Smoldering multiple myeloma: natural history and recognition of an evolving type

Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M-protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM (n = 22), characterized by a progressive increase in serum M-protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non-evolving SMM (n = 26) with stable M-protein that abruptly increases when symptomatic MM develops. Thirty-four patients developed symptomatic MM. The median time to progression in the overall series was 3.2 years and the only feature associated with a shorter time to progression was the evolving versus non-evolving type (1.3 vs. 3.9 years respectively, P = 0.007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty-seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8.2 and 3.5 years respectively.     

Sialyltransferase activity in plasma cells of multiple myeloma

A marked elevation of sialyltransferase activity (STA) was observed in a solid tumor of plasma cells, which had been removed from a patient with multiple myeloma (MM), as compared to normal lymphatic tissues. STA was also determined in mononuclear bone marrow cells of 10 patients with MM and found to be 12 times higher than that of bone marrow mononuclear cells from 5 patients with non-malignant disorders (with less than 1% plasma cells in the bone marrow aspirate). A significant correlation was found between STA and the number of plasma cells in the bone marrow aspirate.     

Carfilzomib,lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study

A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression‐free survival (PFS ) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM ). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR ), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR , 0·753). For patients <70 years the overall response rate (ORR ) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib‐lenalidomide‐dexamethasone has a favourable benefit‐risk profile for patients with RMM , including elderly patients ≥70 years old. Trial Registration: clinicaltrials.gov identifier: NCT01080391.     

Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage

The aim of this study was to develop a flow cytometric test to quantitate low levels of circulating myeloma plasma cells, and to determine the relationship of these cells with disease stage. Cells were characterized using five-parameter flow cytometric analysis with a panel of antibodies, and results were evaluated by comparison with fluorescent consensus-primer IgH-PCR.
Bone marrow myeloma plasma cells, defined by high CD38 and Syndecan-1 expression, did not express CD10, 23, 30, 34 or 45RO, and demonstrated weak expression of CD37 and CD45. 65% of patients had CD19⁻56⁺ plasma cells, 30% CD19⁻56^low, and 5% CD19⁺56⁺, and these two antigens discriminated myeloma from normal plasma cells, which were all CD19⁺56^low.
Peripheral blood myeloma plasma cells had the same composite phenotype, but expressed significantly lower levels of CD56 and Syndecan-1, and were detected in 75% (38/51) of patients at presentation, 92% (11/12) of patients in relapse, and 40% (4/10) of stem cell harvests. Circulating plasma cells were not detectable in patients in CR ( n =9) or normals ( n =10), at a sensitivity of up to 1 in 10 000 cells. There was good correlation between the flow cytometric test and IgH-PCR results: myeloma plasma cells were detectable by flow cytometry in all PCR positive samples, and samples with no detectable myeloma plasma cells were PCR negative. Absolute numbers decreased in patients responding to treatment, remained elevated in patients with refractory disease, and increased in patients undergoing relapse. We conclude that flow cytometry can provide an effective aternative to IgH-PCR that will allow quantitative assessment of low levels of residual disease.     

Diverse niches within multiple myeloma bone marrow aspirates affect plasma cell enumeration

A basic criterion for the diagnosis of multiple myeloma is plasma cell enumeration within the bone marrow (BM). This report showed that flow cytometry under-estimated the number of plasma cells in BM aspirates by an average of 60%, compared with morphological evaluation. The discrepancy was partially because BM smears contain cells associated with the lipid-enriched spicules. In contrast, flow cytometry is performed on the BM fluid, which is depleted of the lipid-adhesive plasma cells. This discrepancy may point to different plasma cell subpopulations associated with diverse niches within the BM.     

IgD multiple myeloma: a cure at 21 years

A 52-year-old man with a plasmacytoma of the body of T-10 in February 1965 returned 6 months later with multiple myeloma characterized by bone pain, osteolytic lesions, and IgD lambda monoclonal protein in the serum, 6.1 g of Bence Jones protein in the urine, and 21% plasma cells in the bone marrow. The M-protein and bone pain disappeared within 6 weeks after therapy with melphalan and prednisone was started. Therapy was discontinued in December 1974. Immunoelectrophoreses and immunofixations of the serum and urine over the years revealed no monoclonal protein. A mediastinal tumor developed, and the patient died of respiratory insufficiency on October 23, 1986. Autopsy revealed a large bronchogenic carcinoma of the right lung extending to the mediastinum, trachea, and esophagus. There was no evidence of multiple myeloma. This patient had responded rapidly to chemotherapy and had no recurrence of myeloma during a 21-year follow-up.     

Lenalidomide in multiple myeloma: current experimental and clinical data

Lenalidomide (LEN) is a structural analogue of Thalidomide and is currently considered a promising compound among immunomodulatory drugs. Following the demonstration of its potent anti-angiogenic, anti-inflammatory, and antineoplastic effects in preclinical models, LEN has emerged as an interesting option for the management of selective hematologic malignancies and may also have a possible role in certain solid tumors as well. It is currently approved in the second-line therapy of multiple myeloma (MM) as well as in myelodysplastic syndrome characterized by 5q minus abnormalities. LEN has been found to be effective in the treatment of both of these conditions and to possess a manageable toxicity profile. In MM, a number of ongoing clinical trials are defining its role in the treatment of newly diagnosed disease as well as in maintenance therapy. Combination approaches pretransplant have shown great promise. Its role in the management of relapsed and refractory disease is now well established. Its long-term tolerability profile appears favorable although an increased risk in new malignancies in patients receiving LEN as maintenance post-stem cell transplant warrants some caution, with follow-up studies being important in determining the long-term implications of this observation.     

Minimal residual disease in multiple myeloma: Benefits of flow cytometry

Over the last 20 years, the approaches to the treatment of multiple myeloma (MM) have changed considerably, which led to an increase in remission rate. Using new diagnostic methods has made it possible to assess the response to treatment more reliably and forecast disease recurrence: allele‐specific polymerase chain reaction, new‐generation sequencing and multicolor flow cytometry enable minimal residual disease (MRD) detection of with sensitivity of 10^?5 to 10^?6. MRD assessment with flow cytometry using is a rapidly developing area of research. The goal of multicenter groups that use flow cytometry as a tool to detect MRD in patients with MM is achieving standardization and increasing sensitivity and specificity of this method. This article provides data about the methods used for MRD monitoring and describes the advances in the field of flow cytometry.     

�෢�Թ��������Ʋ��Խ�չ

多发性骨髓瘤仍是一种不可治愈的血液肿瘤,近10年的治疗突破很大程度上依赖新药的研发,主要包括蛋白酶体抑制剂硼替佐米、免疫调节剂如来那度胺和沙利度胺等。力求达到完全缓解(CR)是目前的治疗目标,因为CR意味着无进展生存期(PFS)甚至总生存期(OS)的延长。以新药为基础的不同诱导方案显著提高一线治疗缓解率。缓解后或移植后进行巩固和维持治疗显著延长PFS。文章主要对包含新药的诱导方案进行总结,并简要讨论难治复发骨髓瘤患者的治疗。     

Vascular endothelial growth factor receptor 3 is a novel marker differing CD138‐positive and CD138‐negative multiple myeloma cells

Considering the unsatisfactory results of salvage therapies for patients with relapsed/refractory acute myeloid leukaemia (R/R‐AML), their value before allogeneic haematopoietic stem cell transplantation (HSCT) remains questionable. However, direct allogeneic HSCT following established conditioning regimens applied in patients with R/R‐AML during active disease has been equally disappointing. In this retrospective observational study, high‐dose melphalan, as part of a sequential preparative regimen, followed by a total body irradiation (4 × 2 Gy)‐based or a treosulfan‐based dose‐adapted conditioning therapy for allogeneic HSCT was administered to 292 adult patients (median age 56 years, range 17–74) with primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). Overall survival rates at 3 years were 34%, 29% and 41%, respectively. Risk factors associated with an inferior survival were higher age, transplantation from a human leucocyte antigen‐mismatched donor and high disease burden. Patients transplanted with blast infiltration <20% showed a notable survival rate of 51% at 3 years. In particular, patients with primary refractory AML showed a more favourable outcome when transplanted early during their disease course. Thus, high‐dose melphalan‐based sequential conditioning chemotherapy followed by an allogeneic HSCT is feasible and enables long‐term remission to be achieved in a substantial proportion of patients with active R/R‐AML.     

Alkaline phosphatase variation during carfilzomib treatment is associated with best response in multiple myeloma patients

The ubiquitin-proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation alkaline phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX-171-003 and 29 patients in PX-171-004 studies, for patients with relapsed/refractory myeloma, were analyzed. All patients received 20 mg/m(2) of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Sixty-seven patients from ALP data were evaluable. In PX-171-003, the ORR (>PR) was 18% and the clinical benefit response (CBR; >MR) was 26%, while in PX-171-004, the ORR was 35.5% overall and 57% in bortezomib-naive patients. ALP increment from baseline was statistically different in patients who achieved ≥ VGPR compared with all others on Days 1 (P = 0.0049) and 8 (P = 0.006) of Cycle 2. In patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline. An ALP increase over the same period of time was seen in 26%, 13% and 11% of patients achieving PR, MR, and SD, respectively. This retrospective analysis of patients with relapsed or refractory myeloma treated with single-agent carfilzomib indicates that early elevation in ALP is associated with subsequent myeloma response.     

Comparative genomic hybridisation identifies two variants of smoldering multiple myeloma

Two variants of smoldering multiple myeloma (SMM) have been recognised: (i) an evolving type, characterised by a progressive increase in the M-protein size and short time to progression to overt multiple myeloma (MM) and (ii) a non-evolving type, with a long-lasting, stable M-protein and longer time to progression. Comparative genomic hybridisation (CGH) analyses in both subtypes of SMM (seven evolving and eight non-evolving SMM) were performed. Evolving SMM showed cytogenetic changes consistent with those found in de novo symptomatic MM (1q gains, chromosome 13 deletions) while the non-evolving variant showed no 1q gains and deletions were uncommon.     

The potential benefits of participating in early-phase clinical trials in multiple myeloma: long-term remission in a patient with relapsed multiple myeloma treated with 90 cycles of lenalidomide and bortezomib

We present the case of a woman with relapsed multiple myeloma (MM) who received combination lenalidomide and bortezomib therapy for 90 cycles followed by continuous lenalidomide monotherapy and has completed over 100 cycles of treatment to date. The patient was diagnosed with advanced-stage, symptomatic MM in 2001. Following a partial response (PR) to dexamethasone in combination with pamidronate and thalidomide, the patient underwent protocol-directed non-myeloablative allogeneic bone marrow transplantation from her matched sibling donor the following year. In 2004, the patient relapsed and was enrolled in a phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and refractory MM. After eight cycles of study treatment, the patient achieved a minimal response. The patient received a total of 90 cycles of treatment with lenalidomide 5 mg given for 14 d every 21 d, and 1 mg/m(2) of bortezomib initially given on days 1, 4, 8, and 11 for the first 20 cycles, and then weekly thereafter on days 1 and 8. Bortezomib was discontinued after 90 cycles, and the patient continued to receive lenalidomide monotherapy. As of cycle 100, the patient achieved a PR. Currently, she is clinically stable with response sustained for over 7 yrs. Therapy has been well tolerated with no significant long-term toxicity; no dose reductions of lenalidomide and bortezomib were required. The excellent tolerability of this steroid-free approach and the durable response seen underscore the potential benefits of participating in early-phase clinical trials evaluating novel therapies and new drug combinations. This case further supports that combination treatment with lenalidomide and bortezomib is an effective therapy in the management of patients with relapsed and refractory MM.     

Liver involvement in multiple myeloma

One hundred twenty-eight records of patients with multiple myeloma were reviewed to assess the incidence and manifestations of liver involvement. Histologic study of the liver was available in 21 patients. Diffuse infiltration of the liver by plasma cells was observed in 10 patients, myeloid metaplasia in four, amyloidosis in two, toxic hepatitis in two, and extrahepatic cholestasis secondary to infiltration of the peripancreatic tissue by plasma cells in one. The clinical signs of plasma cell infiltration of the liver consisted of hepatomegaly in seven patients, mild elevation of liver enzymes in five, and portal hypertension in two. Jaundice was only observed in patients with hepatitis or extrahepatic cholestasis. Liver infiltration by plasma cells did not appear to have a major prognostic significance.     

Clinical impact of chromosomal aberrations in multiple myeloma

Chromosomal aberrations are frequently found in multiple myeloma cells and play a major role in patient outcome and management of the disease. The most important chromosomal aberrations associated with poor outcome are del(17p), t(4;14), t(14;16) and t(14;20). Others that may be associated with adverse prognosis include amp(1)(q21), del(1p32), del(13), del(8p21) and hypodiploidy. Many chromosomal aberrations have no or uncertain impact; for example, t(11;14), t(8;14) and hyperdiploidy. Attempts have been made to overcome the negative prognostic impact of chromosomal aberrations using autologous or allogeneic transplantation or new immunomodulatory drugs such as thalidomide, lenalidomide and the proteasome inhibitor bortezomib, but the results are controversial. Data suggest that allogeneic transplantation and treatment with bortezomib or lenalidomide may help to overcome the negative effect of del(13) on prognosis, whereas bortezomib may have some influence on reducing the impact of del(17p), t(4;14) and t(14;16). Chromosome analysis should always be performed at diagnosis of multiple myeloma to improve the prediction of outcome and to aid treatment decision-making.     

The start of a new wave: Developments in proteasome inhibition in multiple myeloma

Multiple myeloma (MM) accounts for 10% of hematological cancers. Stem cell transplantation remains the cornerstone of first‐line treatment for eligible patients, but historically, pharmaceutical treatment options for MM have been limited. The proteasome was identified as a target for MM therapy in the early 2000s and, in 2004, the boronic acid proteasome inhibitor bortezomib gained European approval. Bortezomib now plays a major role in MM treatment, but the duration of its use can be limited by toxicities such as peripheral neuropathy and the development of resistance. A new generation of proteasome inhibitors has since entered the treatment landscape: carfilzomib, an epoxyketone‐based agent with a distinct mode of action, high clinical efficacy, and lower levels of peripheral neuropathy compared with bortezomib, received approval in 2015 for use in patients with relapsed and/or refractory MM (RRMM). Ixazomib, a second‐generation, orally administered, boronic acid proteasome inhibitor, has also been approved for use in patients with RRMM. In just over a decade, proteasome inhibitor‐based regimens have become an integral component of MM treatment; with more proteasome inhibitors in development, this remains a vibrant research area with potential to improve the lives of patients with MM in the years to come.