Slide 1

Thank you Patrick and good evening. Both diseases are characterized by deposition of monoclonal Ig light chains (LC) that occurs in most tissues. In the last 10 years, new potent but high-risk therapies have emerged, although treatment modalities remain controversial.

Slide 2

AL-amyloidosis is defined by organized, fibrillar deposits of Ig light chain that are stained by Congo red and give the typical apple-green fluorescence by polarized light microscopy. Deposits are usually stained by the anti-l LC antibody and are essentially fibrillar by EM.

Slide 3

In contrast, MIDD is defined by nonorganized, granular deposits of monotypic LC, mostly of the k type, that occur along basement membranes in most tissues. Those deposits are responsible for a marked thickening of TBM and nodular glomerulosclerosis.

Slide 4

Usually, the pathogenic light chain is produced by a plasma cell clone either malign or more often benign, and its deposition induces multisystemic organ involvement. However, it has been shown that tissue deposits could resolve under appropriate treatment. The main goal of the treatment is to eradicate the plasma cell clone, but recent advances suggest that it might be possible to interfere with tissue deposition and to enhance dissolution of the deposits. Supportive measures aimed at compensating organ failure are also of utmost importance, especially in AL-amyloidosis.

Slide 5

Amyloidosis is a devastating disease with a probability of survival less than 10% at 10-15 years. However, median survival markedly differs according to the chief clinical manifestation from 5 months in patients with congestive heart failure to 16 months in those with the nephrotic syndrome and to 34 months when peripheral neuropathy is prominent feature.

Slide 6

Heart failure is indeed a major pejorative prognostic factor, and heart dysfunction should be evaluated by measuring NT-proBNP. As shown by Palladini, the cut-off value of 152 pmol/L discriminates two groups of patients with highly significant survival difference (9 months versus not reached). During follow-up, the modifications of NT-proBNP were closely related to clinical heart manifestations and response to therapy.

Slide 7

A major goal of therapy is to obtain as fast as possible a complete hematologic response that should be evaluated by the Free Light Chain assay. This test has become the gold standard for the measurement of LC concentration in serum and the follow-up of patients affected with AL-amyloidosis and with MIDD as well. In a series of 137 patients followed by H. Lachmann’s group in London, the survival was markedly greater in patients with serum FLC suppressed by more than 50% than in those who had less than 50% reduction in FLC.

Slide 8

For a long time, conventional chemotherapy based on melphalan and prednisone was the only choice. As shown in this study from the Mayo Clinic that compared MP to MPC and to C alone, colchicine was ineffective although it prevents FMF-related AA amyloidosis. With MP, partial or complete hematologic response was obtained in less than 30% of patients and it was slow, thus accounting for the poor median survival of patients with prominent heart involvement.

Slide 9

In order to obtain higher rates of response with a much shorter lagtime, HDT with ASCT was proposed according to a protocol derived from the treatment of high-mass myeloma. Following mobilization of stem cells by SC injection of G-CSF, peripheral stem cells are collected by cytapheresis on day 5 with a collection target of 2x106 CD34/kg. Patients then receive melphalan at a dose of 200 mg or 140 mg/kg depending on age and organ involvement, and stem cells are infused on day 2 to reduce the myeloablative effects of those high doses of melphalan.

Slide 10

HDT was first performed in patients with AL-amyloidosis by the Boston group who recently reviewed his 8-year experience. Among 701 patients, 307 patients were initially excluded because they were considered at high risk of death or complications with HDT. These include patients with CHF, arrhythmia/syncope, hypotension, recurrent serous effusion. In addition, 82 patients were secondarily excluded because of deterioration of their clinical condition or decline of treatment. Therefore, stem cell collection was undertaken in only 45% of the initial population and HDT could be administered in only 40% of patients because of failure of stem cell mobilization or death before HDT in 35 patients. In this highly selected population of patients, results were indeed very good : complete hematologic remission was achieved in 26% of patients, with a median survival of 55 months (instead of 18 months with MP), but at the cost of 36 treatment-related deaths in the first hundred days.

Slide 11

Because of a bias in the selection of patients, the Mayo Clinic’s group analyzed retrospectively the survival of patients treated by conventional chemotherapy who met the criteria for HDT. They reviewed the cases of 1288 patients treated with conventional chemotherapy, and selected the 234 patients that would have been eligible for HDT because of age less than 70, septum thickness less than 15 mm, ejection fraction greater than 55%, serum creatinine below 20 mg/L, and alkaline phosphatase less than 3 times the normal value. They found a median survival of 45.6 months very close to that of the Boston patients treated with HDT, and thus concluded that eligibility for HDT is a favorable prognostic factor for survival.

Slide 12

Because the superiority of HDT over conventional chemotherapy remained controversial, we decided to perform the first randomized trial aimed to compare a high dose of melphalan with the support of ASCT, with an oral regimen of M and Dex (as indicated) which was preferred to the conventional M-Prednisone regimen because of higher efficacy. The study was prospective, randomized and multicentric, with OS as the primary outcome.

Slide 13

Inclusion criteria were age between 18 and 70, newly diagnosed biopsy-proven systemic AL-amyloidosis, an ECOG<3, no more than 2 previous chemotherapy courses, no symptomatic MM, and informed cosent. Patients were stratified at randomization according to age and dominant organ system involvement.

Slide 14

There were no significant differences between the 2 groups in age, heart, kidney, nerve and liver involvement, in the mean number of involved organs, as well as in the number of patients with a single affected organ. 80% of the patients were nephrotic. In those patients with heart amyloidosis, thickness of the septum was similar in the 2 arms.

Slide 15

This slide shows the scheme of the protocol. Of the 50 pts assigned to HDM, 13 did not receive the planned treatment : 10 patients died (four of them during G-CSF treatment), one declined, and stem cell harvest was insufficient in 2 pts. Of the 37 pts who received stem cells, 10 were given M at a dose of 140 mg and 27 at a dose of 200 mg/square meter. Of the 50 pts assigned to M-Dex, 5 pts died from disease progression within 130 days after randomization, one could not tolerate treatment and one received HDM. 43 patients received 3 or more cycles of M-Dex.

Slide 16

Hematologic response did not differ significantly between the 2 groups. It was achieved in 69 and 62% of the pts by conventional criteria, and in 74 and 72% of the pts by FLC binding assay. We confirmed that a rapid hematologic response was associated with a prolonged survival that reached 70% at 5 years.

Slide 17

At least one organ response occurred in 39 and 45% of pts treated with M-Dex and HDM, respectively. Renal response was observed in 33 and 27% of the pts respectively.

Slide 18

The median survival of the entire cohort was 48 months. 51 patients died : 20 in the group (assigned to receive) M-Dex and 31 in the group (assigned to receive) HDM. In the intent-to-treat analysis, the Kaplan-Meier estimated OS was 56.9 months and 22.2 months in the groups assigned to receive M-Dex and HDM, respectively with a P value of 0.04.

Slide 19

Because we were concerned by the fact that HDM could provide better survival over conventional therapy in the low-risk patients, we performed a secondary analysis in high- and low-risk patients. On the basis of the Mayo Clinic criteria, 59 patients were at low risk for an adverse outcome of HDM, and 41 were at high risk (mainly because of severe cardiac disease). OS was similar in the 2 groups with high-risk disease. In the patients with low risk, OS at 3 years was 80% in the M-Dex group and only 60% in the HDM group.

Slide 20

Because we were concerned by the relatively high treatment-related mortality in the HDM group about 24%, which was in the same order of magnitude than in other multicentric series, we performed a landmark analysis for patients surviving at least 6 months after randomization and who had received their planned treatment. It did not show any advantage for the ASCT arm, with 10 deaths among 29 pts as compared with 8 deaths among 37 pts in the M-Dex arm. Note that the 2 late deaths in the M-Dex group were not related to amyloidosis or treatment but they were caused by lung and gastric cancer, respectively.

Slide 21

In conclusion, this first randomized trial (which was powered to show a 25% survival advantage with HDM) did not show any superiority of HDM over M-Dex. On the contrary, the median OS was significantly longer in the group assigned to receive M-Dex (than in the group assigned to receive HDM). Because of substantial treatment-related mortality (and cost) of HDM, M-Dex should be considered the treatment of choice in most patients. HDM could be proposed in highly specialized centers to patients who fail to respond rapidly to M-Dex as assessed by FLC. The place of new drugs including thalidomide, Revlimid® and Velcade® remains to be defined in this setting. Novel approaches to inhibit fibrillogenesis (GAG inhibitors : eprodisate) and to favor amyloid dissolution (including CPHPC and monoclonal antibody specific for a neo-antigen on amyloid substance) are promising, but need to be tested in randomized controlled trials.

Slide 22

This slide summarizes the potential therapeutic strategies in AL-amyloidosis. So far, only chemotherapy with or without ASCT is used in routine clinical practice. Additional approaches are the object of pre-clinical or early phase studies, including high-flux dialysis to remove circulating free light chains, GAG inhibitors such as eprodisate used in AA-amyloidosis to inhibit fibrillogenesis, depletion of serum amyloid P component by CPHPC and immunotherapy that both aim to accelerate fibril breakdown.

Slide 23

The treatment of MIDD raises similar questions to that of AL-amyloidosis although the prognosis of MIDD is more difficult to establish than in AL-amyloidosis because extrarenal deposits of light chains can be (totally) asymptomatic or cause severe organ damage, so that survival varies from one month to 10 years. In the largest series as yet reported including 63 patients with a median follow-up of 27.5 months, 57% of patients reached ESRF, and patient survival rate was only 66% at one year, and 31% at 8 years (although 86% of the patients were treated by chemotherapy). Poor prognostic factors include age, association with multiple myeloma, symptomatic extrarenal LC deposition, and high serum creatinine at presentation.

Slide 24

HDM is a feasible and effective treatment of LCDD with treatment related mortality much lesser than in amyloidosis. In our retrospective study of 11 patients under 65 years of age, an hematologic response was obtained in 8 patients. This was associated with an organ response and with an histologic regression of deposits which could be documented in cardiac, hepatic, and skin biopsies. In sharp contrast with amyloidosis, there was no toxic death, most likely because deposits are less extensive with less severe cardiac involvement. Even more, reversal of dialysis dependency was observed in one patient. Similar results on the efficacy and safety of HDM were obtained more recently by the Boston and Mayo Clinic groups. However, there is no data on the efficacy of M-Dex in patients with MIDD.

Slide 25

To summarize, there is currently no established guideline on chemotherapy in patients with renal amyloidosis and MIDD. However, our results and those of other groups favor M-Dex as the first line of treatment with evaluation of treatment efficacy based on FLC assay at 3 months. If an hematologic response is obtained, we recommend to continue M-Dex for 12 months. In case of no response, treatment should be intensified by using HDM with ASCT or alternative regimens based on CTDex or bortezomib. These regimens are now being used in clinical trials as first-line treatment. In any case, we recommend to harvest stem cells early, to keep an option of HDM with ASCT.

Slide 26

Finally, I would like to say a few words on kidney transplantation. Recurrence of LCDD in the kidney graft is commonly observed after a median time of about 3 years, but even more importantly the median time to ESRF after recurrence is less than one year. There is very little information on kidney transplantation in AL-amyloidosis because patients’ condition often rapidly deteriorates. In both diseases, kidney transplantation should not be an option unless measures have been taken to reduce light chain production. Chemotherapy should be performed first and the level of free light chains carefully monitored to check efficacy.

Slide 27

Finally, I would like to thank the centres in France that contributed to the AL-amyloidosis trial, and especially the patients that are affected by such a serious disease. Thank you very much for your attention.