AL Amyloidosis trials

There are currently four major AL Amyloidosis trials taking place at the NAC:

  1. The ALchemy trial–a study of chemotherapy in AL Amyloidosis patients
  2. Tourmaline AL1 — a phase 3 AL Amyloidosis trial for patients with relapsed disease
  3. EMN 03— a phase 3 AL Amyloidosis trial comparing oral treatments
  4. Plasma studies — an analysis of the bone marrow of AL Amyloidosis patients.

For detailed information about the disease itself, please see the AL Amyloidosis section.

 

ALchemy

The ALchemy (AL amyloidosis chemotherapy) study is a large, on-going, ‘real world’ study of chemotherapy in systemic AL amyloidosis, funded by a grant from the charity Myeloma UK.

The NAC started this study in 2009 in order to address several unanswered questions relating to patients with AL amyloidosis.

An unmet need

Prior to ALchemy, there had been no large systematic studies following and monitoring patients with systemic AL amyloidosis from the time of diagnosis (prospective studies).  Studies that had been carried out were small and usually did not include patients with severe disease.  Many patients were lost to follow up after their initial visits to the NAC.  It was therefore hard to assess accurately exactly which chemotherapy treatments patients around the country were receiving, what side effects they experienced and how the disease and treatment impacted on their quality of life.

ALchemy aimed to fill these gaps in our knowledge and to help us to improve our clinical practice accordingly.

Our goal was to gain a ‘real world’ picture of the disease by close monitoring of all patients with systemic AL amyloidosis regardless of age or disease severity.

Who is eligible for ALchemy?

All patients diagnosed with systemic AL amyloidosis in need of treatment are eligible for enrolment in ALchemy if they are able and willing to give informed consent and have had no (or minimal) prior therapy.

ALchemy monitoring

Patients enrolled in the study are monitored closely by NAC clinical research nurses.

  • Before ALchemy started, our standard follow up protocol involved an NAC assessment at diagnosis then every 6 months.
  • The ALchemy protocol involves:
    • Evaluation of patients’ response to treatment after 3 months, after just 3 cycles of treatment.
    • Requesting that the patients’ local treating physicians and nurses supply us with data regarding chemotherapy and other treatments and side effects after every cycle (every month).
    • Requesting that patients send us blood samples after every cycle (every month) so we can check free light chain (FLC) concentrations and serum protein electrophoresis (SPE).  We provide the blood sample tubes and pre-addressed padded envelopes and patients can go to their GP or local hospital clinic to have the blood drawn.

We wanted to assess the feasibility of this intensive, early monitoring approach.  We also wanted to evaluate whether such early assessments could lead to better treatment outcomes.

ALchemy has already led to improved patient care

Soon after the ALchemy study began, it became clear that patients were benefiting from the more intensive monitoring with the extra appointment after the first 3 cycles of chemotherapy, monthly blood samples and treatment forms from the local doctors.

As a result, we have incorporated all of these into our standard clinical practice for all patients.

Tourmaline AL 1

The trial

This is an international randomised phase 3 trial of a new drug – MLN9708, in patients with AL amyloidosis with relapsed or refractory disease.  MLN9708 belongs to the drug class called proteasome inhibitors.  This drug class also includes bortezomib, a drug which is often effective treatment for AL amyloidosis.

Patients with relapsed disease have responded to a chemotherapy treatment regime in the past, but after a while the AL amyloidosis has worsened again despite continued treatment.

Refractory disease means that patients have not responded to the treatment regime they received.

This trial aims to find out if patients with relapsed and refractory AL amyloidosis respond better to treatment with MLN9708 plus dexamethasone than to other chemotherapy regimes.

What the trial involves for patients

In order to compare the effects of MLN9708 plus dexamethasone to the effects of other chemotherapy regimes that doctors usually select for patients with relapsed or refractory AL amyloidosis, each patient taking part in the trial is randomly assigned to one of the following two groups:

  • Experimental: MLN9708 plus dexamethasone

Patients will receive MLN9708 (4.0 mg) orally (PO) on Days 1, 8, and 15 plus dexamethasone 20 mg/day PO weekly on Days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 40 mg/day after 4 weeks, if tolerated

  • Active comparator: doctor’s choice

Patients will receive one of the following regimes as selected by their doctor:

  • Dexamethasone: 20 mg/day orally (PO) on Days 1-4, 9-12 & 17- 20 of each 28-day cycle
  • Dexamethasone + melphalan: dexamethasone 20 mg/day PO on Days 1-4 of each 28-day; plus melphalan 0.22 mg/kg PO on Days 1-4 every 28 days.
  • Dexamethasone + cyclophosphamide: dexamethasone 20 mg/day PO weekly on Days 1, 8, 15 & 22 of each 28-day cycle; plus cyclophosphamide 500 mg PO Days 1, 8 & 15 every 28 days.
  • Dexamethasone + thalidomide: dexamethasone 20 mg/day PO weekly Days 1, 8, 15 & 22 of each 28-day cycle; plus thalidomide total dose up to 200 mg/day PO
  • Dexamethasone + lenalidomide: dexamethasone 20 mg/day PO weekly on Days 1, 8, 15 & 22 of each 28-day cycle; plus lenalidomide 15 mg/day for 21 days every 28 days

Who can take part in the trial

Patients with systemic AL amyloidosis affecting the heart and/or kidneys who have received one or two previous lines of treatment are eligible for participation in this trial.

Outcomes

The following outcomes will be assessed in this trial:

  • Overall response rate (ORR) – this will include estimation of what proportion of patients have complete response (CR), a very good partial response (VGPR) or a partial response (PR) to treatment.  Response is assessed with the blood test which measures the free light chain (FLC) concentration.  The better the response to treatment, the greater the drop in FLC concentration.
  • Hospitalisation rates for heart failure or progression to end stage kidney disease or death after 2 years.

In addition, the overall survival (OS), progression free survival (PFS), the safety and the number of patients with heart and/or kidney response will be assessed.

Timing

This study is open for recruitment at the NAC in London and in Oxford, Birmingham and Manchester.

EMN 03

The trial

This is an international randomised multi-centre phase 3 trial comparing oral melphalan-dexamethasone with bortezomib-melphalan-dexamethasone for patients with newly diagnosed early stage (stage 1 and 2) AL amyloidosis.

Brief background on advanced stage AL amyloidosis

Advanced stage cardiac AL amyloidosis is also called stage 2 or stage 3 amyloidosis.  Disease stage is determined according to the results of two specific blood tests called cardiac biomarkers:

  • brain-type natriuretic peptide (BNP)

and

  • cardiac troponin T (TnT)

The concentrations of these two biomarkers are low at the time of diagnosis in patients with early stage disease.

High concentrations of these two biomarkers at the time of diagnosis are associated with significant amyloid deposits affecting the heart, and more advanced disease.

In stage 1 cardiac AL amyloidosis, the concentrations of both biomarkers are low.

In stage2 cardiac AL amyloidosis, the concentrations of one of the biomarkers is increased, but not the other.

In stage 3 cardiac AL amyloidosis, the concentrations of both of the biomarkers are increased.

Recently, an additional measure has also been used to help determine the disease stage:

  • dFLC (differential free light chains).  This test analyses of the difference between concentrations of amyloidogenic free light chains and non-amyloidogenic free light chains

What the trial involves for patients

In order to assess the effects of the two different chemotherapy regimes in patients with early stage cardiac AL amyloidosis, each patient taking part in the trial is randomly assigned to one of the following two treatment regimes:

  • MDex:

Administration of oral melphalan (M) at 0.22 mg/kg and dexamethasone (Dex) at 40 mg daily for 4 consecutive days every 28 days (MDex) until end of therapy

  • BMDex:

Cycles 1 and 2 = MDex with bortezomib (B) at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle, cycles 3 – 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle

Who can take part in the trial

Untreated patients diagnosed with stage 1 or2 cardiac AL amyloidosis who are not candidates for stem cell transplantation are eligible for participation in this trial.

Outcomes

The primary outcome assessed will be

the number of patients with complete response (CR) and partial response (PR) to treatment.

Other outcomes assessed (secondary outcomes) will include:

  • complete hematologic response rate after 3 cycles and after completion of therapy
  • hematologic response rate at completion of therapy
  • organ response rates at 3, 6, 9 and 12 months
  • treatment-related mortality
  • toxicity
  • overall and progression-free survival
  • time to hematologic and organ response
  • quality of life

Timing

This study is open for recruitment at the NAC

 

A study of genotype and phenotype in plasma cells in patients with AL amyloidosis

The study

This study will assess the characteristics of abnormal bone marrow plasma cells in patients with AL amyloidosis.

Background

Treatment of AL amyloidosis is chemotherapy targeting abnormal bone marrow plasma cells.  The characteristics of these cells determines the treatment outcomes.  This study seeks to characterise in detail the abnormal plasma cells by flow cytometry, DNA analysis and exome sequencing.

What the trial involves for patients

All patients with AL amyloidosis need a bone marrow test as a part of the diagnostic work up for amyloidosis and for response assessment at the end of treatment.  This study seeks an additional bone marrow sample as well as the usual diagnostic sample.

Who can take part in the trial

Patients with systemic AL amyloidosis may participate in this trial, starting either at the time of diagnosis or after completion of treatment.

Outcomes

It is hoped that the detailed analysis of genetic and other characteristics of abnormal plasma cells in patients with AL amyloidosis will improve understanding of development of disease and response to treatment.

Timing

This study is open for recruitment at the NAC.

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