scholarly journals Differences and Similarities in Treatment Paradigms and Goals Between AL Amyloidosis and Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 680-691
Author(s):  
Monique C. Minnema ◽  
Rimke Oostvogels ◽  
Reinier Raymakers ◽  
Margot Jak
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Residual Disease ◽  
Intensive Treatment ◽  
High Dose ◽  
Al Amyloidosis ◽  
Treatment Schedule ◽  
Bone Marrow Plasma ◽  
High Dose Melphalan

Although there are similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. A similarity is of course the use of anti-plasma cell drugs in both diseases; however, the most serious mistake a hemato-oncologist can make is to use the same treatment schedule in dosing and frequency in AL amyloidosis patients as in multiple myeloma patients. AL amyloidosis patients with >10% bone marrow plasma cell infiltration in particular are at risk of receiving a more intensive treatment than they can tolerate. This difference in dosing and frequency is true for many anti-clonal drugs, but it is most apparent in the use of high-dose melphalan and autologous stem cell transplantation. While in multiple myeloma in the age group of ≤70 years, more than 80% of patients are fit enough to receive this intensive treatment, this is the case in less than 20% of AL amyloidosis patients. A similarity is the alignment in the goal of treatment. Although in AL amyloidosis has long been recognized that the goal should be complete hematological remission, this has become more apparent in multiple myeloma in recent years. A common goal in the coming years will be to evaluate the role of minimal residual disease to improve survival in both diseases.

Short and long-term outcome of treatment with high-dose melphalan and stem cell transplantation for multiple myeloma-associated AL amyloidosis

2009 ◽  
Vol 89 (6) ◽  
pp. 579-584 ◽  
Author(s):  
Saulius Girnius ◽  
David C. Seldin ◽  
Martha Skinner ◽  
Kathleen T. Finn ◽  
Karen Quillen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
High Dose ◽  
Al Amyloidosis ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Short And Long Term ◽  
High Dose Melphalan

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

Maintenance Therapy for Myeloma: How Much, How Long, and at What Cost?

2012 ◽  
pp. 515-522 ◽  
Author(s):  
Michel Attal ◽  
Murielle Roussel
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Second Primary ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy

Overview: Maintenance therapy in multiple myeloma has been under investigation for more than 3 decades and has been without evidence of clear advantage in terms of progression-free survival (PFS) until the mid-2000s. Neither conventional chemotherapy, prednisone, nor interferon-based maintenance regimens offered any benefit after conventional or high-dose therapy. Thalidomide was the first drug, mainly given as maintenance after high dose therapy, to demonstrate clinical benefits in terms of PFS and, in some studies, of overall survival (OS). The role of other novel agents such as lenalidomide and bortezomib as maintenance therapy is emerging. Lenalidomide has been shown to reduce the risk of relapse with longer follow-up needed to see if this will translate into a survival benefit. At present, a number of key questions remain unanswered. What are the optimal dose and duration of those treatments? Is the risk of toxicity and second primary malignancies acceptable? Will the disease be more aggressive at time of relapse? Is the clinical benefit predicted by initial prognostic factors and response to previous therapy? Does maintenance therapy work by further eradication of minimal residual disease or by immunological control of the malignant clone? Ongoing randomized trials are evaluating lenalidomide and bortezomib, both in the transplant and nontransplant settings, to better define the role of these drugs as maintenance in multiple myeloma.

Autologous stem cell transplantation (ASCT) in AL amyloidosis: Feasibility outside national amyloidosis referral centers and proposal for simpler pre-transplant staging

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17545-17545
Author(s):  
N. Jain ◽  
M. Pasquini ◽  
M. Paul ◽  
P. Hari
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hospital Stay ◽  
Stage I ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Safe Procedure ◽  
Hematological Response ◽  
High Dose Melphalan

17545 Background: Single center data from national amyloidosis referral centers suggest that high dose melphalan based ASCT is an effective upfront treatment strategy for AL amyloidosis. Absence of published randomized control trials, referral bias and center experience make generalizability of this data difficult since data from outside of major referrals centers is limited. Pre-transplant staging is complicated by the profusion of articles describing various adverse risk factors. Methods: Retrospective review of bone marrow transplant database at our institution was conducted. All patients with AL amyloidosis who underwent ASCT were included in the study. We stratified patients based on International Staging System (ISS) for multiple myeloma. Organ and hematological response were assessed using 2005 consensus guidelines. Results: 13 patients (6 males) underwent ASCT for AL amyloidosis with risk adapted high dose melphalan dosing (melphalan mg/m2 100 (n = 1), 150 (n = 8) and 200 (n = 4)). Median age of the patient population was 53 years (range 31–75 years). Organ involvement was as follows - single organ = 6, 2 organs = 4 and 3 organs = 3. 4 patients had cardiac amyloidosis. 100 day transplant related mortality (TRM) was 15.3%. Overall survival was 84 % (95 % CI 51–96%) @ 1 yr and 75% (95% CI 38–91%) @ 2 yrs. Median follow up was 18 months. No deaths were observed >17 months post-transplant. 45 % patients had organ response. Complete hematological response was observed in 45 % patients. Mean duration of peri-transplant hospital stay for ISS stage I, II and III were 20.5 days (n = 2), 23.3 days (n = 9) and 29 days (n = 1) respectively. Number of deaths observed in ISS stage I, II and III were 0 (0/2), 2 (2/9) and 1 (1/1) respectively. Conclusions: Autologous stem cell transplant (ASCT) for AL amyloidosis is a feasible, effective and safe procedure outside of major national referral centers. Pretransplant stratification of amyloidosis patients using ISS for multiple myeloma indicated a trend towards longer peri-transplant hospital stay and mortality with increasing ISS stage. This hypothesis needs to be tested in larger studies. No significant financial relationships to disclose.

Impact of Chromosome 13 Deletion and Plasma Cell Load on Long-Term Survival of Patients with Multiple Myeloma Undergoing Autologous Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5148-5148
Author(s):  
Esbjörn Paul ◽  
Tolga Sutlu ◽  
Evren Alici ◽  
Goesta Gahrton ◽  
Hareth Nahi
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Autologous Transplantation ◽  
High Dose ◽  
Prognostic Impact ◽  
Term Survival ◽  
Chromosome 13 ◽  
First Line Therapy

Abstract High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most common treatment for patients under 60–65 years of age with multiple myeloma (MM). In this study, we present a retrospective analysis of the prognostic impact of different factors in patients who have received this treatment as first line therapy in our centre. Abnormalities in chromosome 13 were identified by fluorescence in situ hybridization at the time of diagnosis. The median OS and PFS from transplantation time in the whole group of 193 patients were 90 and 48 months respectively. The median follow-up was 65 months (range: 6–186 months). The complete remission (CR) rate in patients with and without del(13) was 31% and 40% respectively whereas the median OS in patients with del(13) was 58 months but not reached in patients without del(13) (p=0.006). The PFS was 26 months in patients with del(13) and 84 months in those without del(13) (p=0.001). The transplantation related mortality was 2.5% both in the absence and presence of del(13). Patients who achieved CR following ASCT had longer OS and PFS when compared to those who only achieved partial remission. Thus, this study confirms the role of del(13) as a marker of poor prognosis. Multivariate analysis showed that the existence of del(13) was the only single independent factor effecting survival (p=0.001). In patients without del(13), the prognostic impact was even stronger when combined with the plasma cell load in the bone marrow (p=0.020), whereas the plasma cell load had no effect on survival of patients with del(13). Overall, the absence of del(13) in combination with low plasma cell infiltration at diagnosis predicts the best survival.

scholarly journals Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 549-557 ◽  
Author(s):  
Ping Zhou ◽  
Julie Teruya-Feldstein ◽  
Ping Lu ◽  
Martin Fleisher ◽  
Adam Olshen ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Calcium Binding ◽  
Plasma Cells ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Embryonic Fibroblasts ◽  
Knock Out ◽  
High Dose Melphalan

In high doses with stem-cell transplantation, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-) amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival, while no response (a less than 50% reduction) is not. Gene-expression studies and a stringently supervised analysis identified calreticulin as having significantly higher expression in the pretreatment plasma cells of patients with systemic AL-amyloidosis who then had a complete response to high-dose melphalan. Calreticulin is a pleiotropic calcium-binding protein found in the endoplasmic reticulum and the nucleus whose overexpression is associated with increased sensitivity to apoptotic stimuli. Real-time PCR and immunohistochemical staining also showed that expression of calreticulin was higher in the plasma cells of those with a complete response. Furthermore, wild-type murine embryonic fibroblasts were significantly more sensitive to melphalan than calreticulin knock-out murine embryonic fibroblasts. These data have important implications for understanding the activity of melphalan in plasma-cell diseases and support further investigation of calreticulin and its modulation in patients with systemic AL-amyloidosis receiving high-dose melphalan.

Bortezomib Once Weekly Is Well Tolerated as Maintenance Therapy after Less Than a Complete Response to High-Dose Melphalan in Patients with Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5099-5099 ◽  
Author(s):  
Stefan Knop ◽  
Holger Hebart ◽  
Volker Kunzmann ◽  
Ralf Angermund ◽  
Hermann Einsele
Keyword(s):  
Multiple Myeloma ◽  
Interferon Alpha ◽  
Residual Disease ◽  
Meta Analysis ◽  
Treatment Strategies ◽  
Rest Period ◽  
Salvage Treatment ◽  
High Dose ◽  
Significant Prolongation ◽  
High Dose Melphalan

Abstract Background: Despite intensive treatment strategies in multiple myeloma (MM) consisting of one or two cycles of high-dose melphalan (HD-Mel) with autologous stem cell support only a minority of patients (pts) achieves molecular complete remission leading to an event free survival (EFS) of eight to ten years. The median EFS for all patients following HD-Mel, however, is no more than 30 to 35 months. Several agents have been evaluated as a part of maintenance strategies in order to eradicate minimal residual disease and thus extending the period until salvage treatment is required. Interferon alpha, that has been most widely used in this setting showed a significant prolongation of EFS and a trend to better overall survival in a large meta-analysis. Bortezomib (VELCADE® [Vel]), a proteasome inhibitor, has substantial anti-myeloma activity in relapsed and refractory disease and was shown to induce exceptional response rates, including consistently high CR rates in up-front treatment. Patients and methods: We decided to set up a phase II trial in patients up to 70 years with less than CR (SD, PR, or VGPR) after one or two cycles of HD-Mel using a less dose-intense schedule than the standard protocol for monotherapy. The first eleven pts were to receive four cycles of Vel 1.0 mg/m2 once weekly for four weeks followed by a two-week rest period. Since no dose limiting toxicity occurred, the dose was increased as per protocol to 1.3 mg/m2 for the subsequent pts. Results: Up to now, 20 subjects were included with a median age of 60.5 (range, 46 – 69) years, 3 of whom had previously received single, and 17 tandem HD-Mel. Two cases of moderately severe herpes zoster prompted us to generally administer acyclovir prophylaxis throughout the treatment. Five pts experienced symptoms of peripheral neuropathy all of which were of grade I. WBC nadir occurred during cycles 2 and 3 with a median of 3.7 × 109/l while median PLT and HB values did not decline below normal values. Three patients progressed while on the study and received salvage treatment while all other patients enrolled completed all four scheduled cycles of treatment. To date, two patients showed improvement of response by conversion of VGPR into CR with confirmed negative immunofixation. Conclusion: We are currently continuing patient accrual on the once-weekly 1.3 mg/m2 schedule since treatment is considered to be safe. Data on the efficacy (i.e. median EFS, OS as compared to historic controls on interferon alpha), however, will require significantly longer follow up.

scholarly journals "ROLE OF ALLOGENEIC TRANSPLANTATION IN MULTIPLE MYELOMA IN THE ERA OF NEW DRUGS"

2010 ◽  
Vol 2 (2) ◽  
pp. e2010013 ◽  
Author(s):  
Benedetto Bruno ◽  
Luisa Giaccone ◽  
Moreno Festuccia ◽  
Mario Boccadoro
Keyword(s):  
Multiple Myeloma ◽  
Standard Of Care ◽  
Allogeneic Transplantation ◽  
New Drugs ◽  
High Dose ◽  
Newly Diagnosed ◽  
Stem Cell Rescue ◽  
High Dose Melphalan ◽  
Anti Tumor Activity

High-dose melphalan with autologous stem cell rescue has been regarded as the standard of care for patients with newly diagnosed myeloma up to the age of 65-70 years. The recent development of agents with potent anti-tumor activity such as thalidomide, lenalidomide and bortezomib has further improved overall survival and response rates. However, relapse is a continuous risk.            Allografting is a potentially curative treatment for a subset of multiple myeloma patients for its well documented graft-vs-myeloma effects. However, its role has been hotly debated. Even though molecular remissions have been reported up to 50% after high-dose myeloablative conditionings, their applications, given the high toxicity, have been for long limited to younger relapsed/refractory patients. These limitations have greatly been reduced through the introduction of non-myeloablative/reduced-intensity conditionings.             The introduction of new drugs, characterised by low risks of early mortality, indeed requires to define role and timing of an allograft to capture the subset of patients who may most benefit from graft-vs-myeloma effects.   Ultimately, new drugs should not be viewed as mutually exclusive with an allograft. They may be employed to achieve profound cytoreduction before and enhance graft-versus-myeloma effects as consolidation/maintenance therapy after an allograft. However, this combination should be explored only in well-designed clinical trials.

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