Agostina Siniscalchi

Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients.

Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with melphalan-prednisone alone (n = 332), melphalan-prednisone-thalidomide (n = 332), melphalan-prednisone-bortezomib (n = 257), or melphalan-prednisone-bortezomib-thalidomide (n = 254). After a median follow-up of 29 months, the 3-year PFS and OS were 67% and 27% (hazard ratio = 0.16; P < .001), and 91% and 70% (hazard ratio = 0.15; P < .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. This trial was registered at www.clinicaltrials.gov as #NCT00232934, #ISRCTN 90692740, and #NCT01063179.

Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide

Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk of venous thromboembolism (VTE). This prospective, open-label, randomized substudy of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in patients with newly diagnosed MM, treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation. Overall, 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive ASA 100 mg/d (n = 176) or LMWH enoxaparin 40 mg/d (n = 166). The incidence of VTE was 2.27% in the ASA group and 1.20% in the LMWH group. Compared with LMWH, the absolute difference in the proportion of VTE was 1.07% (95% confidence interval, -1.69-3.83; P = .452) in the ASA group. Pulmonary embolism was observed in 1.70% of patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular events, or sudden deaths were reported. No major hemorrhagic complications were reported. In previously untreated patients with MM receiving lenalidomide with a low thromboembolic risk, ASA could be an effective and less-expensive alternative to LMWH thromboprophylaxis.

Characterization of Ph‐negative abnormal clones emerging during imatinib therapy

Imatinib is a tyrosine kinase‐specific inhibitor widely used for the treatment of chronic myeloid leukemia (CML). Studies reported the occurrence of additional cytogenetic abnormalities in the Philadelphia chromosome (Ph)‐negative cell population emerging after treatment‐induced suppression of the Ph‐positive clone. These abnormalities were described in a relatively high proportion of patients treated with imatinib compared with the anecdotal reports of similar cases in patients treated with other drugs. However, the origin of these abnormalities as well as their biological and clinical significance are unknown.

Pain management in multiple myeloma.

Pain is a prominent feature of multiple myeloma (MM) and may be caused by different underlying causes and mechanisms. Indeed, pain may be due to disease-related complications, iatrogenic causes or may be associated with other unrelated medical conditions. This symptom may be particularly devastating and can negatively affect the quality of life of the afflicted patients and their functional status. For most MM patients suffering from continuous nociceptive pain, the WHO’s three-step analgesic ladder can provide adequate relief with oral options, although the high prevalence in MM patients of difficult-to-treat pains, such as pains due to skeletal mechanical instability or sustained by neuropathic mechanisms, makes the treatment approach a challenging concern. The management of pain in this setting requires a multidisciplinary approach integrating analgesics and causal interventions. This review focuses on the most common syndromes afflicting MM patients, attempting to provide an understanding of the underlying pain mechanisms and a discussion of the most commonly used treatment strategies.

Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom's macroglobulinemia: a retrospective multicentric study

Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4–15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstroms macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O2 therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O2/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O2 hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health.

Prognostic Factors Associated With Progression of Smoldering Multiple Myeloma to Symptomatic Form

Smoldering multiple myeloma (SMM) presents a high risk of progression to symptomatic MM (sy‐MM). Herein, we analyzed some predictors of development of sy‐MM. In 144 patients with SMM, we also compared the risk of progression predicted by bone marrow plasma cell (BMPC) involvement on the bone marrow biopsy (BMB) versus bone marrow aspirates (BMA).

Bortezomib-related colon mucositis in a multiple myeloma patient

To the editor, Diarrhoea is a common side effect of bortezomib [1, 2]. It is generally mild and usually does not cause the patient’s hospital admission. The pathogenesis of this unpredictable complication associated with bortezomib remains substantially unclear, although it seems related to a peripheral autonomic neuropathy [2]. Although other pathogenetic mechanisms are involved in the bortezomib-related intestinal toxicity, it is believed that this agent does not induce direct mucosal damage [3]. We report a case of a patient affected by multiple myeloma (MM), presented with severe renal failure, who developed a colon mucositis following bortezomib. On February 2007, a 50-year-old man was admitted for a severe renal failure (serum creatinine 12, 2 mg/dl and creatinine clearance, <15 ml/min) requiring dialysis support. Laboratory tests showed the following: anemia (8, 1 g/dl), serum M protein IgA-k (0, 47 g/dl), Bence Jones proteinuria (10, 5 g/24), bone marrow monoclonal plasma cells (60%) and chromosome 13 deletion. A radiological evaluation revealed multiple litic skeletal lesions. A diagnosis of MM IgA kappa stage III B, according to Durie and Salmon classification, was made; the disease renal involvement was confirmed by biopsy that revealed a light chain tubular damage (myeloma kidney). In view of reported experience on the management of MM complicated by renal failure [4, 5], as induction treatment, the patient was offered a regimen combining bortezomib (1.3 mg/m on days 1, 4, 8 and 11) and dexamethasone (20 mg on days 1–4) given intravenously every 3 weeks for three cycles. He was properly informed and gave his consent. At day +14 of the third cycle of the treatment plan, the patient presented uncontrollable diarrhoea (grade 4 WHO), massive rectorrhage, bloating and severe abdominal pain for which he was admitted. Physical exam showed normal vital signs, diffuse abdominal discomfort with mild tenderness and increased of bowel movements. Oral mucosa was normal, and he did not refer dysphagia. There were no significant changes in blood counts and biochemistry. Coproculture, Clostridium difficilis toxina determination Support Care Cancer (2009) 17:325–327 DOI 10.1007/s00520-008-0573-3

High-dose therapy with autologous PBSC transplantation in the front-line treatment of Waldenstrom's macroglobulinemia.

High-dose therapy with autologous PBSC transplantation in the front-line treatment of Waldenstroms macroglobulinemia

Bortezomib, melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma: a multicenter, open label phase 1/2 study.

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event‐free survival compared with MP alone.

Infection complications in an unselected cohort of patients with multiple myeloma treated with lenalidomide combinations.

To the Editor: Immunomodulatory drugs (IMiDs) exert various effects on the immune system, altering cytokine production, regulating T-cell costimulation, and enhancing NK cell cytotoxicity. Particularly, IMiDs inhibit tumor necrosis factor-alpha (TNF-alfa), playing an important role in immune response against bacterial and virus infections (1). Moreover, lenalidomide causes myelosuppression, mainly neutropenia, that is an important risk factor for infections. We retrospectively assessed the incidence, type, and major factors affecting infections in a population of 127 patients with multiple myeloma (MM) receiving lenalidomide-based regimens. We studied the following parameters as possible major factors: sex, disease status (newly diagnosed vs. relapsed/refractory), monoclonal component level (>3 gr/dL vs. 3 gr/dL), age (>65 yr vs. 65 yr), leukopenia or thrombocytopenia prior to the start of therapy (yes vs. no), renal failure (yes vs. no), Lenalidomide (L)–dexametasone (d) 40 mg weekly vs. L plus chemotherapy, PS 2 vs. <2, prior to the lines of therapy ( 3 vs. <3), International Scoring System (ISS) (II–III vs. I). Median age was 67 yr (40– 88) and 53.5% were older than 65 yr. Fifty-four patients (42.5%) had newly diagnosed MM and four of these received an autologous peripheral blood stem cells transplantation (APBSCT) upfront, whereas the remaining 73 (57.5%) had relapsed/refractory disease. Among this group, 67% of patients received more than one line of therapy and 26% underwent APBSCT prior to lenalidomide. ISS stage 2–3 and renal failure were recognized in 54.5% and 8.5% of patients, respectively; 15% had an ECOG PS 2. Overall, 80 patients (63%) received L-d and 47 (37%) lenalidomide combined with steroids and chemotherapy. Median number of lenalidomide courses was 6 (1–28); 34.7% of patients developed severe neutropenia (26% grade 3 and 8.7% grade 4), while of the nine patients with renal impairment, two developed neutropenia 3. Nearly all patients (95%) received trimethoprim–sulfamethoxazole (TMP-SFZ) as infections prophylaxis and 31% granulocyte colony-stimulating factor according to guidelines (2). Twenty-six patients (20.5%) developed infections, resulting in grade 1–2 in eight patients (6%) and 3–4 in the remaining 18 (14%). Two deaths (1.5%) because of infections were observed. Type of infections was pneumonia in 15 (58%), upper respiratory tract in 3 (11.5%), Fever of Unknown Origin (FUO) in 3 (11.5%), septic shock by gram-negative microorganisms in 2 (8%), cholecystitis in 2 (8%), and Varicella Zoster Virus in one (4%). Risk of grade 3–5 infection was 16% at 12 months; 62.5%, 69%, and 94% of infections occurred at 3, 4, and 6 months, respectively. Among all the parameters evaluated in univariate and multivariate analysis, only ISS resulted as factor affecting severe infection development (Fig. 1). Particularly, the risk of grade 3–5 infections at 6 months was 18% in patients with ISS 2–3, compared with 6% in those with ISS 1 (P = 0.034). A trend for a longer Progression Free Survival (PFS) in patients without infection (median PFS = 8 vs. 16 months in patients with or without infections, respectively, P = 0.064) was documented; however, Overall survival (OS) of patients developing infections was significantly shorter, compared to patients who did not develop infections (median OS = 26 vs. 33 months; P = 0.001). Multivariate analysis adjusted for age, PS, ISS, renal function, and ther-