This document presents the case of a 59-year-old woman who presented with low back pain. Imaging showed osteolytic bone lesions and a bone marrow biopsy revealed 20% plasma cell infiltration, confirming a diagnosis of multiple myeloma. She was started on CyBorD chemotherapy and achieved a complete response. She then underwent autologous stem cell transplantation with conditioning using melphalan, followed by thalidomide maintenance therapy. Currently, she is doing well with no evidence of multiple myeloma on follow up testing and is tolerating the thalidomide maintenance treatment.

1. MULTIPLE MYELOMA
Case Presentation
DR MANAL BESSA
MD HEMATOLOGY,
ALEXANDRIA UNIVERSITY

2. Case:
• 59y old lady , was in good health till August 2014 when she
started to have low back pain that was severe ,more in the right
side and not relieved with analgesic.
• She did not report fever, changes in body weight, paraesthia or
weakness of LL, or bladder or bowel dysfunction
• Revision of systems was unremarkable.
• No past history of chronic disease or surgery..
• Unknown food or drug allergy.
• Family history irrelevant .

3. • She consulted orthopedic doctor. X ray dorsal and lumbosacral
study showed degenerative changes of lumbar and dorsal
vertebrae.
• With persistent pain , she did CT of pelvic bone that showed
osteolytic lesion involving the right aspect of SV2, SV1 with soft
tissue component encroaching upon the sacral canal
• Whole body bone scan with Tc 99 showed increase radioactivity
at 6th & 10th right rib, DV5, DV7, LV3 and right sacroiliac region
suggesting bone mets. MRI denied any cord infiltration or
compression.
• She was referred to hematologist for further management.

4. MRI LUMBAR
VERTEBREA
CT PELVIS
BONE SCAN

5. • On presentation:
– Average weight, conscious, oriented
– Moderate pain score 7/10
– Vital sign stable
– No pallor , no jaundice
– Chest and heart exam with no abnormal finding
– Abdomen was soft, lax with no detected organomegaly.
– Neurological assessment showed intact motor and
sensory system , intact reflex of both upper and lower
limb with tenderness upon palpation of lumbar and
sacral vertebrae.

6. Lab:
• CBC showed mild anemia, Hb 11 gm normochromic , normocytic, with
normal platelet and WBC count.
• Renal and liver function test are WNL
• Serum calcium was 9.9 mg/dL.
• High ESR (124 mm/hr) ,High CRP (4.8 mg/L)
• Normal serum albumin 4 gm/dL
• High LDH 561 U/L(up to 460) , β2 microglobulin 3.42mg/L(up to 3)
• PEP was positive for monoclonal band , Bence Jones protein was
undetected in urine.
• Serum IG assay showed high Ig G serum level 2.5gm/dL (N up to
1.6gm/dL)
• Serum immunofixation revealed monoclonal protein of 5.4 gm/dL with
serum free light chain showed Kappa restriction.

7. • Bone marrow biopsy showed hypercellular marrow
with infiltration of 20% plasma cells.
• The BM immunophenotyping revealed that the
plasma cells are positive for CD38, CD138, and
CD56, negative for CD19.
• BM cytogenetic showed normal female Karyotype
46, XX.

8. Management :
• The diagnosis was confirmed as symptomatic MM, Duri
Salmon IIIA, ISS II.
• The disease prognosis and plan of treatment was
discussed with the patient.
• She was started on Cy/Bor/D protocol with monthly
Zometa for bone disease.
• She was tolerating treatment with no reported toxicity.
• She completed 4 cycles last was on Dec 2014 and
evaluation showed achievement of CR (bone marrow
biopsy showed 2% plasma cells, negative PEP, and
normalization of κ/λ ratio).

9. • Subsequently, she underwent auto-BMT with
conditioning MEL 140 followed by thalidomide
maintenance dose of 50 mg/day
• Currently, she is doing well , her follow up lab
is acceptable with no evidence of MM and she
is tolerating thalidomide.

10. outline
• MM overview
• Management
• Role of consolidation
• Role of maintenance therapy
• Minimal residual disease in MM

11. MULTIPLE MYELOMA
OVERVIEW
• Multiple myeloma is a neoplastic plasma-cell
disorder characterized by clonal proliferation of
malignant plasma cells in the BM
microenvironment, monoclonal protein in the blood
or urine, and associated organ dysfunction.

12. Incidence
• 1% of cancers and 13% of hematologic cancers.
• In Western countries, the annual incidence is 5.6 cases per
100,000 persons.
• The median age at diagnosis is approximately 70 years;
• 37% of patients are younger than 65 years, 26% are
between the ages of 65 and 74 years, and 37% are 75 years
of age or older.
Seigel RL.et al. Cancer J Clin 2015

13. Pathogenesis of Multiple Myeloma.
• Myeloma arises from an asymptomatic premalignant proliferation
of monoclonal plasma cells that are derived from post–germinal-
center B cells.
• Multistep genetic and micro-environmental changes lead to the
transformation of these cells into a malignant neoplasm.
• Myeloma is thought to evolve most commonly from a monoclonal
gammopathy of undetermined clinical significance (MGUS) that
progresses to smoldering myeloma and, finally, to symptomatic
myeloma.
Kuehl WM, et al. Nat Rev Cancer 2002
Avet-Loiseau H, et al.Blood 2007

14. Multi-step pathogenesis of MM

15. Plasma cells and BM micro-enviroment
in MM
Antonio Palumbo, M.D et al. N engl j 2011

16. Multiple Myeloma
Clinical Presentation,
Clinical manifestations are related to malignant
behaviour of plasma cells and abnormalities produced
by M protein
• Plasma cell proliferation:
multiple osteolytic bone lesions
hypercalcemia
bone marrow suppression ( pancytopenia )
• Monoclonal protein
decreased level of normal immunoglobulins
hyperviscosity

17. Multiple Myeloma
Clinical Presentation,
• Anemia, in about 73% of patients at diagnosis.
• Bony lesions develop in almost 58% of patients
with newly diagnosed disease;
• Renal impairment occurs in 20 to 40% of
patients with newly diagnosed disease,
• Infection is increased with active disease but
decreases with response to therapy.
• Fatigue/generalized weakness - 32 percent
• Hypercalcemia
Kyle RA, et al. Mayo Clin Proc, 2003.

19. Multiple Myeloma
Diagnosis
All 3 criteria must be met:
1.Presence of a serum or urinary monoclonal
protein
2.Presence of clonal plasma cells in the bone
marrow or a plasmacytoma
3.Presence of end organ damage related to the
plasma cell dyscrasia, such as:
– Increased calcium concentration
– Lytic bone lesions
– Anemia
– Renal failure

20. Detection Of Clonal Plasma Cells

21. Detection Of Monoclonal protein
Serum free light chain assay

22. Differential Diagnosis of MM
• Monoclonal gammopathy of undetermined
significance (MGUS)
• Smoldering multiple myeloma (SMM)
• Waldenstrom macroglobulinemia
• Solitary plasmacytoma
• Primary amyloidosis (AL)
• POEMS syndrome
• Metastatic carcinoma

23. Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

24. Multiple Myeloma
Staging System

25. International Staging System ISS
Griepp, P, R et al. J Clin Onco, 23;3412-3420, 2005

26. Cytogenetic Abnormalities
Chromsome 1 abnormaities

27. Multiple Myeloma
Management

28. Treatment History
1958 1962 1983-86 1996 20031999 2006 2012
Melphalan/
prednisone
HD dexamethasone
VAD
HD melphalan
Autologous BM
transplants
High-dose therapy with
autologous stem cell
support
Lenalidomide
Thalidomide
Bortezomib
Carfilzomib
Pomalidomide
Elotuzumab
Daratumumab
0
20
40
60
80
100
Dex VAD Thal+Dex CTD VD PAD Rd VTD RVD CRd
Patientswith≥VGPR(%)
S Kumar et al. Cancer Treatment Reviews 2010; Korde et al. ASH 2013.
Sarcolysine

29. MM: INITIAL THERAPY
• The paradigm of management of MM has
been changed recently with the availability of
novel drugs.
• The aim of treatment also is evolving from
disease control without cure to have complete
remission with possible molecular CR.

30. Response Criteria
• Assessing the response is the key determent
of myeloma treatment.
• IMWG response criteria is developed from
EBMT/IBMTR/ABMTR to help uniform
reporting.
• Update in response criteria definitions is
adding immunophenotypic CR and molecular
CR

32. Multiple Myeloma
Treatment Decisions :
• Indications for treatment : presence of any of CRAB ( bone
lesions can be diffuse osteopenia alone)
• Risk Stratification : High-risk factors at diagnosis
• Cytogenetics: del(13), t(4;14), t(14;16), del(17p), del(1p),
and 1q
• Renal failure, elevated LDH, plasma cell leukemia, GEP 70,
EMC-92
• Comorbidities limiting therapy
• International Scoring System stage II or III
Bergsagel PL, et al. Blood2013;
Munshi NC, et al. Blood. 2011

33. Clearly not transplantation
candidate based on age, performance
score, and comorbidity
MPT, MPV, Len/dex
or clinical trial*
Potential transplantation
candidate
Nonalkylator-based
induction x 4 cycles
Stem cell harvest
Initial Approach to Treatment of MM

35. • Is there any role for stem cell transplantation
in the novel-agent era?

36. • Before novel therapy era…

37. 54
42
Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883.
15 30 45 60
25
50
75
100
OS(%)
0
0
High dose
Conventional dose
Mos
20 40 60 80
25
50
75
100
Survival(%)
0
0
Intensive therapy
Standard therapy
Mos
P = .03 by Wilcoxon test
P = .04 by log-rank test
Transplantation vs Conventional
Chemotherapy
In the 2 largest studies, autologous SCT improvement in OS compared with
non-transplant cohorts.

38.  Mel 200 mg/m2 standard conditioning regimen
 Sufficient performance score, and adequate liver, pulmonary,
cardiac function needed
 Higher PR and CR rates than conventional chemotherapy
 Higher OS and EFS than conventional Rx
 Advanced age and impaired renal function are, by themselves,
not contraindications
Attal M, et al. N Engl J Med. 1996;335:91-97. APractice Guidelines. Myeloma.

39. In the era of novel therapy……

40. • Randomized trials to address the value of ASCT
are ongoing.
• Transplant trials that use novel agents clearly
showed that responses are deepened so that
the fraction of patients with CRs and VGPRs
increase between the induction phase and the
post-ASCT consolidation phase.
• SCT is capable of achieving residual disease
negativity, a predictor of PFS. The use of ASCT
for MM is increasing, and survival is increasing
proportionately.

41. Therefore, until trials definitively demonstrate
that the platform of ASCT does not improve
survival, it remains the standard of care for
eligible patients.

42. Consolidation therapy after ASCT
• Consolidation therapy means a short-term
treatment given to upgrade the quality of the
responses obtained in the previous treatment
phases.
• Consolidation therapy should consist of highly
efficient combinations of agents with minimal
toxicity, applied for a limited period of time.

43. • Initial results of phase 2 and phase 3 trials
investigating novel agent–based consolidation
therapy show that this strategy may result in
the achievement of deep molecular–defined
or flow cytometry–defined CRs.
• Yet the impact of consolidation on OS, as well
as the optimal consolidation regimen is not
determined.

44. Phase 2 and 3 trials incorporating novel agent–based consolidation following ASCT
Ladetto M, et al. J Clin Oncol. 2010,Cavo M, et al. Blood. 2012.,Attal M, et al.N Engl J Med. 2012,
Mellqvist UH,et al. Blood. 2013; Leleu X, et al; Leukemia2013,Roussel M, et al. J Clin Oncol. 2014

45. Maintenance treatment in MM
• Maintaining the response of first-line therapy
is an important objective in MM.
• Maintenance therapy is applied for a
prolonged period of time with the goal of
preventing tumor progression prolonging
response duration, PFS, and, ultimately, OS,
while keeping toxicity minimal.

46. Requisite for maintenance in MM
• Patient must have:
– Disease that is in remission (undetectable or at a low
level)
– Recovered from all previous toxicities
• Maintenance agent must have:
– Minimal toxicity or at least not overlapping with the
toxicity of the induction regimen
– Convenient dosing
– Convenient route of administration

47. • The high efficacy of the novel agents,
observed in the front-line settings and
relapse has provided the rationale to also
test their capacity to maintain the benefits
of first-line therapy to prolong remission, and
importantly, to extend overall survival (OS).

48. Thalidomide in MM maintenance
• Thalidomide was the first novel agent examined in this
setting.
• Six randomized studies have been published, with all of
them showing a significant benefit for thalidomide in terms
of response and PFS, while OS was improved in 3 of them.
• The occurrence of peripheral neuropathy, which is
cumulative and was found to be the main cause of
treatment discontinuation, may hinder its use as long-term
maintenance therapy.
• There is a concern about possible emergence of tumor-
resistant clones in patients with prolonged exposure to
thalidomide and its lack of efficacy in patients with adverse
cytogenetic abnormalities.

49. Thalidomide maintenance after Auto-BMT or conventional chemotherapy

50. Lenalidomide maintenance in MM
• Lenalidomide is currently considered the best
candidate for use as maintenance therapy
• lenalidomide maintenance was considered
feasible and manageable, with <30% of patients
having to discontinue the drug because of AEs.
• However, in both studies an unexpected finding
was the occurrence of more secondary primary
malignancies in the lenalidomide group. The
pathophysiology of these secondary neoplasms
remains to be clarified.

51. N Engl J Med 2012

52. Conclusions
Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stemcell
transplantation, was associated with more toxicity and second cancers but a
significantly longer time to disease progression and significantly improved overall
survival among patients with myeloma.

54. CONCLUSIONS
Maintenance, as compared with no maintenance, significantly prolonged
progression-free survival. but 3-year overall survival was not significantly prolonged
(88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P = 0.14).

55. PAD + Bortezomib Maintenance vs VAD + Thalidomide
Maintenance: HOVON Trial
Sonneveld P, et al. ASH 2010. Abstract 40.
Efficacy Parameter PAD → bortezomib VAD → thalidomide P Value
3-yr PFS 48% 42% .005
3-yr OS 78% 71% .02
MM Stage II or III, Age 18–65
CAD + GCSF
3 x VAD
CAD + GCSF
3 x PAD
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
Thalidomide maintenance
50 mg/day for 2 yrs
Allogeneic
Tx
Bortezomib maintenance
1.3 mg/m2/2 weeks for 2 yrs
Bortezomib 1.3 mg/m2 IV
Doxorubicin 9 mg/m2
Dexameth 40 mg
Randomization

56. Bortezomib + Thalidomide vs Bortezomib + Prednisone as
Maintenance: GEM2005MAS65
Arm ORR CR Median PFS
VT maintenance 95% 46% 39 months
VP maintenance 97% 39% 32 months
Mateos MV, et al. Lancet Oncol. 2010;10:934-41.
No significant differences between VMP and VTP in ORR
(80% and 81%) and CR rate (20% and 27%)
Maintenance
Bort/Thal
(VT)
Bort/Pred
(VP)
Bort/Thal
(VT)
Bort/Pred
(VP)
Induction
(6 cycles)
Bort/Mel/Pred
(VMP)
Bort/Thal/Pred
(VTP)
vs
Series of 260 elderly untreated MM patients included in the GEM2005 Spanish trial

57. Bortezomib + Thalidomide Maintenance GIMEMA STUDY
Arm 3 y OS CR 3 Y PFS
VT maintenance 89% 38% 56%
No maintenance 87% 24% 41%
Mateos MV, et al. Lancet Oncol. 2010;10:934-41.
Maintenance
Bort/Thal
(VT)
No Maintenance
Induction
(9 cycles)
Bort/Mel/Pred/Thal
(VMPT)
Bort/Thal/Pred
(VMP)
vs
Series of 511 elderly untreated MM patients included in phase III trial

58. Conclusions About Maintenance Therapy
for Multiple Myeloma
• Maintenance therapy prolongs PFS.
• Low-dose oral agents preferable for maintenance therapy.
• Both bortezomib and lenalidomide are useful maintenance agents
and may need to be combined for patients with high-risk disease.
• Slight increase in incidence of secondary malignancy after
lenalidomide maintenance.
• Overall, everyone who meets prerequisites for maintenance therapy
should be considered candidates for treatment. The real question is
not if maintenance therapy should be given, but how long.

59. Minimal Residual disease in MM
• Along with improvements in therapeutic strategy, the definition of
CR has evolved over time.
• Studies 30 years ago, before the advent of BMT, defined CR as
greater than 75% reduction in myeloma paraprotein, achieved in
only a small fraction of patients.
• With HDT, significant cytoreduction was achieved, and the
definition of CR evolved to include not only disappearance of clonal
PC in BM, but also absence of paraprotein in urine and serum by
immunofixation, achieved in up to30%patients.
• Stringent CR, defined by IMWG includes these parameters along
with a normal kappa:lambda free light chain ratio
• Molecular CR (mCR), defined as absence of detectable disease by
PCR for Ig gene rearrangement, Immunophenotypic CR (I CR)
defined as absence of clonal PC using MPF
Munshi NC, et al. Blood 117:4696-4700, 2011
Martinelli G, et al. J Clin Oncol 18:2273-2281, 2000
Galimberti S, et al: Leuk Res 29:961-966, 2005

60. • However, all patients achieving CR, continue to
experience relapse suggests that clinically meaningful
MRD is not detectable by these parameters.
• Therefore, it was necessary to develop reproducible
sensitive assays:
– to monitor MRD
– to define its prognostic value in predicting for PFS and OS,
– to allow for informing consolidation and maintenance
strategies,
– to evaluate the comparative efficacy of novel therapies.
Nikhil C. Munshi, et al. JCO, 31, 2013

61. • These methods include:
1. Allele-specific oligonucleotide PCR (ASO-PCR)
with sensitivity 105
2. Immunophenotypic assays using multiparameter
flow cytometry (MPF) with 104 sensitivity.
3. A sequencing-based method developed to
quantify cells with specific molecular signatures.
4. MRI and PET/CT for the possibility of patchy BM
infiltration or extramedullary involvement with
an MRD-negative BM.
Ladetto M, et al. Biol BMT, 6:241- 253, 2000
Paiva B, et al. Blood 112:4017-4023, 2008
Faham M, et al. Blood 120:5173-5180, 2012
Moreau P. Blood,118(23):5984-5985.2011

62. A critical question????
• Does the ability to detect MRD by MPF or
ASO-PCR have clinical implications for PFS and
OS???
• May it inform therapy and allow us to tailor
therapeutic decisions????.

64. Number of studies published in PUBMED per MRD technique showing prognostic value for
progression-free survival (PFS) and overall survival (OS) specifically among patients in CR
after therapy.
Paiva B,et al. Blood. 2012. Martinez-LJ,et al. Blood. 2014. Bakkus MH, et al.Br J Haematol. 2004. Puig N, et
al. Leukemia. 2014. Corradini P, et al. Blood. 2003; Rawstron AC,et al. Blood. 2002. Paiva B, et al. Blood.
2008. Rawstron AC,et al JCO. 2013. Zamagni E,et al.Blood. 2011.

65. What is the clinical significance of MRD
monitoring in MM?
So far, no clinical trial has randomized MM
patients according to their MRD status and,
thereby, investigated the role of MRD for
individualized therapy. However, many studies
have shown the value of MRD diagnostics for
evaluation of the efficacy of specific treatment
stages and, therefore, potential treatment
decisions.
Bruno Paiva, et al blood 2015.

66. • Both the Spanish and the United Kingdom study groups
have shown that MRD kinetics before and after
HDT/ASCT allow the identification of chemosensitive
(MRD-negative cases at 2 time points), intermediate,
and chemoresistant patients (MRD-positive patients at
2 time points).
• For the latter, it could be hypothesized that
consolidation is needed to improve outcomes
• When such analysis is restricted to CR patients after
induction, those failing to eradicate MRD levels before
HDT/ASCT will show significantly superior PFS if MRD
negativity is achieved after HDT/ASCT,
Paiva B, et al. Blood. 2008;112(10): 4017-4023.
Rawstron AC,et al JCOl. 2013;31(20):2540-2547.

67. • Maintenance therapy represents another
illustrating example. In the Gruppo Italiano
Malattie EMatologiche dell’Adulto (GIMEMA)
reported PFS rates at median follow up of
100% vs 57% for patients in molecular-CR vs
MRD-positive cases, respectively.
Ladetto M,. J Clin Oncol. 2010;

68. Limitation
• Discordant results between MRD (by
immunophenotypic, molecular, and imaging
techniques) vs conventional response assessment
has questioned the sensitivity and specificity of
MRD monitoring over traditional paraprotein
measurement.
• False negative MRD because the patchy pattern
of BM infiltration lead to a degree of uncertainty
regarding MRD-negative results (ie, are clonal
PCs truly absent, or for non-representative BM
sampling?).
Zamagni E et al,Blood. 2011
Paiva B, et al.J Clin Oncol. 2011

69. Conclusion remark
• MRD clearance is achievable in the era of novel
and more effective treatment strategies and it is
predictive of superior outcomes.
• Persistence of MRD is always an adverse
prognostic feature, even among CR patients.
• Some of the limitations could be potentially
overcome by parallel usage of sensitive imaging
techniques.
• The importance of the 2 consecutive protein
response assessments before the institution of
any new therapy to confirm a response category.

70. Toward an optimal strategy of induction, HDT
plus ASCT,
consolidation, and maintenance
Roussel M, et al. J Clin Oncol. 2014; Usmani SZ, et al.Leukemia. 2013;