PracticeUpdate: Haematology & Oncology

Monoclonal antibodies as

therapeutic tools for myeloma

By Rafael Fonseca,

lthough many new drugs

have been approved in the

last years as tools against

myeloma, a whole new class of

drugs has joined the toolbox:

monoclonal antibodies. These

antibodies have greatly aug-

mented the capacity of myeloma

doctors to control disease. First,

elotuzumab is a monoclonal anti-

body that targets the cell surface

receptor SLAMF7 (previously

known as CS1), which is mainly

present in the surface of natural

killer cells and myeloma cells.

Elotuzumab alone has no direct

anti-myeloma activity; but, when

combined with lenalidomide and

dexamethasone, it was associated

with higher than anticipated re-

sponse rates. This led to a phase

3 clinical trial that was published

in 2016 wherein the three-drug

combination demonstrated a

superior outcome over lenalido-

mide and dexamethasone alone

(ELOQUENT-2).

This drug is

now FDA- and TGA-approved

and is being used in lenalido-

mide-naive patients, including

those with high-risk cytogenet-

ics. Some questions remain, such

as whether it will be useful in

patients progressing on lenalid-

omide maintenance or whether

it will work in combination with

pomalidomide.

The second monoclonal anti-

body approved is daratumumab,

which targets the CD38 receptor

in cells. While CD38 is not ex-

clusively in myeloma cells, the

antibody has shown evidence of

anti-myeloma activity as a single

agent. While this was impres-

sive, the most notable results

are those seen in the context of

combinations with bortezomib

and dexamethasone and also

with lenalidomide and dexameth-

asone.

2,3

The latter combination

has now resulted in the clinical

trial with the greatest rate of

complete responses (43%) in the

relapsed and refractory setting,

and also the longest projected

progression-free survival in any

trial of myeloma that is relapsed

or refractory.

Daratumumab is

here to stay and is quickly gaining

a foothold at the bedside.

My colleague Dr Sagar Lonial

pointed out a few years ago what

he called “oncologic irony”; that

is, that myeloma, the only disease

that produces a monoclonal anti-

body, had no available therapeu-

tic monoclonal. The “oncologic

irony” is finally over.

References

1. Lonial S, Dimopoulos M,

Palumbo A, et al.

N Engl J Med

2015;373:621-631.

2. Palumbo A, Chanan-Khan A,

Weisel K, et al.

N Engl J Med

2016;375:754-766.

3. Dimopoulos MA, Oriol A,

Nahi H, et al.

N Engl J Med

2016;375:1319-1331.

Dr Fonseca is a haematologist

and Site Director of the

Hematologic

Malignancies

Program at the

Mayo Clinic

Cancer Center

in Arizona.

My colleague

pointed out a few

years ago what he

called “oncologic

irony”; that is, that

myeloma, the only

disease that

produces a

monoclonal

antibody, had no

available

therapeutic

monoclonal.

The “oncologic

irony” is finally over.

Minimal residual disease assessment inAML

By Isabel Cunningham,

ith no breakthrough therapies for

acute myeloid leukaemia (AML)

this year, again, and no AML clini-

cal reports in the ASH 2016 plenary session,

it is hard to choose one story for 2016. In-

stead, I’m choosing to highlight a theme of

growing importance – the increase in reports

of minimal residual disease (MRD) assess-

ment in AML.

MRD in AML was the subject of several

ASH presentations. I cite this recent Journal

of Clinical Oncology study of many French

centres that shows how the depth of cell kill

after induction can potentially help doctors

to estimate prognosis and make the decision

about recommending transplant in first re-

mission, somewhat akin to what has already

happened in CML.

The study concerns patients with NPM1

mutations that occur in approximately 30%

of AML and 60% of AML patients without

abnormal karyotypes. Only small numbers

of the 152 studied for MRD had been fol-

lowed over a year, but the early results are

encouraging. The authors documented that

less than a 4-log reduction in NPM1-mutated

cells after induction eventuated in the early

relapses and near 60% relapse rate at 1 year

that is all too familiar in studies of unstratified

AML patients.

However, relapse within 2 years occurred in

only 20% of those patients in whom reduction

exceeded 5 logs. The benefits of our being

able to recognise inadequate cell kill right

after induction are tremendous. Knowing

such results in an individual patient could

lead to making earlier decisions about risking

transplant or going to experimental therapies.

It should also prompt doctors to search for an

unrecognised leukaemic tumour that could

have grown silently in any organ through

therapy. Finding a resistant tumour using

PET/CT or gallium would enable ablation

by excision or radiation before it has time to

metastasise.

Another valuable feature of this French study is

its requirement that the search for a transplant

donor be started at the time of diagnosis. Delay

after remission attainment that often occurs in

identifying a suitable donor is a variable con-

tributing to post-transplant relapse often not

detailed in reports. More large studies such as

this one are likely to improve outcomes as more

markers of residual leukaemia are identified.

Reference

1. Balsat M, Aline Renneville A, Thomas X, et al.

J Clin Oncol

DOI: 10.1200/JCO.2016.67.1875.

Dr Cunningham is Adjunct

Associate Research

Scientist in the Division

of Hematology Oncology

at Columbia University

College of Physicians and

Surgeons, New York, and

Associate Editor of the

PracticeUpdate Oncology Editorial Board.

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