Ma Teresa Cibeira

Bortezomib: an effective agent in extramedullary disease in multiple myeloma

Abstract:  Bortezomib is a potent and selective proteasome inhibitor recently introduced in the treatment of multiple myeloma (MM). This drug produces significant responses in about one‐third of patients with relapsed/refractory disease. We first recognized the lack of efficacy of thalidomide in soft‐tissue plasmacytomas. There is little information on the effect of bortezomib on extramedullary myeloma. Four of 23 patients treated with bortezomib at our institution had extramedullary involvement at the time of relapse. In three of these patients large soft‐tissue plasmacytomas disappeared. This indicates that bortezomib may be useful in clinical situations of extramedullary disease in which other agents, such as thalidomide, may not be effective.

Bortezomib/dexamethasone followed by autologous stem cell transplantation as front line treatment for light‐chain deposition disease

Limited data has been published on the treatment results in patients with light‐chain deposition disease (LCDD). Whenever possible, high‐dose melphalan followed by autologous stem cell transplantation (ASCT) has been the first treatment option, achieving somehow better results than conventional therapy. However, and based on the promising results obtained by treating patients with light‐chain amyloidosis with bortezomib/dexamethasone, new treatment options appear in LCDD. Herein, we describe three patients with LCDD treated with bortezomib/dexamethasone followed by high‐dose melphalan and autologous transplantation. We believe that this new approach should be the treatment of choice in this disease. In addition, those patients achieving hematologic complete response after ASCT could benefit from a kidney transplant if the renal impairment requiring dialysis persists.

Development of rapidly progressive liver light chain deposition under VAD chemotherapy in multiple myeloma

Abstract:  Light chain deposition disease (LCDD) is a multisystemic disorder seen in the setting of plasma cell dyscrasias. The histological characteristic of this disorder is the deposition of a homogeneous, granular, slightly eosinophilic and non‐Congophilic material that shows immunostaining for monoclonal light chains (κ or γ), while in primary amyloidosis (AL) the proteinaceous substance is fibrillar and Congo red positive. In contrast with AL, the light chain in LCDD is usually of the κ‐type. Renal involvement, resulting in nephrotic syndrome, is usually the prominent feature of LCDD. Patients with this disease may also have heart, liver or other organ involvement, mimicking the picture of primary systemic amyloidosis. However, liver failure has rarely been described in patients with LCDD. A patient with myeloma‐associated LCDD who developed rapidly progressive liver κ light chain deposition with fatal outcome after undergoing the first cycle of vincristine/doxorubicin/dexamethasone chemotherapy is reported.

Novel drugs for the treatment of multiple myeloma

The outcome of patients with multiple myeloma (MM) treated with conventional chemotherapy with or without high-dose therapy/autologous stem cell transplantation (SCT) has not been satisfactory, with median survivals ranging from 2 to 3 years for older patients and from 5 to 6 years for younger

Are all myelomas preceded by MGUS

In this issue of Blood , 2 independent articles report for the first time that an MGUS virtually precedes all cases on multiple myeloma.

Evolving M-protein pattern in patients with smoldering multiple myeloma: impact on early progression

Smoldering multiple myeloma (SMM) is a biologically heterogeneous, clinically defined entity with a variable rate of progression to symptomatic multiple myeloma (MM). Reliable markers for progression are critical for the development of potential therapeutic interventions. We retrospectively evaluated the predictive value of the evolving pattern of serum M-protein among other progression risk factors in 206 patients with SMM diagnosed between 1973 and 2012. Median time from recognition of evolving type to progression into symptomatic MM was 1.1 years (95% CI 0.5–2.0) and progression rate at 3 years was 71%. Development of the evolving type drastically worsened the prognostic estimation made at diagnosis for every covariate predictive of progression (serum M-protein size, bone marrow plasma cell infiltration, immunoparesis and Mayo Clinic risk). On average, the hazard ratio for progression to symptomatic MM increased to 5.1 (95% CI 3.4–7.6) after recognition of the evolving type. In conclusion, in patients with SMM the evolving pattern accurately predicts the risk of early progression to symptomatic disease, thereby allowing the identification of ultra-high risk patients who would be candidates for immediate therapy.

Differential humoral responses against heat-shock proteins after autologous stem cell transplantation in multiple myeloma.

Heat-shock proteins (HSP) are important molecules in the pathogenesis of multiple myeloma (MM). Their blockages by drugs or cellular immune response have been investigated, and a possible association with the presence of oligoclonal bands (OB) has been postulated in patients with MM after allogenic stem cell transplantation. The aim of the present study was to ascertain the serum antibody levels against three HSP (60, 70 and 90) by ELISA in patients with MM in complete remission after autologous stem cell transplantation (ASCT), with or without OB, and compare them with those patients with stable gammopathy of undetermined significance (MGUS) and healthy controls. Our results in samples after ASCT showed no differential levels of anti-HSP according to the presence or absence of the oligoclonal response. However, higher levels of anti-HSP90 were found in patients with stable MGUS in comparison with MM patients (p = 0.004). In the same line, a longer progression-free survival was observed in those patients who presented higher anti-HSP90 levels after ASCT (p = 0.042). These results suggest, for first time, the potential of anti-HSP90 humoral immune response for long-term control of malignant plasma cell disorders.

The pattern of the M-protein in smoldering myeloma over the time: an evolving risk factor

We appreciated the comments by Lakshman et al. on our article and we have read with interest the comparison of our results in patients with evolving smoldering multiple myeloma (SMM) in Barcelona [1] with their experience at the Mayo Clinic [2]. They have risen a number of questions that allow us to further clarify and expand on specific points on our manuscript. As described in the methods section, criteria for the diagnosis of “evolving” varied with the initial M-protein concentration. Of the 47 patients with evolving pattern, the M-spike was <30 g/L in 21 (44.7%) and ≥30 g/L in 26 (55.3%). The median time to progression to symptomatic multiple myeloma (MM) of the patients belonging to these two subgroups was short, 12.2 and 6 months, respectively. We have also analyzed the absolute increase of the M component for all evolving patients from the diagnosis of the SMM at the time of finding the evolving type; this value did not allow us further predictive capacity of the evolving subtype. In the first group of patients with <30 gL, 13 had an increase of <5 g/L; the percentage of progression to MM was quite similar between both groups. As mentioned in the correspondence letter, 31, 64 and 5% of all the patients belonged to Mayo Clinic high, intermediate and low-risk categories respectively, based on the M-protein concentration and bone marrow plasma cell percentage at diagnosis. The proportion of evaluable patients with evolving pattern in each group was 25 out of 57 (43.9%), 24 out 110 (21.8%), and 2 out 9 (22.2%). Concerning the prevalence of a pre-existent monoclonal gammopathy of undetermined significance (MGUS), it was more frequent in evolving than in non-evolving patients (13 of 40 evaluable patients (32.5%) vs. 13 of 52 (25%), respectively). These values are lower than those reported in our previous publication for evolving patients (59%) [3], probably because of the smaller number of patients with an available prior serum electrophoresis in the present study. A systematic population revision would be mandatory for the unequivocal analysis of this finding. Unfortunately, and mainly due to the long time span of the study, cytogenetic data was not widely available. In a previous study of 15 SMM, we found a higher prevalence of 1q abnormalities and 13q deletion in patients with evolving pattern. In this series, we only had cytogenetic information of 18 patients, with 5 evolving patients [4]. All but one with no informative results showed normal karyotype and FISH analysis. The implementation in this group of patients of all the available cytogenetic, molecular, and epigenetic techniques potentially useful for the risk stratification of patients with monoclonal gammopathies would be of interest for further investigations. Careful evaluation of the electrophoretic pattern by two hematologists from our group allowed us to rule out spurious variations of the M-protein in those patients with <30 g/L, thereby always confirming the progressive increase in the M-protein size in consecutive measurements. As highlighted in their correspondence, the group from the Mayo Clinic has also analyzed the impact of evolving changes in M-protein and hemoglobin on progression of SMM, but they used a different definition of “evolving M-protein”. While it seems crucial to define criteria that allow an early and precise identification of the evolving behavior, it is important to recognize that the evolving changes are not present at the time of SMM diagnosis [5]. The prognostic model by Lakshman et al., [2] includes data known at time of diagnosis (i.e. percentage of plasma cells in bone marrow) and information that will not be available until later in the course of the disease (changes in the M-component and the hemoglobin level). In consequence, the model cannot be applied at the time of SMM diagnosis. In contrast, in our * Joan Bladé jblade@clinic.cat