welcome

Presenter

Dr. Md. Aminur Rahman

Phase-B Resident

Department of Haematology

BSMMU

Multiple myeloma current treatment algorithms

Introduction

The International Myeloma Working Group (IMWG) diagnostic criteria for MM

10%or more clonal plasma cells in the bone marrow (and/or a biopsy proven plasmacytoma) plus any one or more myeloma defining events (MDE):

• end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions).
• clonal plasma cells ≥60%
• serum involved to uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC level is ≥100 mg/L)
• more than 1 focal lesion (5 mm or more in size) on magnetic resonance imaging (MRI)

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Classification and risk stratification

Four major subtypes of MM

Account for more than 80% of patients.

• Trisomic MM
• t(11;14) MM
• t(4;14) MM and
• MM with translocations of t(14;16) or t(14;20).

Secondary cytogenetic abnormalities

Can occur in any of the primary cytogenetic types of myeloma

Modify disease course, response to therapy, and prognosis

• deletion 17p
• gain 1q
• deletion 1p
• deletion 13q
• monosomy 13

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• High-risk MM is defined by the presence of t(4;14), t(14;16), t(14;20), deletion 17p, gain 1q, or p53 mutation.
• Double-hit MM refers to the presence of any two or more high-risk abnormalities.
• Triple-hit MM refers to the presence of three or more high-risk abnormalities.

Disease assessment

• Bone marrow study
• Fluorescent in situ hybridization
• Whole-body low-dose CT or
• PET–CT studies are preferred
• MRI scans are indicated in clinical SMM to rule out focal bone lesion.
• who are in CR, MRD assessment by next-generation flow cytometry or next-generation sequencing is recommended.

Treatment options

• Alkylating agents (melphalan, cyclophosphamide)
• Corticosteroids (dexamethasone, prednisone)
• Immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide)
• Proteasome inhibitors (bortezomib, carfilzomib, ixazomib).
• Monoclonal antibodies (Daratumumab and isatuximab)

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Other active approved agents

• Elotuzumab (Mab targeting the SLAMF7 antigen)
• Panobinostat (histone deacetylase inhibitor)
• Selinexor ,an inhibitor of exportin-1 (XPO1)
• Anthracyclines (doxorubicin and liposomal doxorubicin).

doxorubicin is incorporated into some multi-agent combination regimens for aggressive or refractory MM.

Treatment of newly diagnosed myeloma

• Two main factors : eligibility for autologous stem cell transplantation (ASCT) and risk stratification.
• Eligibility for ASCT is affected by age, performance status, and comorbidities.

Initial therapy in patients eligible for transplantation

• 3–4 cycles of induction therapy followed by stem cell harvest.
• After stem cell harvest, most patients should proceed to ASCT followed by maintenance.
• Standard-risk MM, ASCT can be delayed until relapse.
• Who deferred ASCT until relapse should resume induction few more cycles followed by maintenance.

Preferred initial therapy for patients who are candidates for ASCT

• Bortezomib, lenalidomide, dexamethasone (VRd).
• Well-tolerated regimen
• High overall and complete response (CR) rates
• In a Southwest Oncology Group (SWOG) randomized trial, VRd led to superior PFS and OS compared with RD.
• Intergroupe Francophone du Myelome found that the 4-year OS rate with VRd was >80% with or without early ASCT.

Daratumumab, lenalidomide, and dexamethasone (DRd).

• An important alternative to VRd in newly diagnosed MM is DRd.
• DRd has shown significant efficacy in a randomized trial conducted in transplant-ineligible patients, with improved PFS compared with Rd.
• VRd is preferred over DRd for most patients.
• DRd is a suitable alternative for patients with preexisting neuropathy or for patients who have intolerance to VRd.

High-risk patients, especially those with double-hit MM or triple-hit MM

• Addition of daratumumab to the standard VRd regimen (Dara-VRd) is recommended.
• In a randomized phase II trial, Dara-VRd has shown better and deeper responses compared to VRd.
• Dara-VTd is superior than VTd

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Carfilzomib, lenalidomide, dexamethasone (KRd)

• Do not recommend (KRd) as initial therapy
• No significant benefit with KRd over VRd in newly diagnosed patients with standard-risk MM.
• KRd is more expensive
• Associated with higher risk of serious cardiac, renal, and pulmonary toxicity than VRd.

�special situations

• Bortzomib, cyclophosphamide, dexamethasone (VCd) is our preferred regimen in acute renal failure.
• VTd is used instead of VRd in some cases.
• Bortezomib/dexamethasone/ thalidomide/cisplatin/doxorubicin/cyclophosphamide/ etoposide (VDT-PACE) in

primary plasma-cell leukemia

significant extramedullary disease

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Initial therapy in patients ineligible for transplantation

• The two main options are VRd and DRd.
• Melphalan based regimens are no longer recommended.
• VRd 8–12 cycles, followed by maintenance therapy.
• In frail,elderly patients, lower dose of lenalidomide and dexamethasone.
• If VRd is not possible due to inability to travel for parenteral administration, ixazomib can be considered in place of bortezomib.

• DRd is approved for patients with newly diagnosed MM in the United States.
• MRD negative rates with DRd were also superior.
• DRd requires treatment with all three drugs until disease progression.
• Expensive and cumbersome regimen in the long term.

Dosage and supportive care considerations

• Significant risk of peripheral neuropathy can be minimized by using bortezomib in a once-weekly and SC administration.
• Dexamethasone should be used once-weekly.
• who have received prolonged lenalidomide therapy, plerixafor may be needed for adequate stem cell mobilization.
• DVT and PE prophylaxis.
• Aspirin is adequate for most patients
• Higher risk of thrombosis should receive LMWH , warfarin, or direct thrombin inhibitor.

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Prophylaxis

• All patients receiving proteasome inhibitors need herpes zoster prophylaxis.
• Prophylaxis against pneumocystis jiroveci for all patients on dexamethasone.
• Levofloxacin daily for the first two cycles in all patients with newly diagnosed MM.

Autologous stem cell transplantation (ASCT)

• ASCT is not curative in MM
• Improves median OS by ~12 months.
• Treatment-related mortality rate is 1–2%.
• The preferred conditioning regimen for ASCT is melphalan 200 mg/m2.
• Early ASCT is preferred, but in some patients with standard-risk MM, ASCT can be delayed until first relapse.
• patient and physician preference plays an important role in deciding the timing of ASCT.

Tandem transplantation

• Tandem (double) ASCT refers to a second planned ASCT after recovery from the first transplantation.
• The role of tandem ASCT in myeloma is limited.
• Consider tandem ASCT only in selected young patients with del 17p.

Allogeneic transplantation

• Remains investigational in MM.
• Restricted primarily to clinical trials, and to young patients less than 60 years
• High risk MM in 1^st relapse
• high treatment-related mortality rate.

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Consolidation therapy

• No benefit with administering consolidation therapy post ASCT.
• Additional cycles of VRd chemotherapy or other forms of consolidation is not recommended.
• Prefer to move straight to maintenance therapy in the absence of significant residual disease.

Maintenance therapy with Lenalidomide �

• Improve PFS and OS following ASCT
• After VRd who have not undergone ASCT.
• Two- to threefold increase in the risk of second cancers, including therapy-related myelodysplastic syndrome with lenalidomide.

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In high-risk patients

• Bortezomib-based maintenance is preferable.
• Administered every other week
• As post transplant maintenance
• Better OS than thalidomide maintenance.
• Can be given alone given every other week, or as part of low-intensity VRd
• If unable to access or tolerate bortezomib, ixazomib is a reasonable alternative.

Duration of maintenance

• Data on optimal duration of maintenance are lacking.
• Indefinite versus definite period (2 yr).
• Long-term indefinite maintenance is associated with cost, toxicity, and inconvenience.
• Duration of maintenance can be modified based on MRD results.
• Continue maintenance until progression in absence of toxicity.

Treatment of relapsed MM

• Almost all patients relapse.
• MM is characterized by multiple remissions and relapses.
• First relapse occurs after ~3–4 years following initial diagnosis.
• subsequent remission is of shorter duration.
• Choice of treatment at each relapse is affected by many factors.

Timing of the relapse,

response to prior therapy

aggressiveness of the relapse

performance status.

Treatment of first relapse

• If eligible for ASCT : consider ASCT
• If relapse occurs more than 6 months after stopping all therapy, the initial treatment regimen can be reinstituted.
• until disease progression.

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Additional options

• Adding M antibody to one of the triplets to create a quadruplet regimen.
• Panobinostat to a proteasome-inhibitor containing regimen.
• Bendamustine or anthracycline-containing regimens.
• selinexor-containing regimen such as selinexor, bortezomib, dexamethasone.

• Venetoclax is not approved for use in MM
• Appears to have single-agent activity in patients with t(11;14) subtype.
• Allogeneic transplantation can be considered in selected young patients with relapsed or refractory MM in whom a suitable donor cells are available.

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