Clonal and subclonal TP53 molecular impairment is associated with prognosis and progression in multiple myeloma.

Aberrations on TP53, either as deletions of chromosome 17p (del17p) or mutations, are associated with poor outcome in multiple myeloma (MM), but conventional detection methods currently in use underestimate their incidence, hindering an optimal risk assessment and prognostication of MM patients. We have investigated the altered status of TP53 gene by SNPs array and sequencing techniques in a homogenous cohort of 143 newly diagnosed MM patients, evaluated both at diagnosis and at first relapse: single-hit on TP53 gene, either deletion or mutation, detected both at clonal and sub-clonal level, had a minor effect on outcomes. Conversely, the coexistence of both TP53 deletion and mutation, which defined the so-called double-hit patients, was associated with the worst clinical outcome (PFS: HR 3.34 [95% CI: 1.37-8.12] p = 0.008; OS: HR 3.47 [95% CI: 1.18-10.24] p = 0.02). Moreover, the analysis of longitudinal samples pointed out that TP53 allelic status might increase during the disease course. Notably, the acquisition of TP53 alterations at relapse dramatically worsened the clinical course of patients. Overall, our analyses showed these techniques to be highly sensitive to identify TP53 aberrations at sub-clonal level, emphasizing the poor prognosis associated with double-hit MM patients.

The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma.

The recent introduction of monoclonal antibodies (MoAbs), with several cellular targets, such as CD-38 (daratumumab and isatuximab) and SLAM F7 (elotuzumab), differently combined with other classes of agents, has significantly extended the outcomes of patients with multiple myeloma (MM) in different phases of the disease. Initially used in advanced/refractory patients, different MoAbs combination have been introduced in the treatment of newly diagnosed transplant eligible patients (NDTEMM), showing a significant improvement in the depth of the response and in survival outcomes, without a significant price in terms of toxicity. In smoldering MM, MoAbs have been applied, either alone or in combination with other drugs, with the goal of delaying the progression to active MM and restoring the immune system. In this review, we will focus on the main results achieved so far and on the main on-going trials using MoAbs in SMM and NDTEMM.

Multiple myeloma: disease response assessment.

Precise assessment of response to therapy is of high importance in every phase of multiple myeloma (MM). In addition to the well-established role of monoclonal protein for clinical monitoring, several methods of minimal residual disease evaluation, both inside and outside the bone marrow (BM), are to date available. Next generation flow cytometry and sequencing are probably the best approaches at the BM level, being highly sensitive and uniformly applied. FDG PET/CT is the best imaging technique for evaluating and monitoring response to therapy outside the BM. Functional whole-body MRI techniques (DCE and DWI) seem promising for response evaluation and need further studies. Standardization of most of these techniques is in progress.

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.

Current and emerging triplet combination therapies for relapsed and refractory multiple myeloma.

Despite significant improvement in outcomes have been observed for multiple myeloma (MM) patients over the past 10-15 years, mainly due to the introduction of novel agents targeting the tumor clone and the bone marrow microenvironment, treatment of refractory and/or relapsed (RR) disease remains a challenge, particularly for patients who have failed prior bortezomib- and lenalidomide-based therapies. More recently, new drugs with different mechanisms of action, including second generation proteasome inhibitors, third generation immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies, have been developed and are under investigation, further increasing treatment options for RRMM patients. Overall, novel agent-based triplet combinations demonstrated superior response rates and prolonged disease control when compared with two-drug regimens in several randomized clinical trials, without adding any relevant additional toxicity. Salvage triplet therapies are likely to play a key role in overcoming drug-resistance and hold promise to further improve long-term outcomes of RRMM patients.

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 (18)F) 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.

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 × 10(6) CD34(+) cells/kg, P=0.220). For poor mobilizers (<4 × 10(6) 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.

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.

Neuropathy in multiple myeloma treated with thalidomide: a prospective study.

BACKGROUND: Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by peripheral neurotoxicity. OBJECTIVE: To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly diagnosed MM. METHODS: Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation, the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and electrophysiologic checkup. RESULTS: At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic pathology (>or=partial response). CONCLUSIONS: Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total dose, and duration of treatment.