Treating myeloma

Dr Rachel Hall

Royal Bournemouth Hospital

Treatment overview

• When to treat ?

• Aim of treatment

• Which treatment ?

• Monitoring response to treatment

• Prevention of complications

• What happens at relapse ?

• New treatments

Myeloma

• Treatable but not curable

• After many years with little change – several new drugs

• Survival improving

• Area of very active research – clinical trials

• Initial treatment – good information from trials –current standard treatments

• Relapsed disease – no standard but several options now

Treating myeloma is more than

just anti-myeloma drugs

• Symptom control

• Supportive care

– Transfusions, EPO

– Treatment of infections etc

• General measures – back care, hydration etc

• Pastoral / spiritual care

When to treat ?

• Calcium increased

• Renal Impairment

• Anaemia

• Bone disease

• Hyperviscosity

• Spinal Cord compression

Emergency treatment

• Steroids

• Emergency radiotherapy

Other treatments: antibiotics,

transfusion, pain killers,

bisphophonates + fluids,

dialysis

Aim of Treatment

Reduce myeloma activity

Chemotherapy

• Alleviate symptoms

• Improve quality of life

• Prevent further bone and organ damage

Strengthen bones

Bisphosphonates

Treatment of bone disease

BISPHOSPHONATESSodium clodronate tablets

Zeledronate intravenously

Pamidronate intravenously

• Strengthen bones

• Stop myeloma driven bone breakdown

• Direct anti-myeloma effect

Kyphoplasty

1 2 3

4 5

Chemotherapy

Chemotherapy Cancer

Myeloma treatment – initial

Divided into two groups:

• Younger patients (<70 years) who are

candidates for autologous stem cell transplant

• Older patients, other patients not fit for

autologous stem cell transplant

Younger patients

• The aim of standard initial treatment is

– to induce remission

– to spare stem cells (avoid melphalan at this

stage)

• Then collect stem cells (peripheral blood)

• Then proceed to high dose melphalan

(200mg/m2) followed by blood stem cell rescue

(autograft / autologous transplant)

Which chemotherapy in newly diagnosed myeloma ?

Myeloma IX Trial

Induction

Consolidation

Maintenance

Eligible for

TransplantationNot eligible for

Transplantation

C-VAD or CTD

Stem cell harvest

Autologous transplantation

Consider mini-allogeneic

transplantation

No treatment or thalidomide

MP or attenuated CTD

Maximal response

Induction chemotherapy

• High response rates

• Most regimens are given as an outpatient

• May require a tunnelled central line insertion

• Steroids important component & synergistic

Intravenous treatment : C-VAD

• Cyclophosphamide weekly orally day 1,8,15

Vincristine and Adriamycin intravenously via pump day 1-4

Dexamethasone (steroids) days 1-4 and 12-15

• Cycle repeated every 3 weeks

• 4-6 cycles

• Alternatives: VAD, C-VAMP, Z-DEX

One cycle

Thalidomide: How it works

Thalidomide: Side effects

• Dose 50 - 200mg daily

• Side effects : drowsinessconstipationperipheral neuropathythrombosis

Oral treatments

• Cyclophosphamide weekly

Thalidomide daily

Dexamethasone in pulses

• Cycle repeated 3-4 weekly

• 4-9 courses

• Melphalan day 1-7

Prednisolone day 1-7

Thalidomide daily 1-28

• Cycle repeated 4 weekly

• 6-9 courses

MPT CTD

Which regimen for which patient?

• MPT

• Generally patients

>70

• Very well tolerated

• Not ideal in renal

failure or if stem cell

collection planned

• CTD (a)

• Generally patients <70

• Patients in whom stem cell collection being considered

• Dexamethasone can give SEs

Treatment complications

Gout Thrush

Shingles Pneumonia

Treatment prophylaxis

Drugs needed in addition to the chemotherapy to

prevent side effects / complications:

Anti-nausea drugs Anti-gout drugs

Antacids (omeprazole) Antibiotics

Antivirals (aciclovir) Antifungals (fluconazole)

Laxatives Blood thinners (clexane)

Markers of disease activity

Healthy plasma cellsAntibodies

Myeloma plasma cells

(cancer cells)

Paraprotein

(M-Protein)

Light chains

(M-Protein)Urinary BJP

Serum free light chains

SFLC

Response to treatment

Treatment Jargon

Paraprotein

Complete response (CR)

Partial response (PR)

Plateau

• Abnormal antibody or protein made by myeloma cancer cells

• No abnormal protein (M-protein) detectable in blood or urine for > 6 Weeks

• < 5 % Plasma cells in bone marrow

• > 50 % reduction in blood M-protein and/or 90 % reduction in urine light chains

• No evidence of continuing myeloma- related organ damage

• Stable M-protein levels for > 3 months

Autologous stem cell transplant

• Used in selected younger patients (<70yrs)

• Used to consolidate the response and increase

the duration of response

• Stem cells collected with chemo and GCSF

• High dose melphalan (HDM) used and the bone

marrow „rescued‟ with patients own stem cells

• High risk chemotherapy with many side-effects.

Mortality 1-3 %

How to replace the bone marrow –

autologous stem cell

transplantation

Collect

stem cells

High-dose

melphalan

Stem cells

returned

RecoveryChemo

GCSF

Remission

Side-effects of stem cell

transplant

• Mucositis

• Infection

– Bleeding

– Fluid retention

– Breathing difficulties

Maintenance treatment

Reference: Attal, M. et al. Blood 2006;108:3289-3294

Figure 1. Event-free survival according to treatment arm

Thalidomide

Treatment of relapsed myeloma

• If first remission lengthy (>1 year) – consider same treatment again

• If not already had thalidomide – consider thalidomide (with dexamethasone)

• Bortezomib (with dexamethasone)

• Bortezomib with liposomal doxorubicin

• Lenalidomide with dexamethasone

• Clinical trials

• Dexamethasone alone

• Supportive care

First Relapse

Second or later Relapse

Initial treatment with MPT

or

CTDa

Initial treatment

With VAD type regimen

And HDT

> 6 months < 6 months < 12 months post

autograft

> 12-18 months post

Autograft.

Suitable for transplantNot Suitable for transplant

HDT not part of 1st

line treatment and

PBSC available

Autograft2nd Autograft

CTD or VelcadeCTD or velcade

regimen

Retreat with MPT

or CTDa

orvelcade C-weekly / dexa lenalidomide Other new agentsor or

Treatment of relapse

CTD

Jacky Pickles, Janice Wrigglesworth and Marie

Morton

29th March 2007: The National

Institute for Health and Clinical

Excellence’s (NICE) announced

a review of its own ruling

denying patients NHS access

to Bortezomib (Velcade)

The “Velcade three”

Velcade : How it works

Side-effects of bortezomib

• Nausea

• Constipation

• Diarrhoea

• Low platelets

• Neuropathy

• Bortezomib, an inhibitor of proteasomes (sites

of protein degradation in cells), has activity

against advanced multiple myeloma

• This study compared bortezomib with high-

dose dexamethasone in relapsed myeloma

• Bortezomib was superior to dexamethasone in

all end points and prolonged overall survival

Bortezomib or High-Dose

Dexamethasone for Relapsed

Multiple Myeloma (APEX study)

Bortezomib

(Velcade)

• Response in 35- 38 % as single agent

• Response 50 % if used with dexamethasone

• Licensed for relapsed and refractory disease

• Major toxicities are neuropathy,

thrombocytopenia

• IV therapy 1.3 mg/m2 days 1,4,8 and 11.

• Dexamethasone tablets days 1,2,4,5,8,9,11,12

Lenalidomide

Lenalidomide

• Strong data for 2nd line use onwards

– Weber D et al Lenalidomide plus Dexamethasone for

Relapsed Multiple Myeloma in North America. NEJM

2007;357:21

– Dimopoulos M et al Lenalidomide plus Dexamethasone

for Relapsed or Refractory Multiple Myeloma. NEJM

2007;357:21

– 700 patients in these trials

– Lena + Dexa vs Placebo + Dexa

– Patients who had progressed after >= 1 therapy

– 48 weeks Lena arm vs 20 weeks Dexa alone

– ORR 65%

Lenalidomide

• Related to thalidomide

• Oral medication taken D1 – 21 in a 28 day cycle

• Well tolerated

• Less sleepiness, constipation, neuropathy

• Clots

• Much more suppression of bone marrow (low white cells and platelets)

• fatigue

Future

• Risk stratified treatment

• Development of new targeted treatments

• New regimes using thalidomide, velcade and

lenalidomide

• Development of other thalidomide analogs

• Continue to improve quality of life

www.myeloma.org.uk