prefers PAM in contrast to the British Committee for Standards in Hematology (BCSH) and International Myeloma Working Group (IMWG), who favor ZOL, due to decreased incidence of ONJ and similar effectiveness. CLOD is preferred in patients that cannot attend hospital visits, but a strict intake protocol should be followed to maximize absorption[ 86 ]. All symptomatic MM patients should be started on bisphosphonates regardless of the presence or not of myeloma bone disease, but the same does not apply for smoldering myeloma[ 46 , 52 , 87 ].

Special precautions are warranted to reduce ONJ incidence, and thorough oral examination is recommended prior to monthly IV infusion. Dental treatment before initiation of BP therapy has been associated with decreased risk of ONJ[ 21 , 88 ]. BP infusion should be withheld, and dose adjustments are recommended in patients with impaired renal function, and specifically ZOL and PAM are not recommended in patient with creatinine clearance (CrCl)<30 ml/min, while CLOD in CrCl<10 ml/min[ 86 ].

The development of DENOS, a human monoclonal IgG antibody that binds to RANKL thus preventing it from activating OCLs, has been tested against ZOL[ 55 , 61 ], in a recent trial including 1718 participants[ 64 ]. Results from that study, with 15.8 months median treatment duration, demonstrated longer PFS in favor of DENOS, especially in younger patients and candidates for autologous stem cell transplantation, and increased TTFSRE[ 64 , 67 ]. Furthermore, it showed non-inferiority in OS, in preventing SREs and similar safety. The incidence of hypocalcemia was more pronounced compared to ZOL, but there is no need for dose adjustments according to renal function[ 89 ]. Overall, these results have led to DENOS being approved by the FDA for use in prevention of SREs secondary to MM[ 23 ].

To test the safety of longer use of DENOS, an open label extension phase of the NCT01345019 trial was conducted[ 90 ], offering patients to the choice to continue or switch to DENOS. A total of 844 patients participated (426 DENOS/DENOS & 418 ZOL/DENOS) with a cumulative exposure of 29.2 months (original and extension phase) and mean exposure during the extension phase of 17.5 months. 23.2 % compared to 19.4% of patients in the DENOS/DENOS and ZOL/DENOS groups respectively, discontinued the medication due to serious adverse events. Hypocalcemia events had similar frequency in both groups (7% vs 7.2%) and ONJ incidence was higher in the DENOS/DENOS group (7.7% vs 6.2%) but notably more patients in the DENOS/DENOS group recovered (42%) compared to ZOL/DENOS group (23%). Sabatelli et al.[ 91 ] used statistical models on data from the primary study ( NCT01345019 ) to try and extrapolate long-term trends on PFS and quantify potential health benefits from DENOS in MM patients. According to their analysis, the effect of DENOS in disease progression could translate in lifetime health benefit between 1.5 and 2.3 extra months in perfect health, 1.9 and 2.8 extra months in the same condition as pre-progression and between 2.3 and 3.5 extra months with the same state (quality of life) as post-progression[ 91 ].

Currently there are two ongoing, single arm, open label studies recruiting. The first will assess the potential value of DENOS in preventing myeloma disease in patients with smouldering myeloma (NTC03839459/ www.clinicaltrials.gov ) and the other will estimate the therapeutic and safety potential of DENOS in patients with MM and renal insufficiency (ClinicalTrials.gov Identifier: NTC02833610). The DEFENCE trial (ClinicalTrials.gov Identifier: NCT03792763 ), a randomized, 2-arm phase II, placebo-controlled trial, which is active but not recruiting, is designed to test whether DENOS may prove beneficial in delaying SREs and reduce the risk of DP in patients with high and ultra-high risk smouldering multiple myeloma patients. Unfortunately, recruiting was slow and only 8 participants were enrolled, when the original estimation was 164.

Regarding ZOL, there is an ongoing randomized, open label study (ClinicalTrials.gov Identifier: NCT02286830 ) that will investigate time to progressive bone disease in patients with newly diagnosed MM continuing ZOL treatment for a total of 4 years. All patients will receive ZOL for the first 2 years and they will be further randomized between ZOL and PLC for the following 2 years.

Conclusion

Bisphosphonates are established drugs in the treatment of MM, with a good safety profile for long-term administration. They are effective in reducing bone disease but their ability to improve overall survival and progression free survival is not clearly established. Their use is not without adverse events and limitations, especially in patients with renal impairment. The use of newer drugs like DENOS, is gaining ground and if long term administration is proved safe and efficacious, it may even replace BP use in the treatment of MM.

Limitations & strengths

Our study has certain limitations. First, we did not conduct a meta-analysis of the studies with bisphosphonates but rather provide a comprehensive evaluation of the included studies. The reason was that no new studies have been identified since the published meta-analysis from the Cochrane Collaboration[ 80 ] and we did not have access to all the raw data. Some publications provided adequate information, while others did not, to be able to extrapolate uniform measures to proceed with a meta-analysis. Another limitation is that we could not gain access to the full publication of the study by Daragon et al.[ 92 ], Kraj et al.[ 93 ] and Rosen et al.[ 94 ]. We extracted data from the publications on the extension phase of the original studies by Kraj et al. and Rosen et al., where the full text was available. Moreover, only articles published in English were included, which did not allow us to consider more studies (see Appendix). Nevertheless, regarding the strengths of this study, it is a comprehensive analysis of the research conducted from 1980 up to date, regarding the effectiveness of bisphosphonates in myeloma patients. We also included trials that compared the more recent pharmaceutical agent, denosumab and its potential value to the management of bone disease in MM patients, as well as ongoing research on the field. In this way we summarized, in a structured way older research and novel perspectives regarding the use of antiresorptive agents in the prevention of bone disease in patients suffering from MM.

Authors’ contributions

VC contributed to the conceptualization, investigation, methodology, data curation and drafting the manuscript. GK contributed to investigation, methodology and data curation of the manuscript. DK contributed to methodology, data curation and editing of the manuscript. CD contributed to editing and reviewing the manuscript. IS contributed in reviewing and approving final version of the manuscript and EZ in validation of methodology, reviewing and approving the manuscript .

Footnotes

The authors have no conflict of interest.

Edited by: P. Makras

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