| Eligibility |
Inclusion Criteria:
1. Patient has provided a signed study Informed Consent Form prior to any study-specific
procedure and is able to comply with protocol requirements
2. Patients with multiple myeloma,relapsed or refractory after failure of two or more
lines of systemic treatments. All patients must have received at least one
immunomodulatory drug (IMiD) and a proteasome inhibitor.
Multiple myeloma requiring systemic therapy must have been confirmed in the medical
history of the patients with criteria established by the International Myeloma Working
Group (IMWG) (Rajkumar V et al. Lancet International Myeloma Working Group updated
criteria for the diagnosis of multiple myeloma. Lancet 2014; 15: 538-548)
3. Written confirmation of BRAFV600E mutation or BRAFV600K mutation in in the majority of
myeloma cells, defined by positive IHC staining with mutations specific antibody of =
50% in the respective biopsy, confirmed by DNA sequencing of the corresponding codon
4. Measurable disease, as defined as: Measurable levels of myeloma paraprotein in serum
(= 0.5 g/dL) or urine (= 0.2 g/24 hours) or FLC of involved light chain > 100mg/l and
abnormal FLC-ratio
5. Age =18
6. WHO performance status 0-3 (WHO 3 is allowed only when caused by MM and not by
comorbid conditions) (see Appendix 3)
7. Negative pregnancy test within 72 hours of inclusion (women of childbearing
potential): For all men and women of childbearing potential: patients must be willing
and capable to use adequate contraception during the complete therapy (see also
exclusion criteria).
8. All patients must agree to abstain from donating blood while on study
9. Adequate cardiac function: left ventricular ejection fraction (LVEF) = 50% as
determined by an echocardiogram, QTc interval = 450 ms
10. Ability of subject to take oral medications
11. Ability of subject to understand character and individual consequences of clinical
trial
Exclusion Criteria:
1. Patient with prior treatment with MEK and/or RAF inhibitors
2. Systemic AL amyloidosis (except for patients with AL amyloidosis of the skin or the
bone marrow)
3. Patients with meningeosis or central nervous system lesion(s) caused by multiple
myeloma. However, patients treated with stereotactic radiotherapy or surgery are
eligible if patient remained without evidence of CNS disease progression = 4 weeks.
4. History or current evidence of retinal vein occlusion (RVO) or predisposing factors to
RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
hypercoagulability syndromes)
5. History of retinal degenerative disease
6. Plasma cell leukaemia which requires the presence of 20% of plasma cell in peripheral
blood leukocytes and at least 2/nl.
7. Patient has received radiotherapy (including therapeutic radioisotopes) = 21 days, if
not restricted to a single osteolytic lesion, or has not recovered from side effects
of such therapy.
8. Patient has had major surgery within 21 days prior to starting study drug or has not
recovered from major side effects of the surgery. Kyphoplasty as prevention of
skeletal related events is allowed.
9. Patient is concurrently using other approved antineoplastic or any investigational
agents in the last 14 days prior to start of treatment. Note: patients may have
received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency
therapy within 4 weeks prior to study entry.
10. Impaired cardiovascular function or clinical significant cardiovascular disease
including any of the following: Symptomatic chronic heart failure, history or current
evidence of clinically significant cardiac arrhythmia and/or conduction abnormality <6
months prior to Screening except atrial fibrillation and paroxysmal supraventricular
tachycardia;
1. LVEF < 50% as determined by ECHO, or uncontrolled hypertension despite medical
treatment (please refer to WHO ISH guidelines)
2. Clinically significant resting bradycardia, unstable angina pectoris = 3 months
prior to starting study drug, history of acute coronary syndromes (including
myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or
stenting) <6 months prior to screening
3. QTcF > 450 msec
4. patients with acute diffuse infiltrative pulmonary and pericardial disease
11. Significant hepatic dysfunction (serum bilirubin = 2 mg/dl or ASAT and/or ALAT = 2.5
times normal level), unless related to myeloma
12. Active hepatitis B, and/or active hepatitis C infection
13. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral LGX818/MEK162 (e.g., ulcerative diseases, uncontrolled
nausea,vomiting, diarrhea, malabsorption syndrome, small bowel resection).
14. Gilbert´s syndrome
15. Patients who have neuromuscular disorders that are associated with elevated CK (e.g.,
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
muscular atrophy)
16. Patients who are planning on embarking on a new strenuous exercise regimen after first
dose of study treatment. Note: Muscular activities, such as strenuous exercise, that
can result in significant increases in plasma CK levels should be avoided while on
MEK162 treatment
17. Patients known to be HIV-positive
18. Patients with active, uncontrolled infections (patients successful treated with
antimicrobial therapy may be enrolled at the discretion of the investigator).
19. Patient is receiving chronic treatment with systemic steroids or another
immuno-suppressive agent at start of study treatment. Note: Topical applications
(e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local
injections (e.g., intra-articular) and the use of systemic steroids up to a prednisone
equivalent of 10 mg daily are allowed.
20. Patient has consumed Seville oranges, grapefruit, grapefruit hybrids, pomelos and
exotic citrus fruits (as well as their juices) during the last 7 days prior to start
of treatment. Regular orange juice is permitted.
21. Second malignancy within the past 3 years except:
1. Adequately treated basal cell or squamous cell skin cancer (adequate wound
healing is required prior to entry in the study)
2. Adequately treated carcinoma in situ of the cervix,
3. Prostate Cancer not requiring systemic treatment or under anti-hormonal treatment
and PSA-level below upper level of normal range.
4. Ductal breast carcinoma in situ with full surgical resection (i.e., negative
margins),
5. solid tumor treated curatively, and without evidence of recurrence for at least 3
years prior to study entry
6. Similar condition with an expectation of > 95 % 5-year disease free survival
22. Patients with any of the following laboratory values at Screening/Baseline.
1. Absolute neutrophil count (ANC) <1,000/mm3 [1.0 x 109/L] without Growth factor
support in the last 7 days
2. Platelets = 50000/mm3 [50 x 109/L] ; patients with platelets 75000- 50000/ mm3
are eligible if thrombocytopenia is confirmed as related to myeloma bone marrow
infiltration and pt. is able to receive thrombocyte concentrates
3. Hemoglobin < 8.0 g/ dl (unless confirmed related to myeloma bone marrow
infiltration and pt. able to receive blood transfusions)
4. Serum creatinine >2 x ULN or calculated or directly measured CrCl = 45 ml/min;
patients with creatinin-clearance between 30-45 ml/min can be enrolled with
approval by the coordinating investigator.
23. Clinically significant autoimmune haemolytic anaemia with positive Coombs test or
immune thrombocytopenia
24. Patient is a woman of child-bearing potential, UNLESS they are using a double barrier
method for birth control throughout the trial.
1. Hormonal contraceptives may be affected by cytochrome P450 interactions, and are
therefore considered neither indicated nor effective.
2. Adequate barrier methods of contraception include: diaphragm, condom (by the
partner), intrauterine device (copper), sponge or spermicide.
3. Reliable contraception has to be maintained throughout the study and for 12 weeks
after study drug discontinuation.
4. Women are considered post-menopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six
months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had
surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks
ago. In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment is she considered
not of child bearing potential
25. Sexually active males unless they agree to use a condom during intercourse while
taking the drug. This practice should be continued for another 12 weeks after stopping
treatment. Also they should not father a child during the study period or the 12 weeks
post study time.
A condom is also required to be used by vasectomized men in order to prevent delivery
of the drug via seminal fluid;
26. Medical, psychiatric, cognitive or other conditions that may compromise the patient's
ability to understand the patient information, give informed consent, comply with the
study protocol or complete the study.
27. Patients taking non-topical medication known to be a strong inhibitor of CYP3A4.
However patients who either discontinue their treatment or switch to another
medication at least three days prior to registration are eligible.
28. Participation in other clinical trials within 1 month prior to enrolment except
patients for supportive care studies and vaccination studies. This does not include
long-term follow-up periods without active drug treatment of previous studies during
the last 6 months.
29. Patient has other concurrent severe and/or uncontrolled medical condition that would,
in the investigator's judgment contraindicate her participation in the clinical study
(e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis ).
No subject will be allowed to be enrolled in this trial more than once.
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