Treatment of Multiple Myeloma .pptx

Presentation on treatment of Multiple Myeloma .

1. Treatment of Multiple Myeloma Dr. Bikramjeet Singh Junior Resident

2. Monoclonal Gammopathy of Undetermined Significance No specific intervention is indicated. All patients with MGUS are taken for follow up in 6 months. If stable, then risk stratification is done:- Low risk: No MGUS follow up and usual medical care is given. Intermediate or high risk: Annual MGUS follow up with CBC, calcium, creatinine, serum protein electrophoresis, free light chain. If possible progression:- workup for lymphoplasmacytic malignancy is done No malignancy : annual followup Malignancy: managed accordingly.

3. Risk stratification of MGUS Low risk : serum M protein less than 1.5 g/dL, IgG subtype, normal FLC ratio ( 0.26-1.65 ). Low to intermediate risk: any 1 factor abnormal High to intermediate risk : any 2 factors abnormal High risk : all 3 factors abnormal.

4. Smoldering Multiple Myeloma ( SMM ) SMM is defined by the presence of serum monoclonal protein >3 g/dL and or Bone marrow plasma cells 10 to 60 % With no evidence of end organ damage ( i.e., CRAB criteria ) Criteria for high risk Smoldering Multiple Myeloma Mayo 2018 criteria ( 20-2-20 criteria ) Any 2-3 of the following: Serum FLC ratio ( involved/uninvolved) >20 Serum M protein >2 g/dL Bone marrow plasma cells >20%

5. Other High Risk Factors Progressive increase in M protein levels ( evolving type of SMM ) Bone marrow clonal plasma cells 50% - 60% T(4;14) or del 17p or 1q gain Increased circulating plasma cells MRI with diffuse abnormalities or with 1 focal lesion PET CT with focal lesion with increased uptake but without underlying osteolytic bone destruction.

6. Treatment of Smoldering Multiple Myeloma If any myeloma defining events? CRAB >60% clonal plasma cells FLC >100 MRI >1 focal lesion Then such cases are treated as Myeloma. If no myeloma defining events High risk SMM patients are put on Lenalidomide or Rd regime or taken for clinical trials. Low risk SMM patients are kept under observation or can be taken for clinical trials.

7. Symptomatic Multiple Myeloma Patients with symptomatic and/or progressive myeloma require therapeutic intervention. In general such therapy has two purposes: Systemic therapy to control myeloma; and Supportive care to control symptoms of the disease, its complications and adverse effects of therapy. Therapy can significantly prolong survival and improve the quality of life for myeloma patients. The therapy of myeloma includes initial induction regimen followed by consolidation and/or maintenance therapy and management of relapsed disease.

8. Treatment of Multiple Myeloma If newly diagnosed MM is not a transplant candidate: VRd regimen( Vcd regimen if acute renal failure) for 6 months followed by lenalidomide maintenance. OR DRd regimen If transplant candidate: VRd regimen is given for 3-4 cycles , followed by ASCT followed by maintenance ( lenalidomide for standard risk ; bortezomib plus lenalidomide for high risk ) OR Stem cell collection and cryopreservation followed by VRd for 4 cycles and then maintenance; reserving ASCT for relapse.

9. Eligibility for stem cell transplantation It is determined by age, performance status and co existing comorbidities. Patients with more than one of the following factors are not usually considered eligible for autologous stem cell transplantation in myeloma: Age >77 years Frank cirrhosis of liver or multiorgan amyloid involvement. ECOG PS 3 or 4 unless due to bone pain. NYHA functional status class III or IV ( EF <50%, PFT <50% ). These are guidelines and the decision on transplant eligibility should be made based on a risk-benefit assessment and the needs and wishes of the patient.

10. Maintenance Therapy Maintenance therapy is given following ASCT or after completion of initial therapy in patients treated without ASCT. Lenalidomide is the current standard of care for maintenance therapy following ASCT. One limitation with lenalidomide maintenance is that a clear survival improvement is not seen in high risk MM. Thus, bortezomib based maintenance may be preferable for high risk patients. More recent data support the combination of bortezomib plus lenalidomide for high risk patients. Although the benefit of maintenance is now established, data on optimal duration are lacking. An ECOG trial is comparing lenalidomide maintenance given until progression vs a limited duration of 2 years.

11. Treatment of Relapsed Multiple Myeloma Almost all patients with MM eventually relapse. The remission duration in relapsed MM decreases with each regimen. The choice of a treatment regimen at relapse is complicated and is affected by 4 major factors: Timing of the relapse Response to prior therapy Aggressiveness of the relapse Performance status TRAP factors.

12. Principles guiding the choice of therapy: To consider ASCT if patients are eligible and have not had an ASCT before. ASCT can also be considered in patients who have had good outcomes with prior ASCT and are still eligible for the procedure. Triplet regimens with atleast 2 new drugs are preferred when possible. Consider retreatment with regimens that have been effective in the past if the initial remission duration was longer than 6 months and the relapse is occurring off therapy. Finally, clinical trials are an important option at each relapse, if available.

13. First relapse If it is not refractory to lenalidomide ( i.e , relapse occurring while off all therapy or while on small doses of single agent lenalidomide or on bortezomib maintenance) DRd regimen is preferred KRd regimen in daratumumab refractory If it is lenalidomide refractory DVd , DKd or DPd regimens are preferred KPd in daratumumab refractory

14. Second or higher relapse Consider other first relapse options Daratumumab based: DRd , DVd , DPd Carfilzomib based: KRd , KPd Ird , Erd , VCd , Pd , Ipd . Additional options Belantamab mafodotin CAR-T cell therapy Quadruplets/multi-drug regimens Panobinostat-Bortezomib-Dex Bendamustine IV Melphalan .

15. Treatment of Plasma Cell Leukemia Plasma cell leukemia is a form of ultra high risk MM characterized by circulating plasma cells that can be detected on regular peripheral blood smear examination and comprise 5% or more of cells on DLC. It can occur with or without involvement of organs such as lungs and liver. It can present at initial diagnosis or may occur during progression of MM. The approach to diagnosis and treatment is similar to MM. Multiagent combination chemotherapy should be considered for these patients as initial therapy since rapid and reliable disease control is essential.

16. Supportive Care Bone Disease Lytic bone lesions, severe osteoporosis, pathological fractures remains a major cause of morbidity in MM. Bisphosphonates significantly decrease the number of skeletal events. Zoledronic acid has comparable efficacy to pamidronate and is preferred due to shorter infusion time. Monthly use of bisphosphonates should be limited to the first 1 to 2 years. Thereafter the frequency should be reduced to once every 3 to 4 months. The main complication of bisphosphonate use is avascular osteonecrosis of the jaw. Thus it is important to limit the duration of bisphosphonate therapy. An alternative approach for prevention of bone disease is the use of denosumab , a high affinity monoclonal antibody targeting RANKL.

17. Denosumab is several times more expensive than zoledronic acid and the drug is probably best reserved for use in patients who are unable to tolerate zoledronic acid or pamidronate or those having significant renal dysfunction. Local radiation should be limited to patients with disabling pain who have a well defined focal process that has not responded to analgesics and/or chemotherapy. Spinal cord compression should be treated with corticosteroids and radiation therapy. In selected patients, rapidly acting chemotherapy can be used in addition to or in place of radiation. In some instances, surgical decompression may be necessary.

18. Aemia Anemia is typically secondary to underlying disease or drug toxicity. Erythropoietin 40000 U sc weekly or darbopoietin 200mcg sc every 2 weeks are useful in patients with persistent symptomatic anemia. Blood transfusions are indicated in case patients do not obtain benefit from other measures. Infections Patients should receive pneumococcal and influenza vaccinations. Routine prophylactic antibiotics for approximately 3 months are recommended in patients starting treatment for MM. Acyclovir or valcyclovir should be administered routinely for patients receiving proteasome inhibitors, anti CD38 monoclonal antibodies or elotuzumab as prophylaxis against herpes zoster.

19. Hypercalcemia Severe hypercalcemia is a medical emergency and can be the presenting symptom in a small proportion of patients with MM. It can also occur during the course of the disease in the relapsed refractory setting. Treatment consists of aggressive hydration with isotonic saline, iv bisphosphonates. Prompt institution of treatment to control MM, including corticosteroids is also important. Occassionally patients will need iv calcitonin to control acute severe hypercalcemia. Renal Failure More than half of patients diagnosed with MM will experience renal dysfunction.

20. The most important cause of acute renal failure in MM is light chain cast nephropathy, also referred to as myeloma kidney. Patients with suspected or biopsy proven light chain cast nephropathy should be treated with rapidly acting chemotherapy such as VCd or VTd to reduce light chain production as quickly as possible. Daratumumab can also be added for prompt response. In addition plasma exchange or hemodyalisis using a specialized high cutoff dialysis filter that can removelight chains should be considered. Prevention of acute renal failure requires maintenance of a high urinary output of 3L/day and avoidance of NSAIDs in patients with high FLC levels.

21. Active Drugs in Myeloma Alkylating Agents Melphalan and cyclophosphamide have been used in the treatment of MM for decades, typically in combination with corticosteroids. They are directly cytotoxic to myeloma cells. Melphalan has fallen out of favour because of long term risk of leukemia and marrow toxicity. Cyclophosphamide has a more predictable dose response and fewer side effects than Melphalan . It is currently used in several treatment regimens for newly diagnosed and relapsed myeloma. Corticosteroids They are directly cytotoxic to myeloma cells.

22. High doses of dexamethasone administered in a pulsed manner can be used for a short duration 1-2 months in patients with aggressive relapse or in the setting of acute renal failure. In most patients and for long term therapy once weekly dosing is preferred. Immunomodulatory Agents Thalidomide was first approved by FDA for the treatment of MM in 2006. The main side effects of thalidomide are neuropathy, sedation, fatigue, rash, constipation and DVT. The use of thalidomide has declined with the arrival of lenalidomide and pomalidomide . Lenalidomide is more potent and has less nonhematologic toxicity than thalidomide.

23. All patients receiving thalidomide and lenalidomide need DVT prophylaxis with aspirin or lmw heparin. Pomalidomide was first approved by the FDA in 2013 for the treatment of relapsed refractory MM. Lenalidomide dose modification in renal failure Creatinine clearance 30 to 60 – 10mg every 24hr Creatinine clearance <30 ( not requiring dialysis) - 15mg every 48hr Creatinine clearance <30 (requiring dialysis) – 5mg once daily on dialysis days

24. Proteasome Inhibitors These drugs induce cell death by blocking degradation of apoptotic molecules that are normally catabolized via proteasome proteolysis. They inhibit nuclear factor kappa B activation by stopping the cleavage of its bound suppressor. Increased NFkB activity has been described in Myeloma cells and Pis seem to overcome chemotherapy resistance. Bortezomib was first approved by the FDA in 2005 for the treatment of patients with relapsed refractory MM. It is a specific inhibitor of the 26S proteasome complex responsible for protein catabolism in all eukaryotic cells. Cellular proteins destined for catabolism are first ubiquitylated , that are targets for enzymatic destruction by the proteasome complex. By blocking the proteasome, bortezomib causes major imbalances in

25. levels of various regulatory proteins affecting critical cellular processes such as cell cycling, signal transduction and transcriptional regulation leading to cell cycle arrest and apoptosis. The main side effects of bortezomib are gastrointestinal toxicity, neuropathy, and cytopenias . Bortezomib is administered subcutaneously in a once weekly schedule to minimize neurotoxicity. Ixazomib is an oral proteasome inhibitor that is active in both relapsed refractory setting and in newly diagnosed MM. It was FDA approved in 2015 and has an advantage of once weekly oral administration. Carfilzomib is a novel keto epoxide tetrapeptide proteasome inhibitor first approved by FDA in 2013 for the treatment of relapsed refractory MM in patients previously treated with lenalidomide and bortezomib .

26. Carfilzomib based regimens are important options at relapse and can work well even in patients who are refract to a bortezomib containing regimens. Monoclonal Antibodies Daratumumab is a monoclonal antibody against CD38 that is highly expressed on plasma cells. It was granted FDA approval in 2015 for the treatment of MM patients who have received at least 3 prior lines of therapy including proteasome Inhibitors and an immunomodulatory agent. Isatuximab is another monoclonal antibody targeting CD38 with proven clinical activity in MM. It is being tested in earlier stages of the disease. Elotuzumab is a monoclonal antibody targeting the signaling

27. Lymphocytic activation molecule F7 and has shown activity in relapsed MM. Elotuzumab does not have single agent activity but has synergistic activity when combined with Rd.

28. Solitary Plasmacytoma Solitary plasmacytomas are early stage plasma cell tumors that are in an intervening stage between SMM and MM. They can be confined to bone ( solitary bone plasmacytoma ) or occur in extramedullary sites ( extramedullary plasmacytoma ). Extramedullary plasmacytoma is localised to the upper respiratory tract ( nasal cavity and sinuses, nasopharynx and larynx )in over 80% of cases. Patients with solitary plasmacytoma are at risk for progression to MM. Treatment consists of radiation in the range of 40 to 50 Gy to the involved site.

29. Patients with solitary plasmacytoma plus minimal marrow involvement are also treated with radiation therapy to the involved site and then observed until disease. There is no proven benefit of adjuvant chemotherapy. Progression to MM , when it occurs usually appears within 3 years; however patients must be followed indefinitely.

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