this ppt. contains the sirius trial and the latest updates on multiple myeloma till date in a systemic easy way...best seen when downloaded.

1. Journal presentation
Daratumumab monotherapy in patients with
treatment-refractory multiple myeloma
(SIRIUS): an open-label, randomised, phase 2
trial
Published on January 6, 2016
in
by–Dr. Shubham Prasad, Department of General Medicine, Institute
Of Medical Sciences, Banaras Hindu Uiversity [B.H.U.],
Varanasi, India

2. REDEFINING ACTIVE MYELOMA
(Not CRAB but now SLiM CRAB)

3. Clonal bone marrow plasma cells ≥10% or
biopsy-proven bony or extramedullary plasmacytoma
AND
any one or more of the following CRAB features or myeloma-defining events:
 Evidence of end organ damage that can be attributed to the underlying
plasma cell proliferative disorder, specifically:
 Calcium-Hypercalcemia
 Renal insufficiency
 Anemia
 Bone lesions
 Any one or more of the following biomarkers of malignancy (MDEs):
 60% or greater clonal plasma cells on bone marrow examination
 Serum involved / uninvolved free light chain ratio of 100 or greater,
provided the absolute level of the involved light chain is at least 100mg/L
(a patient’s “involved” free light chain—either kappa or lambda—is the
one that is above the normal reference range; the “uninvolved” free light
chain is the one that is typically in, or below the normal range)
 More than one focal lesion on MRI that is at least 5mm or greater in size.
Lancet Oncol 2014; 15: e538–48

4. Once diagnosed how do we currently
stage the disease

5. 5 YEAR
OVERALL SURVIVAL PROGRESSION FREE
SURVIVAL
82% 55%
62% 36%
40% 24%
2015 American Society of Clinical Oncology
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6. Treatment options
and its
Evolution

8. --

13. After treatment how do we assess
response

14. TWO NEWER CR
Palumbo et al 2015 American Society of Clinical Oncology
Immunophenotypic CR sCR as defined plus absence of
phenotypically aberrant plasma cells
(clonal) in bone marrow with minimum of 1
million total bone marrow cells analyzed by
multiparametric flow cytometry (with four
colors)
Molecular CR CR as defined plus negative allele-specific
oligonucleotide polymerase chain reaction
(sensitivity 105) –PCR

15. When to label as refractory/relapse
Multiple Myeloma

16. • Refractory - when a patient's disease is resistant to
treatment or the disease progresses within 60 days of
their last therapy. Richardson, et al. “The Treatment of Relapsed and Refractory
Multiple Myeloma.” ASH Education Book January 1, 2007 vol. 2007 no. 1 317-323.
• Relapsed - means the disease has returned after a period
of initial, partial or complete remission. National Cancer Institute.
“NCI Dictionary of Cancer Terms: Relapsed multiple myeloma.” November 2015.
• Double-refractory disease – definition is evolving over
time, and can vary from country to country. The classical
definition refers to patients refractory to bortezomib and
thalidomide and/or lenalidomide—the first generation
proteasome inhibitors and immunomodulatory agents
(IMiDs). Maria-Victoria Mateos, MD, PhD, University Hospital of Salamanca-IBSAL; Jatin J.
Shah, MD, The University of Texas MD Anderson Cancer Center; Andrew Spencer, MD, Monash
University
Published Online: Thursday, December 17, 2015 http://global.onclive.com/insights/Global-
Relapsed-Refractory-MM/treating-double-refractory-multiple-myeloma#sthash.

18. Understanding Relapse – the ‘clonal tide’ way
And
its clinical implications

19. UNDERSTANDING RELAPSE
6 unique clones at diagnosis
Variable chemotherapy response
Minor drug-resistant clone lethal
Multiple clones with variable
drug sensitivity
(Combination chemotherapy a
necessity
and
Continuous therapy logical)
Re-emergence of drug-sensitive clones
(Once resistant not always resistant)
Minor clone is lethal (CR is a goal)
IMPLICATIONS

21. Why daratumumab???

22. Evidence before this study
• Although survival has improved substantially with
new drug classes (eg, proteasome inhibitors and
immunomodulatory drugs), along with autologous
stem cell transplantation, most patients will die
from refractory disease AND MULTIPLE MYELOMA
REMAINS INCURABLE.
Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple
myeloma and the impact of novel therapies. Blood 2008; 111: 2516–20.
Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of improved survival
in patients with multiple myeloma in the twenty-fi rst century: a population-
based study. J Clin Oncol 2010; 28: 830–34.

23. • Outcomes for patients who are resistant to proteasome
inhibitors (bortezomib and carfilzomib) and
immunomodulatory drugs (lenalidomide, thalidomide, and
pomalidomide) are especially poor.
• Additional treatment can be complicated by cytopenias,
secondary to poor haematological reserves, and comorbidities
such as renal insufficiency.
• Therefore, effective treatments that target novel pathways
with little toxicity and favourable tolerability are needed.
• Monoclonal antibodies are a novel class of agents in
myeloma, targeting cell surface markers, such as SLAMF7 (CS-
1) and CD38, with few off-target effects.
Kuroda J, Nagoshi H, Shimura Y, Taniwaki M. Elotuzumab and daratumumab: emerging new
monoclonal antibodies for multiple myeloma. Expert Rev Anticancer Ther 2013; 13: 1081–88

24. Daratumumab
• is a first-in-class human IgG1 monoclonal
antibody
• that binds CD38-expressing malignant cells with
high affinity
• induces tumour cell death through diverse
mechanisms of action:
1. complement-dependent cytotoxicity
2. antibody-dependent cell-mediated
cytotoxicity
3. antibody-dependent cellular phagocytosis
4. induction of apoptosis

25. daratumumab

26. • Daratumumab had gained US Food and Drug
Administration breakthrough therapy
designation based on phase 1 data from a
first-in-human study in patients with multiple
myeloma who relapsed or were refractory to
at least two previous therapies. The first-in-
human study was expanded and Concurrently
this study was initiated to further investigate
the selected dose schedule.

27. Added value of this study
• The current study is the largest study so far of the
single-agent activity of daratumumab 16 mg/kg in
heavily pretreated patients with multiple myeloma
who were refractory to both a proteasome inhibitor
and an immunomodulatory drug.
• As a result of this study, daratumumab was approved
by the FDA for the treatment of refractory myeloma.
• Daratumumab is indicated for patients who have
received at least three previous lines of therapy,
including a proteasome inhibitor and an
immunomodulatory drug, or who are double refractory
to a proteasome inhibitor and an immunomodulatory
drug.

28. Lines Of Therapy
• A line of therapy is defined as one or more cycles of a planned
treatment program.
• This may consist of one or more planned cycles of single-
agent therapy or combination therapy, as well as a sequence
of treatments administered in a planned manner.
• For example, a planned treatment approach of induction
therapy followed by autologous stem cell transplantation,
followed by maintenance is considered one line of therapy.
• A new line of therapy starts when a planned course of
therapy is modified to include other treatment agents (alone
or in combination) as a result of disease progression, relapse,
or toxicity.
• A new line of therapy also starts when a planned period of
observation off therapy is interrupted by a need for additional
treatment for the disease.
Consensus recommendations for the uniform
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1

29. Study design
two-part, interventional
open-label
multicentric
phase 2 study
at 26 sites in Canada, Spain, and the USA, and is
ongoing.
Funding - Janssen Research & Development
Ethics committees and institutional review boards
at the study sites approved the study.

30. Inclusion criteria
1. Age at least 18 years old
2. Documented secretory multiple myeloma
3. Evidence of disease progression on or within 60
days of the last dose of the most recent previous
treatment regimen, based on the International
Myeloma Working Group criteria.
4. Eastern Cooperative Oncology Group
performance status score of 0, 1, or 2.

31. Exclusion criteria
1. Any antimyeloma treatment within 2 weeks
2. Autologous stem cell transplantation within 12
weeks, of day 1 of cycle 1
3. Meningeal involvement of multiple myeloma
and other malignancies within 5 years.
4. Absolute neutrophil counts of 1 × 109 per L or
lower, haemoglobin concentration of 75 g/L or
lower, platelet counts of less than 50 × 109 per L,
and creatinine clearance of 20 mL/min per 1·73
mm2 or lower.

32. Other exclusion criteria were:
4. Myocardial infarction within 1 year,
uncontrolled or unstable angina, congestive
heart failure (New York Heart Association
Class III or IV)
5. Arrhythmia (grade 2 or higher), QTcF interval
that was longer than 470 ms
6. Chronic obstructive pulmonary disease,
persistent asthma, or a history of asthma
within 5 years.

33. Trial profile
PART 1
PART 2
STAGE 1
STAGE 2
PHASE -2
124
124 minus 18 = 106

34. Outcomes Measures
The primary endpoint = overall response rate
(ORR = partial response [PR] + very good
PR + complete response [CR] + stringent CR).
Secondary endpoints = included duration of
response, progression-free survival (PFS),
overall survival, and clinical benefit rate
(minimal response + ORR).

35. Safety assessments = were the monitoring of
adverse events, physical examinations,
electrocardiogram monitoring, clinical
laboratory measurements, vital sign
measurements, and ECOG performance
status. Severity of adverse events was
assessed with the National Cancer Institute
Common Terminology Criteria for Adverse
Events (version 4.03).

36. Statistical analysis
Response assessments were done by an
independent review committee using the
International Myeloma Working Group
response criteria.
 ORRs were reported with two-sided 95%
exact CI.
All patients who received at least one dose of
daratumumab were used for efficacy and
safety analyses.

37. RESULTS
• 124 patients received at least one dose of
daratumumab
(18 received 8 mg/kg and 106 received 16 mg/kg).
• At the first interim analysis, the daratumumab
8 mg/kg group did not meet the criteria for expansion
because of an ORR of 11·1% (95% CI 1·4–34·7).
• At the second interim analysis, after an additional 25
patients were treated in the 16 mg/kg group, the
cumulative ORR justified expansion of the study into
part 2 and an additional 65 patients were enrolled.

38.  Concurrent pharmacokinetic analyses of the 8 mg/kg
dose in the first-in-human study indicated that drug
concentrations were probably less than the trough
threshold for target saturation.
 The results of these analyses also suggested that,
although 24 mg/kg daratumumab would have been
well tolerated, the gain in clinical benefit would have
been small with this dose compared with 16 mg/kg.

39. Patients’ demographic and baseline disease characteristics

40. Patients’ demographic and baseline disease characteristics

42. Swim-lane plot of
responders in the
daratumumab 16 mg/kg
group.

43. OVERALL RESPONSE RATE (ORR)
in patient subgroups in the daratumumab 16 mg/kg group

45. • The median duration of follow-up of patients was 9·3
months
• Median duration of response was 7·4 months
• Median PFS was 3·7 months
• The 12-month overall survival was 64·8%
• Median overall survival was not reached in responders
and was 13·7 months in non-responders .
• 29 (94%) of 31 responders treated with daratumumab
16 mg/kg were still alive, compared with 45 (60%) of
75 non-responders.
• A subsequent clinical cutoff for a safety update to meet
regulatory requirements was June 30, 2015. With this
update, the median overall survival was 17·5 months
(13·7–NE).

46. PFS FIG. 4AProgression Free
Survival
in the daratumumab
16 mg/kg group

47. Overall Survival in the
daratumumab
16 mg/kg group

48. SAFETY PROFILE

49. • Daratumumab was well tolerated, and no patients
discontinued because of drug-related adverse events,
infusion-related reactions, or death.
• The safety profile in the 8 mg/kg group was similar to
that in the 16 mg/kg group.
• Grade 3 or higher anaemia and thrombocytopenia
occurred more frequently in non-responders than in
responders . Grade 3 or higher neutropenia rates were
similar in non-responders and responders.

50. • Few patients required additional supportive care: 40
(38%) of 106 received red blood cell transfusions, 14
(13%) had platelet transfusions, and eight (8%)
needed granulocyte colony-stimulating factor.
• The most common infusion-related reactions
included nasal congestion [12%] f/b throat irritation
[7%].
• No patient discontinued daratumumab because of an
infusion-related reaction. No immunogenicity was
reported.

51. • WITH TIME….90 (85%) of 106 patients
SUBSEQUENTLY discontinued daratumumab 16
mg/kg: 82 (77%) because of progressive disease, five
(5%) because of treatment-unrelated adverse events,
and three (3%) as a result of consent withdrawal
because of symptoms related to disease progression.
• Five (5%) patients discontinued treatment -two with
general physical health deterioration and one each
with H1N1 influenza, hypercalcaemia, and spinal
cord compression).

52. • 31 (29%) patients died after treatment with
daratumumab 16 mg/kg: 29 (27%) because of
progressive disease and two (2%) because of adverse
events (cardiorespiratory failure secondary to H1N1
influenza complications, and general health
deterioration secondary to complications of
aspiration pneumonia).
• 29 (94%) of 31 responders treated with
daratumumab 16 mg/kg were still alive, compared
with 45 (60%) of 75 non-responders.

53. DISCUSSION
• Daratumumab monotherapy showed substantial clinical
activity, with an ORR of 29%, and was well tolerated in
patients with multiple myeloma who had been heavily
treated; most patients were double refractory to bortezomib
and lenalidomide, and many were refractory to pomalidomide
or carfilzomib.
• Resistance to any previous therapy had no effect on the
activity of daratumumab, lending support to a novel
mechanism of action, but these findings need to be confirmed
in larger studies.

54. • Similar response rates were also noted in patients with
moderate renal impairment, older than 75 years of age, and
with extramedullary disease or high-risk baseline cytogenetic
characteristics.
• Although this study did not have a control arm, patients with
the degree of treatment refractoriness in our study
historically have poor outcomes.
• The results of our study corroborate the previously reported
efficacy of daratumumab 16 mg/kg monotherapy in relapsed
or refractory patients with multiple myeloma.
Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with
daratumumab monotherapy in multiple myeloma. N Engl J Med 2015; 373: 1207–19.

55. • Elotuzumab, a monoclonal antibody, that targets
SLAMF7, lacks single-agent activity, increased
median PFS by 4·5 months compared with the
control arm in combination with lenalidomide and
dexamethasone in a population of patients who were
less heavily pretreated than those in the this study.
Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1,
multicenter, open-label, dose escalation study of elotuzumab in patients with advanced
multiple myeloma. Blood 2012; 120: 552–59

56. • Deep responses of very good PR or better, particularly
stringent CR, are associated with improved long-term
outcomes in patients with newly diagnosed multiple
myeloma.
Kapoor P, Kumar SK, Dispenzieri A, et al. Importance of achieving stringent complete
response after autologous stem-cell transplantation in multiple myeloma.
J Clin Oncol 2013; 31: 4529–35.
• Whether the same trend occurs in patients with relapsed and
refractory multiple myeloma remains to be seen, although
many patients treated in this study had responses to
daratumumab that improved over time and might contribute
to prolonged overall survival.

57. • These high-quality responses (9% very good PR, 3% stringent
CR) are notable in treatment-refractory patients with multiple
myeloma.
• The rate of high-quality responses with single-agent
daratumumab were higher than those with pomalidomide
monotherapy in the mm-002 clinical trial (2% of patients with
a very good PR). Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in
combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a
randomized phase 2 study. Blood 2014; 123: 1826–32.
• In the PX-171-003-A1 studyof carfilzomib monotherapy in 266
patients, responses of very good PR or better were noted in
6% of patients. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent
carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.
Blood 2012; 120: 2817–25.

58. • When considering daratumumab monotherapy for treatment of refractory
multiple myeloma, it should be placed in the context of other
combination regimens that are in use in these patients.
• In the POMALIDOMIDE alone versus pomalidomide plus low-dose
dexamethasone treatment groups of the mm-002 phase 2 study, 61% and
62% of 108 and 113 patients, respectively, were refractory to both
bortezomib and lenalidomide, and in these double-refractory patients the
ORR was 21% and 31%, median PFS was 2·0 and 3·8 months, median
duration of response was 11·4 and 6·5 months, and median overall
survival was 12·5 and 13·4 months, respectively.
• In the PX-171-003-A1 study, in those treated with CARFILZOMIB
monotherapy who were refractory to both bortezomib and lenalidomide,
the ORR was 15%, median PFS was 3.6 months, median duration of
response was 7·8 months, and median overall survival was 11·9 months.
• Thus, the ORR of 29%, median PFS of 3·7 months, median duration of
response of 7·4 months , and median overall survival of more than 16
months in this study of DARATUMUMAB monotherapy compare
favourably with these agents, particularly because most of the patients
were refractory to both proteasome inhibitors and immunomodulatory
drugs (95%), and many were refractory to pomalidomide (63%) or
carfilzomib (48%).

59. • Daratumumab has a favourable safety profile
compared with other available agents, and results in
clinically manageable side-effects. No patient treated
with 16 mg/kg discontinued daratumumab
treatment because of a treatment-related adverse
event.
• This result compares favourably with the substantial
risk of neutropenia, febrile neutropenia, and
infections with pomalidomide and dexamethasone
reported in other studies.

60. • Additionally, non-haematological toxicities, such as
cardiopulmonary and renal side-effects, are an
important consideration with carfilzomib,
particularly in patients with advanced disease.
• The overall favourable toxicity profile of
daratumumab makes it an attractive drug for use in
combination regimens, and it has shown early
promising activity in combination with lenalidomide
and dexamethasone.

61. CONCLUSION
• Based on deep and durable response and a
favourable safety profile, daratumumab 16
mg/kg seems to be an effective option for
patients with relapsed and refractory multiple
myeloma for whom available treatments have
been exhausted.

62. Darzalex (Daratumumab)
• Approved By FDA ; has world wide commercialisation rights.
• Originally developed by Genmab pharmaceuticals; but now
being jointly developed by Genmab and Johnson & Johnson
biotech.
• Darzalex is an infused therapy, and it will be available in vials
that come in two sizes: A smaller vial that contains 100 mg of
the drug, and a larger vial that contains 400 mg.
• The recommended dose of the drug is based on a patient’s
weight expressed in kilograms: 16 mg per kilogram. Infusions
should be given once a week for the first 8 weeks of
treatment, once every two weeks during weeks 9 through 24,
and once every four weeks thereafter.
• the wholesale price per vial of Darzalex will be $450 for the
100 mg vial and $1800 for the 400 mg vial.

63. T
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UTHE END