Katia Mancuso

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.

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.

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.

Role of serum free light chain assay in the detection of early relapse and prediction of prognosis after relapse in multiple myeloma patients treated upfront with novel agents

Monoclonal (M) protein can be detected in the serum and/or urine of patients with multiple myeloma (MM) as either intact immunoglobulins (Ig) or free light chains (FLC). Current guidelines recommend the use of serum and urine electrophoresis plus immunofixation to evaluate and monitor response to therapy in MM patients with measurable M-protein. In addition, measurement of serum FLC (sFLC) ratio (sFLCR) is required to fulfill the definition of stringent complete response and to define response or progressive disease (PD) in oligosecretory or non-secretory MM. Nonetheless, sFLC assay might be an appropriate tool also in secretory MM, since an imbalance in sFLCR can be detected in approximately 90% of patients with Ig-secretory MM (Ig-MM) and in almost all patients with light chain MM (LC-MM). Moreover, it is well recognized that sFLC escape might occur before, or at the time of, relapse and increasing levels of sFLC at progression have been reported to predict a worse prognosis. However, most of these studies are biased by the lack of serial assay measurements. Furthermore, the prognostic significance of increased levels of sFLC in the absence of any additional parameter defining PD or clinical relapse (Rel) remains an area of investigation. To address this issue, we analyzed a cohort of 100 MM patients at our center who received first-line, fixed-duration, novel agent-based therapies and for whom sFLCR measurements after treatment were available every 3-4 months until relapse. sFLC assay was performed by BN II nephelometer as part of routine clinical care. International Myeloma Working Group (IMWG) criteria were used for the definition of measurable disease, PD and Rel. Criteria defining PD in oligo/non-secretory MM according to sFLC levels were used to identify patients with secretory MM who showed rising sFLC levels in the absence of any additional parameter consistent with PD or Rel. Time to second progression (2 TTP) and overall survival (OS) after relapse were calculated from the date of first progression to the date of second progression or death, respectively, or of last follow up. Time to secondline therapy was the interval between the date of first progression and the date when salvage treatment was started. At diagnosis, 80 patients were classified as having IgMM, 15 LC-MM and 5 oligo/non-secretory disease. sFLC measurements were available at baseline in 81 patients, of whom 63 had sFLC measurable disease, as defined by an abnormal sFLCR and involved sFLC levels 100 mg/L or more. First-line treatments included the proteasomeinhibitor (PI) bortezomib in 45 patients, the immunomodulators (IMiDs) thalidomide or lenalidomide in 25 patients, and both bortezomib and IMiDs in the last 30 patients. Fifty patients received a single or double autologous stem cell transplantation. Median follow up was 63 [interquartile range (IQR) 38-83] months from diagnosis and 23 (IQR 13-37) months from progression. Best response rates were: complete response, 32%; very good partial response, 35%; partial response, 27%, and stable disease or PD, 6%. Overall, in 66 patients, sFLCR after up-front therapy was in the normal range. According to IMWG consensus recommendations, 88 patients required a second-line therapy due to Rel (n=72) or paraprotein relapse (n=16). The remaining 12 patients did not receive salvage therapy due to a paraprotein relapse not fulfilling criteria for restarting treatment (n=8) or early death (n=3) or a concomitant solid tumor (n=1). Serial monitoring of serum/urine M-protein and sFLC levels throughout the follow-up phase after first-line treatment allowed 4 different patterns of relapse to be identified. These were characterized by: 1) an increase in both M-protein and sFLC (n=30); 2) an increase in M-protein only (n=42); 3) an increase in sFLC levels only (n=15), as established according to IMWG criteria for oligo/nonsecretory MM; 4) the presence of one or more criteria defining Rel, without any concurrent change in M-protein or sFLC (n=13). Patterns of relapse characterized by an increase in sFLC levels, with or without concomitant rise in M-protein, were observed more frequently in patients with abnormal versus normal sFLCR at baseline (62% vs. 17%; P=0.001). Among the 80 patients with IgMM, patterns of relapse were: 32% both M-protein and sFLC (n=26), 48% M-protein only (n=38), 10% sFLC only (n=8), and 10% Rel without change in M-protein or sFLC (n=8) compared with 27% both M-protein and sFLC (n=4), 27% M-protein only (n=4), 40% sFLC only (n=6) and 6% Rel without change in M-protein or sFLC (n=1) for the 15 patients with LC-MM. Patients with LC-MM had a higher frequency of relapse characterized by isolated sFLC increasing than those with Ig-MM (P=0.043). In the subgroup of 14 patients with secretory-MM (8 IgMM and 6 LC-MM) and an sFLC only pattern of relapse, an increase in sFLCs preceded by 2.3 months (IQR 1.76.1) the onset of any conventional parameter defining PD, including Rel with organ damage in 10 (71%) of them, and by 4.0 (IQR 2.8-9.3) months the start of subsequent salvage therapy. Median increase in the difference between involved and uninvolved sFLC levels was 224.1 mg/L (IQR 138.3-437.9) at the time of escape and 687.5 mg/L (IQR 224.1-1819.8) at the time of PD or Rel. Overall, patients who experienced a relapse with an increase in both M-protein and sFLC or sFLC only had higher creatinine levels than those with an increase in Mprotein only or Rel without change in M-protein or sFLC (P=0.025). Conversely, no differences between these subgroups were seen with respect to the other diseaseand tumor-related characteristics that could potentially influence clinical outcomes. Second-line treatments including IMiDs (47%), PI (23%) or both these agents (30%) were equally distributed among patients with different patterns of relapse. Time to second-line therapy was shorter for patients relapsing with both M-protein and sFLC, sFLC-only or Rel without increase in M-protein or sFLC levels, than for those relapsing with M-protein only (P=0.001, trend P=0.0001). Moreover, patterns of relapse characterized by an increase in sFLC, with or without a concomitant rise in M-protein levels, correlated with worse 2 TTP and OS after relapse as compared to the other patterns. In particular, patients relapsing with both M-protein and sFLC or sFLC only had a 2-fold increase in

Prognostic impact of serial measurements of serum-free light chain assay throughout the course of newly diagnosed multiple myeloma treated with bortezomib-based regimens

Abstract We retrospectively investigated the role of serial serum-free light chain (sFLC) evaluations in 150 multiple myeloma (MM) patients treated with first-line bortezomib-based regimens. Baseline sFLC ratio (sFLCR) identified three groups of patients – normal, lightly abnormal (<100), and highly abnormal (≥100) – with different progression-free survival (PFS: 3-year estimate 72% versus 61% versus 44%, respectively, p = 0.03). Moreover, the achievement of a normal sFLCR correlated with extended PFS (49 versus 17 months, p < 0.0001) and overall survival (75 versus 43 months, p < 0.0001) as compared with abnormal sFLCR, a gain maintained in a multivariate analysis for PFS. At relapse, a high sFLCR was associated with earlier start of salvage therapy compared with sFLCR <100 (3-month probability: 89% versus 64%, p = 0.0426). In 20% of patients, sFLC escape preceded the conventional relapse by a median of 3.8 months. Our results highlight the role of sFLC assay in the prognosis and follow-up of MM.

Successful mobilization of PBSCs predicts favorable outcomes in multiple myeloma patients treated with novel agents and autologous transplantation

Incorporation of novel agents into auto-SCT for patients with multiple myeloma has led to improvement in their outcomes. However, the effects of new drugs, either single or combined, on PBSC mobilization have not been fully evaluated, particularly in phase 3 clinical studies. We analyzed the impact of two novel agent-based induction treatments in patients enrolled in the GIMEMA MMY-3006 study comparing bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) in preparation for double auto-SCT. Results showed that a short-term induction therapy with VTD did not adversely affect CD34+ cell yields as compared with TD (9.75 vs 10.76 × 106 CD34+ cells/kg, P=0.220). For poor mobilizers (<4 × 106 CD34+ cells/kg), 5-year rates of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were significantly shorter than for successful mobilizers (TTP:17 vs 48%, P<0.0001; PFS: 16 vs 46%, P<0.0001; OS: 50 vs 80%, P<0.0001). These differences were retained across patients randomized to the TD arm; conversely, no differences in outcomes were seen in patients treated with VTD, irrespective of the number of harvested CD34+ cells. The number of collected PBSCs predicted better outcomes after auto-SCT and VTD overcame the negative impact of a poor stem cell mobilization.

Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138−CD19+ B cells identifies two subgroups of patients with multiple myeloma and different prognosis

Hyperactivation of the Hedgehog (Hh) pathway, which controls refueling of multiple myeloma (MM) clones, might be critical to disease recurrence. Although several studies suggest the Hh pathway is activated in CD138− immature cells, differentiated CD138+ plasma cells might also be able to self-renew by producing themselves the Hh ligands. We studied the gene expression profiles of 126 newly diagnosed MM patients analyzed in both the CD138+ plasma cell fraction and CD138−CD19+ B-cell compartment. Results demonstrated that an Hh-gene signature was able to cluster patients in two subgroups characterized by the opposite Hh pathway expression in mature plasma cells and their precursors. Strikingly, patients characterized by Hh hyperactivation in plasma cells, but not in their B cells, displayed high genomic instability and an unfavorable outcome in terms of shorter progression-free survival (hazard ratio: 1.92; 95% confidence interval: 1.19–3.07) and overall survival (hazard ratio: 2.61; 95% confidence interval: 1.26–5.38). These results suggest that the mechanisms triggered by the Hh pathway ultimately led to identify a more indolent vs a more aggressive biological and clinical subtype of MM. Therefore, patient stratification according to their molecular background might help the fine-tuning of future clinical and therapeutic studies.