MULTIPLE MYELOMA

Case PresentationDR MANAL BESSA

MD HEMATOLOGY, ALEXANDRIA UNIVERSITY

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 .

• 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.

MRI LUMBAR VERTEBREA

CT PELVIS

BONE SCAN

• 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.

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.

• 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.

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).

• 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.

outline

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

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.

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

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 2002Avet-Loiseau H, et al.Blood 2007

Multi-step pathogenesis of MM

Antonio Palumbo, M.D et al. N engl j 2011

Plasma cells and BM micro-enviroment in MM

Antonio Palumbo, M.D et al. N engl j 2011

Multiple MyelomaClinical Presentation,

Clinical manifestations are related to malignant behaviour of plasma cells and abnormalities produced by M protein

• Plasma cell proliferation:multiple osteolytic bone lesionshypercalcemiabone marrow suppression ( pancytopenia )

• Monoclonal proteindecreased level of normal immunoglobulinshyperviscosity

Multiple MyelomaClinical 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.

Multiple MyelomaDiagnosis

All 3 criteria must be met:1. Presence of a serum or urinary monoclonal

protein2. Presence of clonal plasma cells in the bone

marrow or a plasmacytoma3. Presence of end organ damage related to the

plasma cell dyscrasia, such as:– Increased calcium concentration– Lytic bone lesions– Anemia– Renal failure

Detection Of Clonal Plasma Cells

Detection Of Monoclonal protein

Serum free light chain assay

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

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

Multiple MyelomaStaging System

International Staging System ISS

Griepp, P, R et al. J Clin Onco, 23;3412-3420, 2005

Cytogenetic Abnormalities

Chromsome 1 abnormaities

Multiple Myeloma Management

Treatment History

1958 1962 1983-86 1996 20031999 2006 2012

Melphalan/prednisone

HD dexamethasoneVAD

HD melphalanAutologous BM

transplants

High-dose therapy with autologous stem cell

support

LenalidomideThalidomide

Bortezomib

Carfilzomib

Pomalidomide

Elotuzumab

Daratumumab

Dex VAD Thal+Dex CTD VD PAD Rd VTD RVD CRd0

102030405060708090

100

Patie

nts

with

≥ V

GPR

)%(

S Kumar et al. Cancer Treatment Reviews 2010; Korde et al. ASH 2013.

Sarcolysine

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.

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

Multiple MyelomaTreatment 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

Clearly not transplantation candidate based on age, performance

score, and comorbidity

MPT, MPV, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction x 4 cycles

Stem cell harvest

Initial Approach to Treatment of MM

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

• Before novel therapy era…

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

)%(

00

High dose

Conventional dose

Mos20 40 60 80

25

50

75

100

Surv

ival

)%(

00

Intensive therapy

Standard therapy

Mos

P = .03 by Wilcoxon testP = .04 by log-rank test

Transplantation vs Conventional Chemotherapy

In the 2 largest studies, autologous SCT improvement in OS compared with non-transplant cohorts.

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. V.3.2010 .

In the era of novel therapy……

• 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.

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

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.

• 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.

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

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.

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

• 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).

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.

Thalidomide maintenance after Auto-BMT or conventional chemotherapy

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.

N Engl J Med 2012

ConclusionsLenalidomide maintenance therapy, initiated at day 100 after hematopoietic stemcelltransplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overallsurvival among patients with myeloma.

CONCLUSIONSMaintenance, as compared with no maintenance, significantly prolongedprogression-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).

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 maintenance1.3 mg/m2/2 weeks for 2 yrs

Bortezomib 1.3 mg/m2 IV

Doxorubicin 9 mg/m2

Dexameth 40 mg

Randomization

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%)

MaintenanceBort/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

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 .

MaintenanceBort/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

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.

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, 2011Martinelli G, et al. J Clin Oncol 18:2273-2281, 2000

Galimberti S, et al: Leuk Res 29:961-966, 2005

• 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

• 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, 2000Paiva B, et al. Blood 112:4017-4023, 2008Faham M, et al. Blood 120:5173-5180, 2012Moreau P. Blood,118(23):5984-5985.2011

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????.

Number of studies published in PUBMED per MRD technique showing prognostic value forprogression-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.

What is the clinical significance of MRDmonitoring 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.

• 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.

• 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;

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. 2011Paiva B, et al.J Clin Oncol. 2011

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.

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;