High-risk patients can be treated with high-dose chemotherapy regimens plus either autologous stem-cell transplantation (ASCT) or allogeneic bone marrow transplantation. Recommendations for the treatment of symptomatic MM are reported in Fig. 8.2. Historically, the initial treatment for newly diagnosed MM (induction therapy) was high-dose melphalan. This therapy limits the ability to collect stem cells. In transplant eligible patients, it is preferable to use thalidomide/lenalidomide and bortezomib-based regimens. ASCT improves complete response and prolongs median overall survival by approximately 24 months, though with an intrinsic mortality rate ranging from 1% to 2%. The conventional approach to consolidation therapy has been high-dose melphalan. Induction regimens with a higher response rate before transplant result in longer time to progression after transplant. Thus, the introduction of thalidomide/lenalidomide and bortezomib increased progression-free survival after high-dose melphalan and ASCT and also increases their use as a consolidation regimen after initial response. Continued initial therapy as well as the use of combinations of bortezomib–thalidomide–dexamethasone, bortezomib–lenalidomide–dexamethasone, or cyclophosphamide–lenalidomide–bortezomib–dexamethasone have been proposed because they may increase the overall response rate >90%. Conditioning regimens based on total body irradiation are inferior to high-dose melphalan. Dose intensification reduces the possibility of recurrence, but it increases the risk of ­treatment-related toxicity and mortality (64%). On the other hand, intensity-reduced conditioning may result in high relapse rates (54% 5-year mortality rate). Myeloablation as part of radioimmunotherapy (RIT, see above) can be used 10–14 days before transplantation to reduce the dose of the conditioning treatment. Ongoing studies aim at assessing whether the conditioning regimen can be improved by the addition of bone-seeking radiopharmaceuticals such as ¹⁶⁶Ho-DOTMP or ¹⁵³Sm-EDTMP. A second sequential ASCT has been investigated as additional consolidation therapy to further reduce disease burden. Such tandem ASCT seems to be beneficial for patients who have failed to achieve good partial response after the first ASCT. Allogeneic transplant may be an option only for few patients, because of selective inclusion criteria (age, availability of an HLA-matched sibling donor, and adequate organ function) as well as high treatment-related mortality associated with graft-versus-host disease. Maintenance therapy with thalidomide is currently recommended for standard-risk patients treated with single high-dose melphalan in case of failure to achieve a very good partial response or with lenalidomide in all high-risk patients until progression of disease. In patients not eligible for ­transplantation, treatment with melphalan–prednisone–­thalidomide, melphalan–prednisone–bortezomib, or melphalan–prednisone–lenalidomide is preferred. Maintenance therapy for standard-risk patients is melphalan, prednisone, and thalidomide or melphalan and prednisone for elderly patients, to reduce the risk of toxicity. For high-risk patients, treatment with melphalan, prednisone, and bortezomib is the current recommendation, limiting therapy to 54 weeks. At relapse, patients can be treated with either single agents or melphalan and prednisone or with different drug combinations in case of more aggressive disease. The standard protocol consists of a single drug/regimen until new progression of the disease or toxicity. At this time, a new drug/regimen is introduced. When recurrences occur within 6 months after completion of first-line treatment, chemotherapy consists of the same drug/regimen previously administered. In case cryopreserved stem cells are available, ASCT as salvage therapy is possible. Thalidomide, lenalidomide, and bortezomib, steroids, melphalan, VAD, and other alkylating agents can be effective in relapsed and refractory myeloma [9, 12, 22].

Supportive care with bisphosphonates can decrease bone pain as wells as reduce the progression of osteolytic lesions and prevent pathologic fractures. The exact time of start and optimal duration of treatment are still under investigation. However, according to ASCO recommendations, such therapy should be started in the presence of significant bone loss or of pathological spine fractures (lower bone density leads to weaker bones) and should continue for no longer than 2 years [12, 23].

A fully humanized mAb to RANKL (denosumab, that binds and inhibits the RANK ligand thus reducing bone resorption markers) is still under clinical investigation. Erythropoietin or darbepoetin is useful in patients with persistent symptomatic anemia. Indication for prophylactic antibiotic therapy in patients undergoing chemotherapy is still debated, while it should be considered in all patients receiving high-dose steroid therapy [12]. Gammaglobulin administration is indicated if patients have recurrent severe infections associated with severe hypogammaglobulinemia. Plasmapheresis is useful in patients with the hyperviscosity syndrome. Vertebroplasty and kyphoplasty generally result in rapid and long-lasting reduction of bone pain and improvement in functional activity in patients with vertebral compression fractures. The standard treatments for cord or cauda equina compression are steroids and radiation therapy, whereas surgical decompression is rarely necessary. Radiotherapy is generally used for the treatment of painful bone lesions or to prevent complications and is performed at least once in about 70% of patients with MM. Typically, doses <30 Gy are preferred, to avoid permanent side effects which could jeopardize subsequent chemotherapy or ASCT [12, 24].

Appropriate use of imaging techniques is essential both for determining the severity of bone involvement and for identifying and characterizing the skeletal complications. Imaging is also critical for detecting extramedullary foci, for diagnosing infection and other complications, and for evaluating progression of the disease. However, there is still no consensus on a standardized imaging protocol for either newly diagnosed myeloma patients or for evaluating patients in the course of treatment and for disease progression.

For staging purpose, the detection of osteolytic lesions is generally based on conventional planar X-ray (Fig. 8.3). Lytic lesions on plain X-ray are typically holes, punched-out lesions with absent reactive sclerosis of the surrounding bone, typically localized in the flat bones of the skull and pelvis. In the long bones, lesions may appear as endosteal scalloping, small lytic lesions (<1 cm), mottled areas of multiple small lesions, or large destructive lesions [25]. These lesions are the consequence of nodular replacement of marrow by plasma cells with destruction of the entire bone [24]. Conventional X-ray may also reveal diffuse osteoporosis, which is best recognized in the spine [26]. Radiological and clinical findings (presence of pain) are used in the score system (Table 8.4) to predict the risk of fracture of long bones and to identify optimal treatment (Table 8.4): patients with a high score benefit from internal fixation, whereas patients with a low score can be treated with radiotherapy alone. Asymptomatic patients with X-ray evidence of disease (at least one lytic lesion) have a high risk of progression, with a median time to progression of 8 months.

Whole-body skeletal survey, traditionally used in the Durie and Salmon staging system, is burdened with a relatively high rate of false negatives (30–70%), thus resulting in a significant underestimation of the severity of disease. In fact, conventional X-ray cannot always identify the presence of bone lesions, especially in the early stages of the disease, since lytic lesions become apparent when as much as 30–50% of the bone mineral density is lost. Furthermore, in plain X-ray, some areas are not well visualized (i.e., lateral and anteroposterior views of the spine are needed for better visualizing the vertebral bodies), and it is not possible to distinguish myeloma-related osteoporosis from osteoporosis due to other causes (i.e., steroid-induced or postmenopausal osteoporosis) [27]. Conventional X-ray examinations are also somewhat operator- and technology-dependent, thus increasing the risk of underdiagnosing lytic disease. A major disadvantage of conventional X-ray is the relatively long imaging time and the necessity of maintaining different positions that not all patients (often elderly and suffering pain for previous pathological fractures) are able to maintain. To overcome this latter limitation, the potential of low-dose whole-body radiographic system (Statscan, that enables to obtain high-quality imaging of the bones in shorter time) for detecting focal myeloma lesions has been explored; preliminary results are very promising, but clinical experience with this technique (which was originally developed for trauma and emergency patients) is still limited.

If skeletal X-ray survey is negative and clinical symptoms are present, CT or MRI has been used to increase the sensitivity and specificity of early detection of myeloma-associated bone destruction. CT can be considered as the ideal diagnostic investigation for identifying early bone destruction and extramedullary lesions. CT sensitivity is superior to that of conventional X-ray (between 70% and 89% for CT, depending on stage of the disease) [28–31] as it can detect more lesions, with an extremely high resolution (very small lesions can be detected, even <5 mm) and better performance when evaluating areas that are critical for planar X-ray. However, specificity of CT for assessing certain skeletal changes often associated with myeloma, such as osteopenia, is low. CT is especially useful for guiding biopsy and for planning surgical and radiation therapy, while it can also identify long bones ­(femora and humeri) at risk of fracture; furthermore, it can be employed in cases of suspected spinal cord compression when MRI is contraindicated.

However, actual bone destruction must occur for CT imaging to become positive, since focal tumor infiltration confined to the bone marrow remains undetectable. In fact, diffuse interstitial infiltration of the bone marrow is not invariably associated with trabecular/cortical bone destruction, so that the rate of false-negative CT scans is relatively high [32]. To reduce the radiation burden, low-dose whole-body CT (LDCT) may be used [15, 19]. Since the administration of iodinated contrast agent is not required for evaluating the skeleton with CT, this option is possible even in patients with Bence-Jones proteinuria, who are at risk of cast nephropathy and renal failure. Figure 8.4 represents typical CT examples of lytic lesions of the spine and of a solitary plasmacytoma.

MRI is the method of choice for evaluating bone marrow involvement, based on the loss of the fatty bone marrow component consequent to replacement by plasma cells. MRI has high sensitivity in distinguishing focal or diffuse infiltration of the bone (especially in the spine), as well as detecting destruction of the mineral bone. Myeloma lesions in the marrow appear typically hypointense in T1-weighted sequences and hyperintense in T2-weighted and STIR sequences (Fig. 8.5). MRI findings reflect ­pathophysiological processes such as iron overload, amyloid deposition, or reactive marrow hyperplasia. Patients with MM may exhibit normal MRI appearance when the tumor burden is low, while focal or diffuse bone marrow infiltration exhibits variable patterns. At diagnosis, bone marrow infiltration is detected by MRI in 29–50% of the patients with Durie–Salmon stage I disease and negative plain radiographs. Furthermore, MRI has a certain prognostic significance, as the number of lesions detected correlates with response to treatment and with overall survival. Patients with advanced disease and normal MRI respond better to conventional chemotherapy and have better survival than patients with focal/diffuse bone marrow infiltration. Nevertheless, patients with positive MRI do not always require immediate treatment. In fact, in stage I treatment is not indicated until symptoms appear (Fig. 8.2). The detection of ≥10 spine lesions in patients with advanced stage is associated with an increased risk (6–11-fold) of fracture than patients with normal MRI or with less than 10 lesions have. MRI also enables to distinguish osteoporotic from malignant fractures and is the technique of choice when cord compression is suspected on clinical ground; in fact, it provides accurate information about the epidural space, the level and extension of cord or nerve root compression, and size of the lesion. The main disadvantages of MRI are represented by relatively low availability/access, high cost, and long scan duration (about 45 min). Moreover, claustrophobic patients or patients with metallic implant/device cannot undergo the exam. The typical MRI protocol for evaluating MM patients does not include some skeletal segments (i.e., the sternum, clavicles, and ribs) and therefore may underestimate the disease burden. Whole-body MRI (WB-MRI, Fig. 8.6) may overcome those limitations; in fact WB-MRI is more sensitive than WB-CT for assessing bone marrow infiltration (both focal and diffuse) and is recommended immediately after the X-ray survey. It allows to identify lesions early in their course (before osteolysis occurs) as well as to identify nonsecretory and macrofocal myeloma (especially in the spine and pelvis), which is characterized by lesions with low metabolism and activity. MRI may also be improved with the use of dynamic contrast-enhanced sequences (DCE-MRI) that evaluate the bone marrow microcirculation caused by myeloma-induced angiogenesis. The DCE-MRI-derived “A” variable describes intensity of the signal (therefore angiogenesis) and is found to be significantly increased in MM patients, in whom it correlates with the presence of osteolytic lesions, with the degree of bone destruction, and with the presence of local complications. The amplitude of “A” is a negative prognostic factor for event-free survival and for overall survival in MM [15, 19, 33].

Bone scintigraphy with ^99mTc-labeled disphosphonate is not useful for diagnosis nor for staging of MM, as the detection of bone lesions is about 35–60% [15, 33], with sensitivities generally lower than that of conventional X-ray. In a comparison of the X-ray skeletal survey versus bone scintigraphy [34], increased uptake of the radiopharmaceutical in radiographically abnormal regions occurred in only 44% of the cases, while normal uptake was seen in 48% and reduced uptake in 8% of the cases. Lesions that are well defined on the bone scan are the result of complications in MM, mainly osteoblastic response to a compression fracture of a vertebral body or pelvic insufficiency fracture, soft-tissue calcifications within a plasmacytoma [35], or tumor-associated amyloidosis [36]. This pattern is consistent with the prevalent loss of bone mass not associated with osteoblastic activation, which is typical of the myeloma bone lesions. Thus, in MM, bone scintigraphy is generally nearly normal, or it may demonstrate areas with decreased radiopharmaceutical accumulation or the typical osteoporotic pattern (see example in Fig. 8.7a). On the other hand, bone scintigraphy may be helpful for evaluating some specific skeletal segments such as the sternum and ribs that can hardly be explored with plain X-ray (Fig. 8.7b).

Nuclear medicine imaging with nonspecific oncotropic radiopharmaceuticals, such as ⁶⁷Ga-citrate, ^99mTc(V)-DMSA, ²⁰¹Tl-chloride, ^99mTc-sestamibi, or [¹⁸F]FDG, has all met greater success in imaging MM than typical bone scanning agents. ⁶⁷Ga-citrate localizes in areas of active tumor either through primary localization within the tumor cells or because of the presence of mononuclear cell and lymphocytic infiltrates observed along with the plasma cells and characterizing the tumor-induced secondary “inflammatory response.” Whether these mechanisms act singly or in combination remains unknown [37–40]. ⁶⁷Ga-citrate is rarely used for tumor detection in MM because increased uptake may be observed in some abnormal soft-tissue sites and in solitary myelomas of bone [41–44], although with variable degrees. Furthermore, the use of this radiopharmaceuticals is hampered by certain disadvantages versus ^99mTc-sestamibi or [¹⁸F]FDG imaging, such as multiday scanning and low resolution. When infection is suspected in MM patients, ⁶⁷Ga-citrate may be used if ^99mTc-HMPAO-/¹¹¹In-oxine-labeled autologous WBCs are not available. ^99mTc(V)-DMSA has been reported to accumulate in plasmacytoma, irrespective of the presence of amyloidosis [45, 46].

²⁰¹Tl-chloride has been used for the detection of MM, based on uptake mediated by either increased metabolic demand of the tumor or secondary inflammatory response induced in the marrow [47]. In a study comparing ²⁰¹Tl-chloride and ^99mTc-labeled bone-seeking agents in patients with MM, ²⁰¹Tl-chloride was shown to be a promising agent for detecting disease [48]; however, in the clinical routine based on single-photon radiopharmaceuticals for characterizing MM patients, this agent is currently replaced by ^99mTc-sestamibi, which shows similar localization properties, associated however with images of higher quality and lower cost.

^99mTc-Sestamibi accumulates in cells with high metabolic requirements and can therefore be employed to assess in a semiquantitative manner the degree of bone marrow infiltration by plasma cells; this technique is both highly sensitive (92%) and specific (96%). The patterns of ^99mTc-sestamibi uptake typical of MM can be described as normal (N), focal (F), diffuse (D), and mixed (F  +  D). Another semiquantitative score (similar to that originally described by Pace et al.) is based on extension (E) and intensity (I) of ^99mTc-sestamibi uptake, as follows (Fig. 8.8):

The degree of radiopharmaceutical uptake correlates well with the degree of plasma cell infiltration, with the amount of a monoclonal component, with the clinical status, and with stage of the disease. In some studies, good correlation was also found between ^99mTc-sestamibi uptake and other parameters of disease activity, such as the serum levels of lactate dehydrogenase, C-reactive protein, and β₂-microglobulin. Diffuse ­moderate or intense ^99mTc-sestamibi uptake or focal uptake correlates with poor prognosis. Furthermore, ­statistically significant correlation between the baseline ­^99mTc-sestamibi uptake patterns and overall survival was found in patients with newly diagnosed symptomatic MM, with focal or combined focal and diffuse patterns associated with worst prognosis with shorten overall survival (of 50 and 9 months versus 68 months of patients with normal pattern) [49]. However, ^99mTc-sestamibi imaging is less sensitive than MRI (50.5% vs. 100%) [50] for evaluating focal lesions localized in the spine (especially in patients with early disease stage), because scintigraphic assessment of such segment is hampered by the high physiologic uptake in the liver and bowel. SPECT imaging has been shown to overcome the relatively poor spatial resolution of planar ^99mTc-sestamibi scintigraphy. It is important to emphasize that the ^99mTc-sestamibi scan is always negative in case of MGUS, while false-negative results have been described in case of overexpression of P-glycoprotein, associated with multidrug-resistant myeloma [15, 19, 51–53].

Agool et al. [54] have recently proposed the use of somatostatin receptor (SSTR) imaging as an alternative method to visualize malignant plasma cells. In fact, in vitro studies have demonstrated that MM cell lines express functional SSTR2, SSTR3, and SSTR5, the latter being the most represented. Additionally, in vitro growth of myeloma cells can be inhibited by somatostatin and octreotide. Preliminary data in patients with relapsing MM indicate that SSTR imaging is very sensitive, demonstrating abnormal accumulation in 82% of patients compared to a 33% detection rate with whole-body X-ray. Partial or total normalization of the scintigraphic pattern has also been observed in patients responding to treatment. The expression of SSTR could be related to aggressiveness of the disease. However, the limitation represented by poor spatial resolution of planar images (used in this trial) can be overcome either by employing SPECT/CT or by using PET/CT with a positron-emitting SSTR analogue (i.e., ⁶⁸Ga-DOTATOC).

Scintigraphy with the serum amyloid P (SAP) labeled with either ^99mTc or ¹²³I has been proposed to confirm the diagnosis [15, 33, 54] and to quantify the extent of the deposits of light chain (AL) amyloidosis. However, additional data is required to define the potential clinical role of this imaging technique.

[¹⁸F]FDG is the standard for radionuclide imaging in patients with MM because it identifies early bone marrow infiltration in patients with apparent solitary plasmacytoma and demonstrates that the extent of extramedullary involvement in [¹⁸F]FDG-PET shows both high sensitivity (86.3%) and high specificity (92%) [55], with the additional advantage of distinguishing between metabolically active disease ([¹⁸F]FDG positive) and clinical conditions characterized by very low burden, such as MGUS or smoldering disease ([¹⁸F]FDG negative). [18F]FDG uptake of bone marrow in MM patients is related to the percentage of CD38/CD138 expressing plasma cell infiltration of bone marrow [57]. Therefore, [¹⁸F]FDG-PET shows focal or diffuse pattern of uptake reflecting the distribution of bone marrow disease. While patients with MGUS generally have a negative [¹⁸F]FDG-PET scan (although diffuse low-grade bone marrow uptake can occasionally be observed), the appearance of [¹⁸F]FDG focal uptake in a patient with MGUS indicates transformation into an active myeloma. Identification of extramedullary disease on a [¹⁸F]FDG-PET scan performed at diagnosis correlates with poor prognosis (see Figs. 8.9 and 8.10 for different representative patterns of [¹⁸F]FDG uptake in patients with plasmacytoma and MM, respectively). An early clinical investigation on the performance of [¹⁸F]FDG-PET in MM (66 patients followed serially) showed the capability of the technique to identify patients with high-risk disease and to monitor patients either nonsecretory myeloma or in CR without measurable M-component [58]. Such initial observations were subsequently confirmed by other studies, also demonstrating that [¹⁸F]FDG-PET could lead to upstaging of the disease in 31–37.5% of patients (depending on the series) and to changes in treatment management in up to 56% of the cases [59]. These results stimulated larger studies with [¹⁸F]FDG-PET in patients with myeloma [ 60]. Data derived from the National Oncologic PET Registry (NOPR), a large prospective program aiming at recording changes of the intended clinical management of cancer patients on the basis of the [¹⁸F]FDG-PET/CT findings, have further confirmed this trend. The registry has so far included over 1,300 myeloma patients (13.1% scan/incidence in 2007), showing a definite impact on management in about 52% of patients when the scan was requested for staging purpose, 46% in case of restaging, and 51% in presence of suspected recurrence.

In MM, the 2.5 threshold for the standardized uptake value (SUV, often considered as the cutoff for other forms of cancer) may not be applicable. In fact, many lesions <10 mm (that are obvious on MRI or using dedicated CT) cannot be detected on the [¹⁸F]FDG scan using this threshold if one does not take into account the recovery coefficient, whereby SUV decreases along with decreasing lesion size. Therefore, the complementary imaging information provided by the CT component of a [¹⁸F]FDG-PET/CT examination is very effective, even if CT is performed in most cases in the low-dose mode. With all these considerations in mind when interpreting [¹⁸F]FDG-PET/CT scans, this imaging modality has greater sensitivity than both plain X-ray (89.2% vs. 47.4%) and CT alone (89.2% vs. 70.4%) [61]. In addition to demonstrating persistent or recurrent osseous disease, [¹⁸F]FDG-PET/CT is more sensitive than other imaging modalities for localizing extramedullary sites of disease, thus revealing additional lesions in almost 30% of the patients who had been diagnosed with solitary plasmacytoma by MRI [62, 63]; this results in upstaging extent of the disease and has therefore a relevant impact on the choice of therapeutic strategies [64–66]. However, sensitivity of [¹⁸F]FDG-PET for assessing diffuse disease in the spine and pelvis remains almost half than that of MRI [53].

Thus, while [¹⁸F]FDG-PET/CT performs better than either ^99mTc-sestamibi scintigraphy or MRI in detecting focal bone and bone marrow lesions, MRI remains the method of choice for evaluating diffuse bone marrow infiltration in the spine, considering that diffusely increased nonspecific [¹⁸F]FDG uptake is frequently observed in the bone marrow of young people or in patients with anemia [53, 59, 67]. [¹⁸F]FDG-PET/CT is therefore recommended for accurate initial staging of patients with MM, while MRI is to be preferred when assessing the degree of bone marrow infiltration by plasma cells in the early phase of the disease. By combining MRI of the spine/pelvis and whole-body PET/CT, the ability to detect sites of active MM, both medullary and extramedullary, can be as high as 92%. Particularly, the association between a SUVmax value > 3.5 in spine lesion and either diffuse or multifocal vertebral body involvement at MRI seems to indicate an impending fracture [68]. Although rarely, active disease demonstrated with osteo-medullary biopsy may be missed by both [¹⁸F]FDG-PET/CT and MRI (false-negative cases); however, when [¹⁸F]FDG-PET/CT and MRI are concordantly positive, no false-positive results are generally observed, thus yielding specificity and positive predictive values close to 100%. This consideration is of value in aiding clinicians to either continue with or change chemotherapy regimens on the basis of persistently positive findings on imaging studies. The low negative predictive values of [¹⁸F]FDG-PET/CT (50%) and MRI (59%) and also of the combination of the two (64%) suggest that negative results should always be considered with caution and correlated to other markers of disease activity [69].

The prognostic significance of [¹⁸F]FDG-PET/CT is not yet well established. Bartel et al. [70] recently evaluated the prognostic value of [¹⁸F]FDG-PET/CT in patients with newly diagnosed MM. By applying tertile-derived cut points, several imaging parameters affected overall survival and event-free survival adversely, in particular the presence of extramedullary disease and the number of lytic lesions detected by metastatic bone survey, and the number of focal sites of [¹⁸F]FDG uptake. Abnormal MRI findings and high SUV of focal [¹⁸F]FDG uptake were associated with shorter event-free survival, while having borderline effects on overall survival. The number of lesions detected by PET/CT was the parameter most closely correlated with other prognostic variables, such as β₂-microglobulin, lactate dehydrogenase, and C-reactive protein and gene expression profiling-derived indices: positive correlation with high-risk and two proliferation parameters and inverse correlation with low bone disease subgroup. The PET/CT findings also maintained an independent adverse prognostic value, if combined with positive cytogenetic abnormalities and elevated lactate dehydrogenase levels. [¹⁸F]FDG-PET/CT identified 30% of patients who had poorer prognosis despite having low-risk disease as defined by gene expression profiling analysis. Based on logistic regression analysis, the PET findings were independently positively correlated to both MRI and metastatic bone survey. Among the non-imaging parameters, the results of PET correlated positively with C-reactive protein and negatively with gene array-defined low bone disease.

[18F]FDG uptakes of bone marrow and extramedullary lesions on PET/CT scans are significantly correlated with established prognostic factors and a baseline higher SUVmax value of extramedullary lesions significantly predicted inferior OS (). Although 18F-FDG uptake of bone marrow on PET/CT scan significantly predicts the percentage of plasma cell infiltration (SUVmax > 2.05 predicted > 30% plasma cells in bone marrow biopsies with sensitivity 71.9% and specificity 58.2%), in multivariate analysis MRI was the independent predictor of the bone marrow plasma cell counts in MM patients [71]. [¹⁸F]FDG-PET also offers the advantage of identifying any superimposed infectious condition (not rarely associated with MM) or possible complications of treatment (such as vascular infections), with resulting changes in patients’ management. On the other hand, such high sensitivity (associated with the intrinsically low specificity of [¹⁸F]FDG uptake) can increase the false-positive results when the scan is performed within a short interval after radiotherapy or surgery; it is therefore recommended to perform the scan when about 4 weeks after a surgical procedure or 2–3 months after completion of radiotherapy [59, 72].

The diagnostic potential of non-[¹⁸F]FDG positron-emitting radiopharmaceuticals has been investigated also in patients with MM. In particular, [¹¹C]choline (a precursor of phospholipid synthesis whose uptake is increased in proliferating cells) has recently been comparatively evaluated by Nanni et al. versus [¹⁸F]FDG [73]. These authors suggest that the superior sensitivity of [¹¹C]choline-PET/CT over [¹⁸F]FDG-PET/CT for detecting bone lesions is due to the high phospholipid metabolic rate of myelomatous cells, as these compounds are involved in the modulation of intracellular growth signal transduction pathways. The main clinical disadvantage in the use of [¹¹C]choline is its high physiological liver uptake that prevents detection of hepatic lesions.

Results of in vitro experiments showing that the radiolabeled amino acid [¹¹C]methionine is incorporated into immunoglobulins produced by the malignant plasma cell clones have prompted a clinical study performed with [¹¹C]methionine-PET/CT in MM patients by Dankerl et al. [74]. Consistently with the underlying hypothesis, osteolytic lesions exhibited a high uptake of [¹¹C]methionine, similar to that of [¹⁸F]FDG. Furthermore, newly diagnosed osteolytic lesions in untreated patients were strongly [¹¹C]methionine positive, while recurring osteolytic lesions were [¹¹C]methionine negative. Although the series evaluated in this study was relatively small, the substantial mismatch between the number of lesions identified by [¹¹C]methionine-PET and those identified by CT represented an important added value of metabolic imaging for early detection of lesions not yet obvious as macroscopic bone changes; these findings would therefore provide an accurate estimate of tumor burden, particularly for clinically silent and unexpected localizations.

PET/CT with 3′-¹⁸F-fluoro-3′-deoxy-l-thymidine ¹⁸F-FLT, whose uptake mirrors DNA synthesis via thymidine kinase-1, which is highly expressed in tumor cells during the S-phase of the cell cycle) has been proposed to distinguish hematological malignancies (specifically highly proliferating syndromes such as myelodysplasia and myeloproliferative disorders) from other clinical conditions causing pancytopenia. Although the exact mechanism of ¹⁸F-FLT uptake in bone marrow remains unclear, several studies suggest that such event is linked to the cycling activity of hematopoietic cells, thus reflecting the state of the entire bone marrow compartment [19]. Bone marrow uptake of ¹⁸F-FLT is intense in patients with myelodysplasia and myeloproliferative disorders, while it is lower to absent in patients with MM, myelofibrosis, or aplastic anemia. Patients with MM may present variable degrees of ¹⁸F-FLT uptake in response to bone marrow expansion into the peripheral bones.

Extensive skeletal involvement has also been incidentally detected during PET with [¹¹C]acetate [75]. It is not entirely clear why myelomatous lesions would exhibit such high uptake of [¹¹C]acetate, although this observation is consistent with a much earlier in vitro study with plasma cells obtained from patients with MM, showing enhanced uptake of acetate as a substrate for the Krebs cycle [76]. On the other hand, it is well known that malignant cells (including MM cells) typically have increased glycolysis versus their normal counterparts, as also confirmed by a correspondingly increased [¹⁸F]FDG consumption; since the Krebs cycle (whose metabolic substrate is acetate) constitutes a component of overall glycolysis, it is not surprising that uptake of both [¹⁸F]FDG and [¹¹C]acetate can be found enhanced in MM.

Despite the considerable amount of favorable results reported so far, the “guideline for the use of imaging in the management of myeloma” does not recommend [¹⁸F]FDG-PET nor ^99mTc-sestamibi scintigraphy for routine use in the management of MM patients [15, 33]. Instead, the possibility of employing either imaging technique is considered only in selected cases, as follows: (a) to clarify previous indetermined imaging findings, preferably within clinical trials (grade C recommendation, level IV evidence) and (b) when suspecting extramedullary disease in cases where other imaging techniques have failed to define the condition ([¹⁸F]FDG-PET preferred, with grade B recommendation, level III evidence, and performing the procedure within 4 weeks of chemotherapy or 3 months of radiotherapy). More recently, [¹⁸F]FDG-PET/CT has been included in the National Comprehensive Cancer Network 2010 guidelines, as an option under some selected circumstances in the initial diagnostic workup [77]. SAP scintigraphy is included in the “guideline for the use of imaging in the management of myeloma” with a grade 2 recommendation, level IIB evidence [33].

Many criteria can be employed to assess response to therapy in MM patients, including those set by the European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry, by the Chronic Leukemia-Myeloma Task Force, by the Southwest Oncology Group (SWOG), and by the Eastern Cooperative Oncology Group (ECOG). In 2006, the International Myeloma Working Group (IMWG) recognized the importance of standardizing such criteria and elaborated the so-called uniform response criteria (Table 8.5). While adopting the classical categories of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), the system introduced the new category of “positive response of additional clinical significance” following treatment. Although the IMWG response criteria deleted the category “minor response” (considered to be somewhat vague and therefore unreliable), more recently, this category has been reintroduced by the ASH-FDA in patients with relapsed refractory myeloma, while specific criteria for progression have been defined for SMM (Table 8.6) [7]. Although changes in bone marrow infiltration is not employed as a guiding criterion for assessing response to treatment, finding <5% plasma cells is one of the requisites for complete remission. Furthermore, in patients without measurable disease, it is possible to monitor the disease by the serum-free light chain assay criteria. Irrespective of the specific system employed to classify response to treatment, the main pitfall of these systems is represented by the method used to assess bone marrow and bone lesions. In fact, plain radiography is of limited value for evaluating the response to treatment; in particular, even if the appearance of new bone lesions clearly indicates disease progression, lytic bone lesions rarely show radiologic signs of recovery. Furthermore, new compression vertebral fractures may occur either in case of disease progression or in case of bone loss or in case of reduction of the tumor mass that supports the bone cortex [3 7, 19, 53]. CT is not generally used for assessing response to treatment, since osteolytic lesions rarely recover. In selected cases, mainly those characterized by significant soft-tissue component (i.e., plasmacytoma), response to therapy can instead be demonstrated by reduction in tumor size as assessed with CT. Moreover, CT may be of value in patients with persistent unexplained symptoms despite therapy, or with risk if impending fracture, or when no clinico-biochemical response to treatment is observed. The disappearance of any MRI-detectable bone marrow lesions typically represents complete response, while a partial response to therapy is associated with changes of the MRI pattern from diffuse to focal/variegate or with the reduction of the signal on the T2-weighted spin echo images. Nevertheless, MRI has limited value for the early assessment of response to treatment, since complete resolution of bone marrow lesions may take as long as 9–12 months from the completion of the therapy. DCE-MRI has shown to be superior to standard MRI for this purpose; in particular, favorable response is indicated by the disappearance of gadolinium enhancement or by the absence of contrast-induced rim enhancement in a follow-up study as compared to the baseline scan. However, the real added value of this technique seems to lie in the possibility to predict which patients might benefit from therapy with anti-angiogenetic drugs, i.e., bevacizumab (a monoclonal antibody that inhibits the vascular endothelial growth factor, VEGF). In a recent study comparing post-treatment bone marrow changes at whole-body dynamic contrast-enhanced MRI with clinical response, quantitative MRI analysis demonstrated extensive overlap of results between good and poor responders and a substantial number of outliers, underlining that MRI may be of limited use for the evaluation of treated patients [78]. Therefore, this approach has not yet gained a definite role in the evaluation of the course of the disease and of activity of the myeloma lesions. Given the heterogeneous nature of the disease and inconsistent response to treatment, along with the relatively small number of published studies in this field, MRI currently has a limited role in response assessment.

Several studies [53, 79] have found a close correlation between the results of ^99mTc-sestamibi scintigraphy (i.e., disappearance of any area of uptake) and the conventional criteria used for defining clinical response to therapy (i.e., measurement of the M-protein component). Overall, these findings support the hypothesis that bone marrow uptake is an indicator of myeloma activity in bone marrow, even in the absence of focal areas of increased uptake. This procedure has shown high specificity (86%) in patients in CR, whereas sensitivity was 45% in presence of PR; these findings emphasize the high performance of ^99mTc-sestamibi scintigraphy for identifying absent disease, whereas its sensitivity is lower for the definition of residual disease when response is not complete. Multivariate analysis also showed that the sensitivity of ^99mTc-sestamibi scintigraphy was low in presence of bone marrow infiltration <30.

The prognostic value of ^99mTc-sestamibi imaging for predicting recurrence of the disease has been extensively investigated by Pace et al. [51]. In a group of patients evaluated both at baseline and after chemotherapy, they demonstrated a significant association between pretreatment scintigraphic pattern and clinical status at follow-up. In particular, none of the patients responding to therapy had a posttreatment ^99mTc-sestamibi scan showing focal uptake or diffuse uptake with a summed score higher than 2; by contrast, the nonresponders showed either diffuse bone marrow uptake or areas of focal uptake with summed score higher than 2. A negative baseline ^99mTc-sestamibi imaging showed high prognostic value for clinico-biochemical remission, and multivariate analysis demonstrated the added value of the ^99mTc-sestamibi uptake pattern with respect to known prognostic variables, such as C-reactive protein. Furthermore, ^99mTc-sestamibi imaging patterns at follow-up were significantly associated with the clinical status evaluated after chemotherapy.

In an independent study, a semiquantitative parameter of ^99mTc-sestamibi washout derived from dual point scintigraphic acquisitions as the counts/pixel at early imaging (10 min) minus counts/pixel at delayed imaging (60 min) divided by counts/pixel at 10 min (corrected for decay) has been also employed to distinguish patients responding to treatment from nonresponders. A fast clearance of ­^99mTc-sestamibi from the bone marrow of patients with MM is associated with poor response to subsequent chemotherapy. ^99mTc-sestamibi washout reflects the degree of expression of the P-glycoprotein (Pgp), a transmembrane protein which mediates the outward transport of many cytotoxic compounds including a variety of anticancer agents and confers tumor cells the capability to escape the lethal effect of many cytotoxic compounds, thus causing multidrug resistance (MDR). Overexpression of Pgp in resistant cultured tumor cells causes a reduced net uptake of ^99mTc-sestamibi as a consequence of an enhanced Pgp-dependent outward transport of the tracer [80]. Thus, since overexpression of Pgp is one of the primary mechanisms of MDR in MM as well as in other malignancies [81, 82], it can be hypothesized that the ^99mTc-sestamibi washout rate could serve to predict response to chemotherapy in MM patients.

However, all these studies have included small groups of patients, and none of them evaluated the impact of ^99mTc-sestamibi scintigraphy on progression-free survival and overall survival.

The first indications that mid-treatment scans reflected treatment response came from the study of Jadvar et al. [83], in which 3 MM patients were followed before and after therapy. A decline in metabolic activity on [18F]FDG PET scan concordant with clinical improvement was present in 2 patients while in the remaining patient the appearance of new hypermetabolic lesions and higher metabolic activity in the previously known lesions was concordant with disease progression. In case of effective response to therapy, [¹⁸F]FDG uptake declines rapidly (within hours). The persistence of a positive [¹⁸F]FDG-PET has high prognostic value, as it correlates with early recurrence. Baseline SUV is helpful for the prediction of progression-free survival after first-line anthracycline-based chemotherapy, but the decrease of SUV after 1 chemotherapy cycle lacked of clinical significance [84]. Furthermore, [¹⁸F]FDG-PET/CT represents the most sensitive imaging technique to evaluate response of the bone lesions to treatment, particularly for distinguishing treated bone marrow lesions from viable neoplastic tissues [7, 19, 67, 85].

[¹⁸F]FDG-PET/CT has recently been employed in patients with newly diagnosed MM as part of the “Total Therapy 3” study, characterized by 4 distinct phases of induction therapy (2 cycles of VDT-PACE with peripheral blood stem cell collection after the first cycle  +  tandem transplantation with melphalan 200 mg/m², consolidation with 2 cycles of dose-reduced VDT-PACE, and maintenance therapy for 3 years, with monthly cycles of VTD for the first year and thalidomide plus dexamethasone in years 2 and 3) [70]. The exam was performed at baseline (together with metastatic bone survey and MRI) and within 10 days from starting the first induction cycle of VDT-PACE. The follow-up studies included annual metastatic bone survey, while MRI scans were performed before each of two transplantations, before consolidation and maintenance phases, and semiannually thereafter. All imaging studies were also repeated at relapse, defined by M-protein and bone marrow criteria and by any of the imaging procedures. Similarly as in the case of other malignancies such as lymphoma, disappearance of [¹⁸F]FDG uptake before transplantation proved to be an independent favorable prognostic factor, thus demonstrating the importance of complete suppression of tumor metabolism in myeloma. Using the [¹⁸F]FDG-PET/CT criteria (absence of [¹⁸F]FDG focal uptake in bone segments and extramedullary disease), the authors were able to define CR status in 92% at 18 months, which became obvious earlier than the median onset of clinical n-CR (87%) and CR status (56%) by 4 and 12 months, respectively. The cumulative proportion of patients qualifying for MRI-defined CR was 29% at 18 months and reached 59% at 48 months. In patients without focal lesions, MRI-defined CR (hypointensity on STIR images) was reached in 62% at 18 months, similar to 56% of the patients attaining clinical CR status. While very early [¹⁸F]FDG-PET/CT changes (at 10 days) did not affect outcome, complete [¹⁸F]FDG suppression and extramedullary disease before transplantation conferred superior overall and event-free survival; in fact, 30 months after the first autotransplantation, 92% and 89% of the patients were alive and event-free compared with 71% and 63% among those with less than 100% disappearance of [¹⁸F]FDG uptake. Complete [¹⁸F]FDG suppression before the first transplantation correlated with superior outcomes in both low-risk and high-risk gene array-defined risk groups, reaching statistical significance for overall survival in low risk and for event-free survival in high-risk myeloma. Normalization of the PET findings before transplantation was associated with improved outcomes, whereas gene array-defined high-risk designation conferred poor overall and event-free survival. In the absence of molecular genetic data, the favorable implications of pretransplantation [¹⁸F]FDG suppression were canceled by elevated serum levels of lactate dehydrogenase and β₂-microglobulin. Clinical CR or n-CR status before transplantation did not impact post-transplantation survival outcomes. The prognosis of high-risk patients not achieving complete [¹⁸F]FDG suppression was especially poor. In the post-transplant setting (either autologous or allogeneic stem cell transplantation), [18F]FDG PET/CT may contribute to the detection and localization of disease, provide information about the extent of distinct myeloma manifestations and the total disease burden and add information about the metabolic activity of disease. Overall performance of [18F]FDG PET/CT in terms of sensitivity, specificity, positive predictive value and negative predictive value was considerably better in patients who had received only autologous stem cell transplantation (64.7%, 88.9%, 91.7% and 57.1% versus 50.6%, 80%, 78.2% and 53.3%, respectively). However, lower sensitivity for this purpose compared to the pretreatment setting was found since in patients with very good partial response (90% or greater reduction in serum paraprotein) ability of PET to detect myelomatous lesions was low (34.1%), possibly as a consequence of reduced myeloma cell mass [86].

The World Health Organization has identified dual-energy X-ray absorptiometry (DEXA) as the gold standard for measuring the severity of osteoporosis, for defining the risk of fractures, and for assessing changes in bone mineral density over time. This method is fast and noninvasive and implies a low radiation burden to patients (between 0.001 and 0.01 mSv). However, bone mineral density can be affected by pathological conditions such as vertebral collapse and spinal osteophytes that are often concomitant in patients with MM. At present, DEXA scanning cannot distinguish benign osteoporosis from osteoporosis induced by myeloma. Furthermore, the reduction in bone mineral density in patients with MM usually is not diffuse, but is rather confined to the hematopoietically active portion of the skeleton. For these reasons, the use of DEXA scanning in patients with MM is controversial [15, 33].

Leukemia is a cancer of the bone marrow and blood. Over 250,000 people are diagnosed with leukemia each year, accounting for 2.5% of all cancers and 30.4% of all hematologic malignancies. Leukemias are the most common pediatric tumor (about 35% of cancers in children aged 0–14 years), but all age groups can be affected. Approximately 11% were diagnosed  <  20 years, 11% between 20 and 44, 10% between 45 and 54, 14% between 55 and 64, 21% between 65 and 74, 23% between 75 and 84, and 10% after 85 years [87].

The leukemia is considered lymphocytic or lympho­blastic if it occurs in a marrow cell that forms lymphocytes while is “myelogenous” or “myeloid” if occurs in a marrow cell that forms red cells, some kinds of white cells, and platelets. Leukemias are usually divided into four major categories:

The four main types of leukemia are further classified into subtypes that are based on specific features of cells [88].