Beatrice Anna Zannetti

Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation

We prospectively analyzed the prognostic relevance of positron emission tomography-computed tomography (PET/CT) at diagnosis, after thalidomide-dexamethasone (TD) induction therapy and double autotransplantation (ASCT) in 192 newly diagnosed multiple myeloma (MM) patients. Presence at baseline of at least 3 focal lesions (FLs; 44% of cases), a standardized uptake value (SUV) > 4.2 (46%), and extramedullary disease (EMD; 6%) adversely affected 4-year estimates of progression-free survival (PFS; ≥ 3 FLs: 50%; SUV > 4.2: 43%; presence of EMD: 28%). SUV > 4.2 and EMD were also correlated with shorter overall survival (OS; 4-year rates: 77% and 66%, respectively). Persistence of SUV > 4.2 after TD induction was an early predictor for shorter PFS. Three months after ASCT, PET/CT was negative in 65% of patients whose 4-year rates of PFS and OS were superior to those of PET-positive patients (PFS: 66% and OS: 89%). In a multivariate analysis, both EMD and SUV > 4.2 at baseline and persistence of fluorodeoxyglucose (FDG) uptake after ASCT were independent variables adversely affecting PFS. PET/CT involvement at diagnosis, after novel agent-based induction and subsequent ASCT is a reliable predictor of prognosis in MM patients. This study is registered at www.clinicaltrials.gov as NTC01341262.

Multiple myeloma, venous thromboembolism, and treatment-related risk of thrombosis.

Venous thromboembolism (VTE) is a disease with a high prevalence in elderly people, affecting > 5% of the population > 65 years of age. Cancer patients have a 4.3-fold higher incidence of thrombotic complications, due to multiple risk factors that are not always related to the disease. Among hematologic malignancies, multiple myeloma (MM) confers a high risk of developing such complications, with a VTE rate of nearly 10%. Multiple factors are involved in MM-related VTE, such as increased blood viscosity, high levels of immunoglobulin, procoagulant activity of monoclonal protein, and inflammatory cytokines. Since the introduction of the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide in the therapeutic armamentarium of MM, VTE has emerged as one of the leading complications, in particular in patients with newly diagnosed MM. In this setting, IMiDs-based treatments are associated with rates of VTE reaching values up to 14 to 26%, particularly when dexamethasone or chemotherapy are added. The optimal prophylaxis for patients receiving these antiangiogenetic agents is still a matter of debate. Due to the lack of prospective randomized clinical trials, different studies have used various anticoagulant prophylaxes, including fixed low-dose warfarin (1 mg or 1.25 mg), therapeutic doses of warfarin (international normalized ratio between 2.0 and 3.0), low molecular weight heparin, or low-dose aspirin. As yet, no study has clearly demonstrated a significant superiority of one prophylactic regimen in comparison with the others. Further investigation and more randomized clinical trials are needed to define the best thromboprophylaxis.

18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease

Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide 18F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58–5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.

PET/CT Improves the Definition of Complete Response and Allows to Detect Otherwise Unidentifiable Skeletal Progression in Multiple Myeloma

Purpose: To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012. Experimental Design: All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months. Results: Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUVmax was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUVmax >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUVmax >4.2 following first-line treatment was independently associated with exclusive PET/CT progression. Conclusions: PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression. Clin Cancer Res; 21(19); 4384–90. ©2015 AACR.

The value of 18F-FDG PET/CT after autologous stem cell transplantation (ASCT) in patients affected by multiple myeloma (MM): Experience with 77 patients

Aim The objective of this study was to analyze the prognostic value of 18F-FDG PET/CT after therapy in patients with multiple myeloma (MM). Patients and Methods One hundred seven patients prospectively recruited with MM had FDG PET/CT at staging 3 months after therapy (autologous stem cell transplantation) and every 6 to 12 months during the follow-up (mean 41 months). Patients were divided into group 1 (relapsed) and group 2 (nonrelapsed). In group 1, PET results and SUVmax were compared to the time to relapse (TTR). In group 2, the presence of PET finding changes during follow-up was analyzed to identify typical patterns of disease behavior (ie, late responders or stabilized disease). Patients with a negative PET at staging were excluded from further evaluation. Results Forty-seven out of 107 (44%) patients relapsed: 10 were excluded because of a negative PET at staging. In group 1, 22 patients had a negative posttherapy PET (59%, mean TTR = 27.6 months) and 15 had a positive posttherapy PET (41%, mean TTR = 18 months). There was a significant difference between the TTR of the two subgroups (t test P = 0.05). In patients with a positive posttherapy PET, the SUVmax was inversely correlated to the TTR (correlation coefficient = −0.7; P < 0.01). Sixty out of 107 (56%) patients did not relapse. Twenty patients were excluded because of a negative PET at staging. In group 2, 27 patients had a negative posttherapy PET (68%) and 13 had a positive posttherapy PET (32%). None of nonrelapsed patients showed a progressive increase in SUVmax during the follow-up. There was no significant difference between relapsed and nonrelapsed patients in terms of SUVmax at posttherapy PET/CT (t test P = 0.7). Conclusion In our series of MM patients, a negative posttherapy PET was predictive for nonrelapse or a long disease-free survival. In contrast, a persistent significantly increased SUVmax after therapy was correlated to a short TTR.

Bortezomib-based therapy combined with high cut-off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment

Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular‐interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib‐based therapy combined with high cut‐off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL−1 and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) creatinine equation, was 8 mL/min/1.73 m2. Serum free light chain (sFLC) median concentration was 6,040 mg L−1. Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3‐year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI. Am. J. Hematol. 90:647–652, 2015.

HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma.

Role of Consolidation Therapy in Transplant Eligible Multiple Myeloma Patients

The role of high-dose therapy and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM) has continued to evolve in recent years. The novel agents thalidomide, bortezomib, and lenalidomide have been successfully incorporated into induction therapy in preparation for ASCT and are currently being investigated also as post-ASCT consolidation and maintenance therapy. Consolidation treatment is generally short term and aims to increase the frequency and depth of response obtained with the previous treatment phases, including novel agent-based induction therapy and ASCT. This review will focus on recent trials of novel agents as post-ASCT consolidation therapy, offering an overview of pros and cons of this new treatment strategy in the ASCT sequence for MM patients.

Positron Emission Tomography With Computed Tomography–Based Diagnosis of Massive Extramedullary Progression in a Patient With High-Risk Multiple Myeloma

Extramedullary disease (EMD) is an uncommon manifestation of multiple myeloma (MM). The incidence ranges from 2% to 20%, with higher frequency in later phases of the disease. Positron emission tomography with computed tomography (PET/CT) proved to be accurate in the detection of EMD. We report here on a massive EMD progression of MM in an elderly patient with cytogenetically high-risk disease that was treated up-front with novel agents. The extramedullary spread was huge, involving both common and atypical sites. The diagnosis of EMD was based on findings of PET/CT at the time of biochemical relapse, before the progression of MM became clinically evident. Considering PET/CT results in the restaging of MM patients at relapse may help to possibly detect, as in the present case, unsuspected and uncommon sites of EMD. This finding might ultimately affect prognosis and therapeutic decisions. Early and prompt diagnosis of EMD by novel imaging techniques, such as PET/CT, may be the first step toward improved management of patients with this rare manifestation of MM.

Peripheral neuropathy induced by subcutaneous bortezomib-based induction therapy for newly diagnosed multiple myeloma

Lok et al.1 recently reported in this Journal on the efficacy and toxicity of subcutaneous (sc) bortezomib given at a reduced dose in combination with thalidomide and dexamethasone (sc vTD) as induction therapy before, and as consolidation after, autologous stem-cell transplantation (ASCT) in 31 patients with newly diagnosed multiple myeloma (MM). The treatment plan included four cycles of induction therapy and two cycles of consolidation, both comprising sc bortezomib (1.0 mg/m2 twice weekly), thalidomide (100 mg per day) and dexamethasone (total dose 320 mg per cycle on the first two cycles and 160 mg per cycle on the subsequent two cycles of the induction phase). The rate of at least very good partial response (VGPR) after induction therapy was 52% for all patients and increased up to 73% among patients who actually received consolidation therapy. The incidence of treatment-emergent peripheral neuropathy (PN) after the induction phase (16% grade 1–2, including 3% grade 2) was lower than that previously reported by the same group after four cycles of either vTD at the same doses but using intravenous (iv) bortezomib (53% all grades, including 14% grade 2 or higher) or iv standard dose bortezomib (1.3 mg/m2) and dexamethasone (VD) (70% all grades, 34% >grade 2, 11% grade 3–4).2 We report, herein, on the outcomes of 22 newly diagnosed, ASCT-eligible, MM patients who were programmed to receive at our center four 21-day cycles of sc bortezomib (1.3 mg/m2 twice weekly) plus dexamethasone (total dose 320 mg per cycle) and either thalidomide (100 mg per day) (sc VTD: 13 patients) or cyclophosphamide (500 mg/m2 on Days 1 and 8 per cycle) (sc VCD: 9 patients). All patients were prospectively evaluated for efficacy and toxicity of sc bortezomib-based induction therapy. Presence of higher than grade 1 PN at diagnosis was an exclusion criterion for enrollment. Symptoms and signs of PN were carefully assessed at every programmed clinical appointment and were graded according to National Cancer Institute’s Common Toxicity Criteria (NCI CTCAE) v.3.0. No electrophysiological study was performed. Base-line patients’ characteristics and treatment response are summarized in Tables 1 and ​and2.2. A median of four cycles was administered. The overall response rate among all patients was 95%, including 27% stringent complete response (sCR) and 77% VGPR or better. Treatment-emergent grade 1–3 PN was observed in 14 patients (64%), including 18% (4 patients: 2 treated with VCD and 2 with VTD) grade 2 and 14% (3 patients: 2 receiving VTD and one VCD) grade 3. In one of these 3 patients, treatment was discontinued after the third cycle. Among the 7 patients with grade 2–3 PN, the median time from start of induction therapy to the first onset of PN was 72 days (range 48–109). In 3 patients, symptoms and signs of PN (grade 2 in 2 cases and grade 3 in the remaining one) emerged after the induction phase was completed, more specifically 103, 106 and 109 days after starting induction therapy. With appropriate treatment modifications,3,4 symptoms and signs of PN resolved or improved to grade 1 in 9 out of 14 (64%) patients within a median time of 94 days. Table 1. Base-line patients’ characteristics. Table 2. Efficacy and neurological toxicity of sc VTD or VCD induction therapy. Data reported here raise several considerations, but should be interpreted with caution due to the limited number of patients. The high overall response rate of 95%, including 27% sCR and 77% VGPR or better, further supports the conclusion that the efficacy of sc bortezomib reported in the relapsed/refractory setting5 is retained when the drug is administered in patients with newly diagnosed MM.1 Although cross-trial comparison is inadequate due to heterogeneities in the design of the studies and patients’ characteristics, it is likely that the discrepancy in the rates of high-quality responses between our series and that reported by Lok et al.1 reflects the lower activity of reduced-dose bortezomib used in the French study, with the possible contribution of the lower total dose of dexamethasone given in the third and fourth cycles of the induction phase. Differences between the two studies with respect to the doses of sc bortezomib incorporated into induction therapy may only explain in part the controversies about the frequency and severity of treatment-induced PN. Additional factors potentially compromising a meaningful interpretation of our data, as well as of those reported by others,1,6,7 include: i) the retrospective nature of several analyses which were performed either on patients who, due to their age, were eligible or ineligible to receive ASCT or on patients who had plasma cell dyscrasias other than MM, such as systemic amyloidosis;6,7 ii) the possible different methodological approaches used to assess PN. In our study, clinical evaluation of PN was performed at baseline, at the beginning of each cycle of induction therapy, before each dose of bortezomib, and every 21–28 days after the last dose of bortezomib was given. Neurological monitoring was continued until ASCT was received and allowed us to register 3 patients who suffered from late emergence of neurological toxicity, after induction therapy was completed. Although worsening of taxane-induced neurotoxicity was observed even after treatment was stopped,8 to the best of our knowledge, a similar phenomenon has not been reported for bortezomib. As far as this last issue is concerned, it is important to highlight that all the patients described here had a late emergence of previously undetected, typical bortezomib-induced PN (BiPN) and that in each of them any additional cause potentially contributing to the development of neurotoxicity was excluded. With the limits of the small sample size of patients analyzed, the 32% rate of grade 2 or higher PN is very similar to values previously reported after four cycles of iv VD or VTD incorporating standard-dose bortezomib.2,9,10 Knowledge of the mechanisms underlying BiPN has remained limited for many years.11 Recently, new insights into a better understanding of the pathogenesis of BiPN have been provided by analyses of gene expression profiles and single nucleotide polymorphisms of MM plasma cells.12–14 Results of these studies, performed in patients treated in Western countries but whose ethnicity was not detailed, showed that differently expressed genes involved in drug-induced apoptosis, DNA repair, inflammatory pathways, and development and function of nervous system are related to a different risk for, and time to onset of, BiPN. In addition, the patient’s inherited genetic background might also contribute to the individual risk for neurological toxicity.12,13 The possibility that patient- and disease-related genetic profiles might have been differently expressed in our series of patients compared to those reported by Lok et al.,1 thus partly contributing to the controversies observed in terms of frequency, severity and time to onset of PN, cannot be confirmed or ruled out. In conclusion, our data support the efficacy of sc bortezomib when incorporated into induction therapy for newly diagnosed, ASCT-eligible, MM patients. On the other hand, no conclusions about the different rate and severity of sc versus iv BiPN can be drawn. The possibility of late emergence of PN, even after an uneventful induction phase, should be taken into consideration and alert the physician to the need to continue close neurological monitoring after sc bortezomib-based induction therapy has been discontinued. Results of ongoing studies that aim to prospectively evaluate the efficacy and toxicity of sc bortezomib as part of first-line therapy will hopefully clarify the controversies discussed here.