Лечение болезни костей миэломы: Когда, как часто и как долго?

Introduction

Multiple myeloma

Multiple myeloma (MM) is a plasma cell dyscrasia defined by clonal bone marrow plasma cells ≥10 % or biopsy-proven bony or extramedullary plasmacytoma and presence of one myeloma-defining disorder [1] . According to recent American cancer statistics, MM accounts for 17 % of all hematological malignant disorders [2] . MM has a number of complications including anemia, hypercalcemia, kidney damage, and immunoparesis [3] . The most notable complication to MM however is bone disease with 79 % of new MM patients presenting with pathological imaging, and with 60 % experiencing bone pain at diagnosis [3] .

Myeloma treatment and survival

Randomized studies of the bone protective bisphosphonates clodronate and pamidronate were published 20 years ago. Since then a number of more effective anti-myeloma treatments have become standard MM treatment including immunomodulatory drugs [4] , proteasome inhibitors [5] and CD38 antibodies [6] , with bispecific antibodies [7] and CAR-T recently becoming standard of care in many countries The results have been increasing survival, with studies demonstrating 5-year survival increase from 27.4 % (1994–2001) to 47.4 % (2010–2016) and median OS from 2.8 years (2000–2004) to 4.4 years (2017–2021), and even 9.2 years for patients who received autologous stem cell transplant [8] . Data from the Norwegian cancer registry shows even further improvement with overall 5-year survival of 78 % for patient 70 or younger and 55 % for older patients [9] . With longer survival, supportive treatment to prevent morbidity becomes increasingly important.

Morbidity in multiple myeloma patients

MM bone disease severely affects morbidity in MM patients. A Danish registry study found MM patients had 44 % risk of ending on disability pension compared to 5 % in controls. Even compared to more aggressive hematological cancers like Diffuse Large B cell Lymphoma and Acute Myeloid Leukemia the risk of disability pension was still increased 3-fold in MM [10] . The high morbidity of MM is considerably increased due to bone disease. In a quality-of-life study 50 % of MM patients complained of pain, of which half considered it of severe degree [11] . Other common complaints in MM patients were trouble with role functioning, physical role functioning and fatigue, which was found in 80 %, 54 % and 67 % of patients respectively [11] . In addition, effects of MM bone disease include vertebral collapse, which can lead to paresis or paralysis due to nerve- or spinal-cord compression [3] .

Myeloma bone disease

In healthy people bone remodeling includes resorption of old bone followed by replacement with new bone matrix in the form of osteoid. The involved cells in this process are osteoblasts, which are specialized bone anabolic cells [12] , [13] , and osteoclasts that resorb bone by attaching to the bone surface and secreting hydrogen ions and enzymes [14] . Both osteoclasts and osteoblasts are essential for bone remodeling and for upholding calcium homeostasis [15] . Additionally, osteocytes initiate bone remodeling through endocrine and mechanic sensors [16] , [17] , and bone lining cells cover the bone surface [18] .

MM disrupts normal bone homeostasis in several ways (see Fig. 1 ). An important mechanism is disruption of the balance between receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG) by increasing the RANKL/OPG ratio. RANKL is pivotal as osteoclast differentiation is supported by RANK/RANKL interaction, [19] and RANKL is inhibited by OPG. Co-cultures of MM and stromal cells have been found to decrease OPG production and increase RANKL [20] , [21] .

MM cells can interact with the microenvironment, which may increase risk of MM relapse as well as drug resistance [22] . MM interaction with stromal cells have further been shown to increase IL-6, which can interrupt the Wingless type (Wnt) pathway increasing MM cell survival and activating osteoclast formation [23] , [24] . Another antagonist of the Wnt pathway is the secreted Frizzled-related protein, which has been found to be highly secreted in patients with advanced bone disease [25] . MM cells can produce a number of molecules reducing osteoblasts function e.g. dickkopff-1 as well as sclerostin [26] , [27] Finally, Runt-related transcription factor 2 (Runx2), which leads mesenchymal stems cell in the direction of differentiation to osteoblast, is possibly inhibited by MM cells [28] , [29] .

Overall, MM severely affects bone health and increase risk of skeletal related events (SRE) (spinal cord compression, pathologic fracture, radiation to bone, or surgery to bone) as well as osteolytic lesions and hypercalcemia [3] . These symptoms can by itself indicate need for initiation of myeloma treatment (CRAB criteria) [30] .

Imaging/monitoring

CT imaging (whole body low dose CT, WBLDCT) is the gold standard for myeloma bone imaging, as it has shown superiority both retrospectively and prospectively to conventional radiography for detecting osteolytic lesions [31] , [32] , [33] , [34] . Conventional radiography was previously used for staging [35] , but is no longer recommended today [36] , [37] , [38] . Conventional radiography have limited sensitivity, and large amounts of bone can be destroyed without lesions being visible on images [39] . Several of the studies we will discuss are based on conventional radiology, and may underestimate the extent of skeletal related events in patients compared to the studies based on WBLDCT.

MRI and PET can supplement WBLDCT and can be relevant for prognosis. MRI examines the tissues polarity in a magnetic field taking advantage of water being a polarized molecule, unlike fat. It can thus estimate the cellular infiltration of a normally fatty bone marrow. Unlike other modalities MRI investigation can be done without exposure to radiation [40] which can be relevant especially in younger patients. PET-CT combines CT investigation with a radioactive tracer (usually 18F-fluorodeoxyglucose) and is especially useful to show extramedullary disease. Additionally focal lesion found by PET-CT have been shown to have predictive value with more than 3 PET-positive focal lesions predicting inferior OS and PFS, and normalization on PET after treatment indicating better PFS and OS [40] , [41] .

MRI can also define treatment demanding myeloma according to current guidelines with >1 focal lesions [42] Still the WBLDCT is primarily used for its availability and high accuracy and specificity [40] .

For newly diagnosed MM patients the presence of abnormal MRI patterns or SRE have been found to predict shorter OS compared to patients who do not have these findings [43] .

Topics for discussion

An overview of discussed studies can be seen in Table 1 . An overview of recommendations from International Myeloma Working group (IMWG), European Society for Medical Oncology-European Hematology Association (ESMO-EHA) and National Comprehensive Cancer Network (NCCN) related to SMM, MM, relapse of MM and treatment period can be seen in Table 2 .

Smouldering MM

Bisphosphonates for smouldering MM (SMM) have been investigated with both pamidronate [44] , [45] and ZOL [46] , but not with denosumab. The two pamidronate studies included 177 and 90 patients with untreated SMM. In these studies, patients with pamidronate treatment had significantly less SRE at progression to active myeloma (22/56 vs. 40/55P = 0.009), (4/10 vs. 9/11, p < 0.01), however no difference in time to progression was observed. Regarding ZOL, a 2008 study by Musto et. al . [46] prospectively investigated 163 SMM patients who were randomized to receive either monthly ZOL for one year (n = 81) or no ZOL (n = 82). Patients were followed for a median of 65 months. Imaging was performed with conventional X-rays every year or if deemed clinically indicated. While ZOL did not delay progression to symptomatic myeloma, patients who had received ZOL had significantly lower incidence of SRE at progression (55.5 % vs 78.3 % p = 0.041). While this was found to be significant, the difference was small (29 vs. 20 patients) and the overall number and nature of lesions was not described. The 2008 Musto et.al . study was ended early for safety concerns as reports of MRONJ in MM treated with ZOL began to emerge at the time [46] . Furthermore, these studies were performed before the introduction of the 2014 SLiM CRAB criteria [42] and likely a number of patients designated SMM would have been treatment demanding by these current criteria and would hence receive treatment.

The overall consensus has so far been that SMM should not be treated with bone protective treatment unless there are concomitant osteoporosis in which case osteoporosis guidelines with treatment every six months are recommended [30] . Patients with SMM who are being treated with regimens containing dexamethasone, should be evaluated for osteoporosis before and during treatment.

Active MM

The myeloma IX study investigated different MM treatment regimens, as well as monthly ZOL and clodronate, on 1960 newly diagnosed treatment demanding MM patients.

The induction regimens were: cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) versus cyclophosphamide, thalidomide, and dexamethasone (CTD; intensive) or melphalan and prednisolone versus attenuated oral CTD (CTDa; nonintensive) In the intensive arms patients were planned for ASCT which 747 received. Patients were further randomized to either receive thalidomide or no anti-myeloma maintenance [47] . While relevant at the time, the induction and maintenance were suboptimal compared to the current SOC which often include combinations of bortezomib, lenalidomide, daratumumab and lenalidomide [48] , [49] .

The study randomized all patients between ZOL and clodronate, and found that monthly ZOL reduced risk of death (HR = 0.84, P = 0.012) In the Intention to treat group the difference in overall survival was 5.5 months and difference in progression free survival 2 months. ZOL further decreased risk of SRE compared to clodronate, regardless of whether bone disease was found at baseline radiological examination of the skeleton. The hazard ratio for risk of SRE with or without bone disease at baseline was HR = 0.77, P = 0.0038) and HR = 0.53; P = 0.0068, respectively [50] . Given that clodronate is known to have bone protective effects in MM [51] , the effects of ZOL is likely to be larger compared to no bone protective treatment, overall underlining effects of ZOL even in MM patients with no bone disease at diagnosis. However, radiological evaluation in this study was performed on X-rays, not CT. As CT is a more sensitive modality it is uncertain whether these findings can be extrapolated to MM patients with no bone disease at baseline on CT. Though acknowledging this weakness, it is still recommended to treat all symptomatic myeloma patients from diagnosis regardless of bone status [30] . However, it remains unclear if the intensity of bisphosphonate treatment in patients with no bone disease on CT should be reduced.

The importance of early ZOL initiation was investigated in a retrospective study by Wu et. al . This study compared 126 MM patients who had ZOL treatment initiated within 60 days of diagnosing symptomatic MM compared to 186 patients who had not [52] .The follow up period was two years, and the endpoint was time to first SRE, number of SRE, and pathological fractures. MM patients with initiation of ZOL within 60 days were found to have both longer time to first SRE (SRE free rate 74.6 % vs. 56.5 % after 2 years, p = 0.005), fewer overall SRE, and fewer pathological fractures (mean SRE 0.39 vs. 0.72p = 0.002). It must be noted that this was a non-randomized retrospective study. The patients who received early ZOL had higher age (62.1 vs. 60.1P = 0.02), higher average myeloma stage, and higher average number of osteolytic lesions at diagnosis (7.1 vs. 4.8P = 0.0006) compared to the patients without early ZOL treatment. On the other hand, osteopenia was more common in the group with ZOL treatment later than 60 days after diagnosis (11.9 % vs. 15.6 % P = 0.03) [52] .

Type of treatment: Bisphosphonates/denosumab

Bisphosphonates function by attaching to the hydroxyapatite binding sites in the skeleton. Osteoclasts are exposed to bisphosphonates as they absorb bone. Bisphosponates can inhibit osteoclast absorption through an number of mechanisms [53] . In MM, pamidronate [54] , clodronate [55] , and zoledronate (ZOL) [47] , [56] , [57] have been investigated [58] . Bisphosphonates have been found to decrease bone pain and pathological fractures, vertebral collapse as well as other skeletal related events [58] , and the bisphosphonates clodronate and pamidronate have shown efficacy in randomized trials compared to placebo [54] , [55] . Randomized studies on ZOL have shown superior efficacy compared to other bisphosphonates and has even demonstrated increased progression free survival and overall survival [47] , [56] , [57] . ZOL is furthermore superior to pamidronate for decreasing malignant hypercalcemia [59] . ZOL have been found to have a long half-life in bones with bisphosphonate still being present in bones 10 years after treatment [60] . Yearly administrations have been found sufficient in some nonmalignant diseases [61] .

RANK/RANKL interaction is essential for function and development of osteoclasts. Denosumab is a humanized RANKL antibody inhibiting this process [62] ). In a large landmark study by Raje et. al. in 2018 [63] long term treatment with ZOL was compared to denosumab. The phase 3 study was double blinded, randomized and included 1718 newly diagnosed MM patients with at least 1 lytic or focal lesion [63] . Included patients were stratified by first-line myeloma treatment novel-based (IMiDs, proteasome inhibitors) yes/no, intent to undergo autologous stem cell transplant, and ISS disease stage, as well as whether they had previous skeletal-related events [63] . In this study denosumab was found non-inferior to ZOL relating to time to first SRE. They also found a higher PFS in patients treated with denosumab (HR 0·82 (95 % CI 0·68–0·99, P = 0.036) for a median increased PFS of 10.7 months although OS showed no difference [63] . A secondary analysis they compared findings of new SRE in ZOL and denosumab group using patients treated for 15 months as a new baseline and following patients up until 42 months. In this sub-analysis they found lower rate of SRE (HR 0.66 95 % CI 0.44–0.98, P = 0.039) for denosumab, [63] . A later analysis of this phase 3 study was performed by Terpos et. al. in a 2021 paper to identify which factors contributed to the longer PFS of denosumab and whether the benefit was larger in specific subgroups [64] . The analysis was performed by age (<70 years vs older), treatment, intent to have ASCT, and kidney function (<60 mL/min). The study found better PFS of denosumab in patients intended for ASCT with a hazard rate of 0.65 [0.47–0.90]. The study also found increases in PFS in patients younger than 70 and with better kidney function of at least 60 mL/min while no PFS was found in patients not intended for ASCT, older than 70 or with kidney function (<60 mL/min). This study demonstrates the viability of denosumab for long term treatment and suggest that denosumab might be favorable to ZOL especially in fitter subgroups of MM patients.

A meta -analysis later found denosumab non-inferior for preventing spinal cord compression [65] . Non-inferiority of denosumab to ZOL has also been seen in earlier small studies including other cancers. These studies had similar side effect profile to ZOL apart from not being nephrotoxic [65] , [66] . Overall, denosumab has been less studied than ZOL, and it has overall been found non-inferior for time to first SRE and with similar side effects to ZOL except for renal insufficiency. While PFS may be increased by denosumab compared to ZOL, no increase in OS has so far been shown [63] . Denosumab is currently recommended for MM over ZOL in case of renal dysfunction [30] .

Side effects to bone protective treatments

Bisphosphonates have several significant side effects. The most notable is treatment-related osteonecrosis of the jaw (MRONJ), a side effect which can cause part of the jaw to dissolve, leading to significant pain and disability [67] . Studies demonstrate that MRONJ is observed in 2.6–4 % of MM patients treated with bisphosphonates [56] , [57] . Increased risk of MRONJ is seen with prolonged treatment duration, increasing potency of bisphosphonates, as well as in patients with poor dental health status before initiation of treatment, and in patients undergoing tooth extractions after initiation of bisphosphonate treatment [68] , [69] . Denosumab may also cause MRONJ and does so at a level comparable to ZOL [63] .

A number of precautions have been identified to decrease risk of MRONJ in bisphosphonate treated patients. Baseline dental inspections and necessary dental procedures being done before ZOL initiation, waiting 6–8 weeks after procedures to initiate ZOL as well as practicing less invasive techniques when possible was investigated in MM patients. The study compared occurrence of MRONJ before or after preventive measures were implemented. An almost fourfold reduction was seen (26.3 % vs 6.7 % P = 0.002) [70] ). A related study in solid cancers (mostly breast) with early dental inspections showed a smaller but similar effect [71] . A 2008 retrospective study compared patients who received prophylactic antibiotics before oral surgeries to patients that did not, and found that antibiotics had significantly protective effect [72] . Pausing Zoledronic acid for oral surgery (drug holiday) has later been investigated in a review and a randomized study, but this was not found to decrease risk of MRONJ [73] , [74] ,

As most of the studies are made with bisphosphonates (mostly ZOL), it is uncertain whether the effect of these precautions is similar in patients treated with denosumab. Patients treated with denosumab have been found at risk of accelerated bone degradation and fractures upon pausing or ending treatment [75] . This has been seen in metastatic breast cancer, osteoarthritis, osteoporosis, as well as in patients who received glucocorticoids and denosumab due to kidney transplant, but the effect has not yet been investigated specifically for MM [75] , [76] . As RANKL is found on immune cells and is produced by activated T-cells, it has been suggested that denosumab could affect the immune system [77] . However, this has not been seen in the non-inferiority study, which found similar rates of infections and neutropenia between ZOL and denosumab groups [63] .

An important side effect to bisphosphonates is nephrotoxicity. A common complication of MM is decreased kidney function, and bisphosphonates should be avoided in MM patients with considerably decreased kidney function (eGFR < 30). Additionally, ZOL can negatively affect kidney function in MM patients leading to the need for dose reduction, pause in treatment or termination of treatment. In these cases, denosumab is often recommended [62] , [63] .

Special care must be taken when deciding whether to end denosumab treatment, as it has been shown to have a rebound phenomenon with increased risk of SRE upon discontinuation, especially vertebral fractures and increases in catabolic bone markers [76] . While some studies suggest that this risk can be somewhat mitigated by bisphosphonate treatment at the end of denosumab treatment, the evidence is not strong and is generated from other diseases than MM [78] , [79] , [80] , thus more data is needed regarding this question.

Length of treatment

Currently, the 2021 recommendations from the International Myeloma Working Group, suggest that for patient achieving at least very good partial regression (VGPR) frequency of ZOL doses could be reduced or even terminated after one year of treatment [30] . Logically, sufficient suppression of MM should stop development of MM bone disease, and with development in effectiveness of MM treatment the importance of ZOL may be lowered over time. It has also been reported that most cases of SRE occur early in MM disease, which could indicate less value of long-term treatment [63] , [81] .

The original studies showing effects of bisphosphonates (clodronate, pamidronate) had intervals of four weeks and a follow up 21 and 24 months, respectively [51] , [54] , [55] . As described earlier, the risk of side effects has been found to increase with treatment length and potency [70] .

Two studies have shown low rates of SRE without any bisphosphonates or bone protective treatment at all. [82] , [83] . In these studies patients with at least partial regression (PR) after autologous stem cell transplant (ASCT) were followed by consolidation with either bortezomib and lenalidomide (n = 59) or VTD (n = 42), [82] , [83] . These studies had high response rates including 36 % and 51 % achieving stringent complete response (sCR). The treatments further resulted in suppression of circulating CTX possibly indicating reduced bone catabolism. For these two studies, it must however be noted that the number of patients were of limited size (59and42patients), the studies were non-randomized and SRE evaluations were done with traditional radiology with limited sensitivity.

The Myeloma IX trial was the first randomized trial that investigated long term treatment with ZOL for MM. In addition to analysis of the whole patient group of 1960 patients described earlier, a sub analysis on the 582 MM patients who received at least two years of bisphosphonate treatment was performed [50] . [50] , [84] . This study showed increased overall survival (OS) (median not reached HR 0.60, P = 0.02) from randomization and significant reduction in incidence of SRE in ZOL compared to clodronate (P = 0.01) as well as OS benefit after first disease progression (median 34 vs 27 months HR 0.58, P = 0.03) [50] That bisphosphonates can increase PFS and/or overall survival in phase 3 studies may not be solely due to the bone protective properties as increased apoptosis of myeloma cells lines has been demonstrated in vitro [85] , [86] .

A prospective observational study by Wyngaert et. al . was published in 2013 [87] . This study followed 298 patients with either MM (n = 93) or solid tumor bone metastases (n = 205) who had received 24 months of ZOL treatment, and patients were observed for an additional 18 months for whether ZOL treatment was continued and whether patients had new SRE. The study was observational, and imaging was conducted as conventional x-ray when clinically indicated. It showed that patients who continued ZOL in the observation period had lower risk of SRE (Hazard ratio 0.42, P = 0.01), but could not show this specifically for the smaller MM subgroup (Hazard ratio 1.08, p = 0.9). Due to the observational nature, strict conclusions cannot be drawn. The study does not describe baseline characteristics of the different groups.

Avilés et. al. (2017) [88] investigated if ZOL treatment for four years compared to two years increased progression free survival (PFS) or OS, as well as safety of prolonged ZOL treatment. A secondary endpoint was the difference in SRE rate. The population consisted of 170 previously untreated, but symptomatic, ISS grade III MM patients randomized to two (n = 86) or four (n = 84) years of monthly ZOL treatment. Patients underwent x-ray examination and oral examination at inclusion and every 6 months of study. OS after 5 years was compared between the two groups and found to not be significantly different with 72 % (95 % CI: 62–78 %) in the four-year group vs 68 % (95 % CI:60–75 %) in the two-year group. The study observed significantly fewer cases of SRE in the group treated for up to four years, with a considerable reduction in SRE by 20 percentage points (41 % vs. 21 %, p < 0.01). Side effects were described as modest with no cases of renal impairment, and surprisingly no cases of MRONJ at all.

The Magnolia study [89] followed a total of 193 of symptomatic MM patients (any ISS) who were randomized to either stop ZOL after two years of initial treatment or continue for an additional two years. Both groups were followed by WBLDCT imaging every 6 months. The study showed a significantly reduced rate of progression in bone disease by 22 percentage points from 43 % till 21 % in the treatment group (HR 0.40, p = 0.021). A non-significantly higher number of MRONJ cases was seen in the treatment group (6 vs. 1, P = 0.12), but only two cases of symptomatic MRONJ grade 2 were seen. There was no significant difference in the number of patients with creatinine increase (p = 0.08) or change in OS. This study also included QoL data, in which pain was found to be significantly increased in the months before SRE, and pain was found near-significantly increased in the observation group overall [89] .

Overall, studies including myeloma IX [50] data and the landmark denosumab study [63] and the studies randomizing ZOL to two or four years treatment, demonstrated limited side effects of long term treatment. In the randomized studies significant reductions in occurrence of SRE were observed with continued treatment with ZOL beyond two years [88] , [89] .

Re-initiation of treatment at relapse

Reinitiating bone protective treatment in cases of relapse makes intuitive sense, especially in the case of progressive bone disease, however the studies in this area are limited. In the Spanish AZABACHE trial [90] 100 MM patients were randomized to either initiate ZOL or observation at biochemical relapse. In both groups no anti myeloma therapy was initiated; the median follow up was 38 months. The group randomized to initiating treatment at biochemical relapse had significantly fewer SREs (2 vs. 14, P < 0.001), while the overall time to next therapy was not increased. Of the 100 patients in study, one patient in the treatment group experienced MRONJ. There were no significant differences in other adverse events in the study. This study suggests that treatment with ZOL should be re-initiated at biochemical relapse. It must however be noted that in the AZABACHE trial anti-myeloma treatment was not initiated at biochemical relapse but at symptomatic progression. This may affect the results compared to current standard of care as anti-myeloma treatment at relapse could lessen risk of SRE and thus lessen importance of initiating ZOL. It should also be mentioned that patients with frequent relapses would thus be on bisphosphonate treatment continuously if ZOL is initiated at each relapse. Considering this, a case-by-case judgement should be performed, aiming to balance long-term toxicity with the need for bone protective treatment, and the extent of the patients’ bone disease should be an important part of this decision.

It is worth noting that most patients in the AZABACHE study (exact proportions are not described) probably had received long term treatment with ZOL before inclusion, and 24 months bisphosphonate treatment for new MM patients was the recommended treatment in Spain at the time [90] . This indicates that the benefit is not likely to be limited to patients without previous long-term bisphosphonates.

The length of treatment in relapse is not well studied. The AZABACHE trial [90] used at total of 12 ZOL doses with one dose given every 4 weeks, which could be a suggestion. With time to progression often decreasing with each line of treatment, initiation at every relapse does risk some patients receiving ZOL for the rest of their lives which would result in large overall exposure with additional risk of side effects. The value of treatment with ZOL beyond first relapse is currently not known, and the value in relapsing patients specifically without increasing bone disease is not known.

Treatment interval

As the risk of side effects increase with higher cumulative doses, an important question is whether longer spaced regimens could retain bone protective effect with diminished side effects. In breast as well as lung cancer patients with bone metastases, administration of ZOL with 12-week intervals have been found non-inferior to 4-week intervals, [91] , [92] , [93] .

In 2007 Corso et. al . retrospectively followed 106 MM patients who were treated with ZOL or pamidronate [94] . The treatment schedule was monthly the first year and then either continued monthly treatment as long as tolerated (n = 51) or treatment every three months (n = 55). The baseline characteristics were comparable. Mean observation time after the first year was 25.8 months. Baseline characteristics were not significantly different regarding gender, bone disease, bisphosphonate type, thalidomide treatment, bone status or disease status at baseline. No difference was observed in the incidence of SRE between the groups (incidence 100 person years 95 % CI 8.4–27.3 vs. 11.0–28.4). In the group with lengthened interval treatments, cox regression demonstrated a lower hazard rate of MRONJ of 0.12 (p = 0.049) [94] . However, it must be noted that this is a retrospective study, and the lower hazard rate was based on only 7 cases of MRONJ of which 1 was in the regimen with treatment every three months. While interesting, one should be careful not to overestimate the value of marginally significant findings in retrospective studies based on a small number of cases.

In a study published in 2017, Himelstein et. al. prospectively investigated treatment intervals in 1822 patients suffering from either MM (n = 278), bone metastatic breast cancer (n = 855) or bone metastatic prostate cancer (n = 689), who were randomized to receive ZOL every four (n = 911) or 12 (n = 911) weeks for two years [95] . The baseline or treatment status of MM patients was not described distinctly from the other cancers, but overall the groups were not significantly different. No significant differences were found for the primary endpoint of incidence of at least one SRE within two years at 29.5 % (4 weeks) vs. 28.6 % (12 weeks). This finding was non-inferior within the planned 7 % non-inferior margin. Further, this proportion did not significantly differ between treatment regimens for any specific cancer (including MM). The study further found no significant difference in reported pain, and a near significant higher risk of MRONJ in the 4-week group (2 % vs 1 % p = 0.08). The study also investigated the rate of grade 3/4 kidney dysfunction, which was not significantly different (1.2 % vs. 0.5 % P = 0.1). Although no clinical difference was found between groups, the study also used C-terminal telopeptide (CTX) as a marker of bone turnover, which was found to be higher in the longer interval treatment group, suggesting that the shorter interval treatment might have achieved stronger suppression of bone catabolism.

Another study treating MM patients with ZOL either every four or 12 weeks is the Z-MARK study published in 2016 by Raje et. al . The study used urinary measurements of the bone degradation marker N-telopeptide of type 1-collagen (uNTX) to determine intervals of continued ZOL treatment [96] . The patient group consisted of 121 MM patients with 52–104 weeks (1to2years) previous ZOL treatment, with patients with uNTX < 50 mmol/mmol creatine receiving ZOL every 12 weeks and patients with higher uNTX receiving treatments every four weeks. 117 MM patients started on the 12-week regimen and four patients on the 4-week regimen. During the study 38 patients were changed to 4-week regimen due to either MM progression (n = 20), increased uNTX (n = 14) or SRE (n = 4). The value of the uNTX measurements for guiding ZOL treatments is not clear, and most patients in the study received ZOL every 12 weeks. 5.8 % of patients experienced SRE within the first year [89] . The rate of MRONJ was within what we currently expect at 3.3 % [96] .

Considering these studies overall, treatment regimens with ZOL every 12 weeks seems to be well tolerated and efficacious. Data from breast-, prostate-, and lung cancer [95] , [91] , [92] , [93] finds the 12-week regimen non-inferior, and the data we do have from myeloma patients support this. The studies seem to trend towards fewer side effects with a longer interval regimen, but the data are far from clear. If a 12-week regimen becomes generally accepted, then the question is when to increase treatment intervals from four to 12 weeks. In both the study by Corso et. al . [94] and the Z-MARK study by Raje et. al. [96] patients received at least one year of ZOL before lengthening intervals, while the Himelstein et. al . study [95] started randomization at inclusion. From a cautionary point of view the value of ZOL treatment in MM patients is well established, and until stronger data is available one might be wary of lengthening interval before the first year of treatments have been completed. A possible solution to this question may be bone markers. However, it is uncertain whether bone turnover is an indication for initiating more intensive treatment and the predictive value of bone markers in this area have yet to be shown. Treatment regimen may pose a specific problem in patients treated with denosumab. The studies comparing denosumab to ZOL compared treatment every 4 weeks. As seen earlier, 4 vs. 12-week non-inferiority studies of ZOL in MM have been conducted [95] , [96] , but it is far from certain that this can be transferred to denosumab. In the FREEDOM studies of long term denosumab for osteoporosis, treatment every 6 months however is safely used [80] although this might not transfer directly to MM.

Changes in ZOL treatment depending on treatment response

As MM cause bone disease, one would logically assume that patients with less MM disease due to better treatment responses are at lower risk.

Data from a subgroup analysis the Myeloma IX study showed ZOL superior to clodronate for SRE in patients having achieved VGPR or less by day 100 post-transplant. For OS, ZOL was superior only in patients achieving PR or less [97] . For patients with better responses this superiority was not seen. When considering this, it is important to note that ZOL was not compared to no treatment, but to another bisphosphonate that (while inferior to ZOL) does have bone protective properties one should therefore be careful not interpret no difference in better responses as evidence that no bone protective treatment is needed in these patients. The sub-analysis was also conducted on transplant eligible MM patients only, who represent around one third of MM patients. On a contrary point of view both induction and maintenance in the study was subpar compared to current regimens with better responses and maintenance likely to reduce overall risk of SRE. The SRE investigations were made by conventional radiography, which have a lower sensitivity than WBLDCT [31] , [32] , [33] , [34] , and as such some cases of SRE could have been missed in the study possibly affecting results.

The long term ZOL vs observation study by Aviles et. al. did not present treatment response data, and can therefore not answer this question [88] . In the Magnolia study by Lund et. al. comparing two additional years of ZOL vs. observation after two years of ZOL for newly diagnosed MM, it was reported that a number of SRE findings were seen on patients who had achieved VGPR. 16 of cases with SRE had achieved VGPR at latest treatment and 9 had achieved CR or better [89] . A subgroup analysis of patients in the study who had achieved VGPR or better during latest treatment before randomization at two years was later performed. It was found that there were still significantly higher risk of SRE in the ZOL non-treatment group (HR 0.37 with 95 % CI (0.15–0.89) P = 0.027) indicating that ZOL treatment may be warranted even in patients with deep responses to anti-myeloma treatment [98] . The Magnolia study did not have a size that allowed further sub-analyses for patients receiving autologous stem cell transplantation. It is unclear at what treatment response, if any, that ZOL can safely be withdrawn, and if there is a difference between patients undergoing autologous stem cell transplantation or not. As suggested previously, a compromise is a reduction in frequency in patients with a deep hematological response.

Treatment modification by monitoring

Monitoring MM patients with imaging without symptoms is currently not recommended [38] .

An early study tested serial imaging with conventional x-ray over a time period of 60 weeks in 15 MM patients without significant findings, and as such did not find serial X-rays suitable for monitoring MM [39] . A sub-study of the Magnolia study by Gundesen et. al. followed 267 symptomatic MM patients with preplanned WBLDCT every 3–6 months for up to four years. The study found a number (n = 21) of incidences with SRE in patients without biochemical progression, symptoms or other CRAB criteria. These findings suggest that monitoring of bone disease with WBLDCT at regular intervals could reveal early bone disease possibly allowing for early treatment [99] .

An important way forward for bone protective treatment for MM would be if a marker or measurement could indicate if a patient had a need for bone protective treatment, allowing for an individualized approach. In the Z-MARK study, a strategy measuring urinary NTX was used with low rates of SREs [96] . However, it is unknown if this shows value of uNTX as a marker for treatment strategy, or if the lower treatment regimen of ZOL every 12 weeks is simply sufficient.

Other markers have been suggested including mRNA strands [100] . However, while correlation to bone disease have been seen in a number of markers, a predictive finding on individual patient level sufficient to guide treatment have yet to be shown [101] .

Anti myeloma treatment effect on bone in MM

Selected anti-myeloma treatment have shown bone protective or even possible anabolic effects; especially proteasome inhibitors including bortezomib but also carfilzomib [102] , [103] and later the CD38 antibody daratumumab [104] . For proteasome inhibitors an increase in alkaline phosphatase has been seen and in the Vista trial, radiological signs of bone healing was seen in more than half of patients treated with bortezomib plus melphalan and prednisone [105] . However, side effects of bortezomib, especially neuropathy, can limit the possibility of long term treatment. For ixazomib, a nonrandomized study showed significantly decreased catabolic bone marker and significantly increased trabecular bone in bone biopsies after 3 months of treatment [106] . Daratumumab has been investigated in a bone marker study (REBUILD) and showed decrease of catabolic markers (CTX, TRACP 5B) and increases of the anabolic markers osteocalcin, bone-specific alkaline phosphatase and procollagen type-I N-pro-peptide though the suggesting improved bone formation with reduced osteoblast inhibition [104] .

Conclusions

Determining the optimal initiation, length, and treatment intervals of ZOL or denosumab is no simple matter, and existing bone disease, side effects, treatments status, and bone markers must be considered.

For active MM, regardless of bone status, bone protective treatment should be initiated early after diagnosis. ZOL is superior among bisphosphonates, and denosumab, while less examined, has been found to be non-inferior to ZOL. Most cases of SRE happen within the first year and monthly treatment with ZOL is recommended, except for patients with considerably decreased kidney function (eGFR < 30) where denosumab is the preferred choice.

After the first year of treatment with monthly ZOL, prolonging interval of treatment to every 12 weeks have been tried in a number of myeloma and non-myeloma studies and have generally been found non-inferior to monthly treatment. Increasing intervals of denosumab in MM is experimental but have been tested in other cancers and osteoporosis with good results. If stopping denosumab treatment, extra care should be taken as risk of especially vertebral SRE may increase, and additional bisphosphonate treatment may be warranted. It is uncertain whether treatment safely can be stopped after one year for patients with deep remissions. Data from the Magnolia trial suggests that a response of at least VGPR is not sufficient to omit ZOL treatment without risking an increased SRE rate.

While most SREs in myeloma happen within the first year, two separate randomized studies indicate that longer term treatment may significantly reduce the risk of SRE at least up to four years with few side effects. Data beyond four years of treatment is very limited.

To minimize risk of MRONJ Dental evaluation should be performed before initiating bone protective treatment and prophylactic antibiotics should be used for oral surgeries.

A suggestion that is based on the totality of data discussed here, is to reduce ZOL treatment to every 12 weeks after at least 12 doses, and when reaching 24 months of treatment or at least VGPR, whichever comes first. Treatment can then be continued to 4 years with a frequency of 12 weeks.

In patients who are not actively receiving bone protective treatment, it should be re-initiated at disease progression, or at new SREs unless there are contraindications. Treatment of relapsing patients without bone disease can be based on individual judgement. The only relapse trial with bisphosphonates used ZOL every 4 weeks for 12 months.

While individualized bone protective treatment in MM patients based on bone markers may be tempting, the clinical value is still unproven.

CRediT authorship contribution statement

Michael Tveden Gundesen: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Conceptualization. Fredrik Schjesvold: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Conceptualization. Thomas Lund: Writing – review & editing, Writing – original draft, Supervision, Investigation, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thomas Lund reports financial support was provided by Nordic Cancer Union. Thomas Lund reports financial support was provided by Danish Cancer Society. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

This article is part of a special issue entitled: ‘Myeloma bone disease’ published in Journal of Bone Oncology.

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