Multiple Myeloma (MM)

Transcription

1 EloreMed Editor: Le Wang, MD, PhD Date of Update: 2/14/2018 UpToDate: New FDA approval anti-myeloma drugs: Carfizomid, Ixazomib, Daratumumab, Elotumumab, Pomalidomide. Autologous stem cell transplantation remains the first line option for eligible patient. INTRODUCTION: Madian age of diagnosis is 60yrs. Black >> White > Asia. Monoclonal gammopathy of unknown significance, also known as MGUS, is considered as a predisposing state for multiple myeloma. The frequency of MGUS in general population aged > 50yrs is about 3%. RISK FACTORS: MGUS: 1% risk each year of progressing into multiple myeloma. Smodering myleoma: 10% risk each year of progressing to multiple myeloma (most in the first 5 years). Familial tendency (no genetic gene identified) BIOLOGY: N/A - unclear CLINICAL PRESENTATION: Fatigue and bone pain (most common presenting symptoms), lytic lesions (67% of MM) CRAB (hypercalcimia >11, renal insufficiency (Cr>2), anemia, or bone lesions) Others: hyperviscocity, amyloidosis, recurrent bacterial infection (>2 episodes in 12 months), neurologic disease (cord compression, etc). DIAGNOSIS: A. Initial Testing: LDH, β2-microglobulin "SPEP/IF plus 24hrs UPEP/IF"; or, "SPEP/IF plus serum FLC ratio (97-98% sensitivity. 2% MM are nonsecretary need BM for dx. BM Biopsy at diagnosis for all MM, except MGUS (<1.5g/dl) Skeletal Survey for all MM at diagnosis. Serum viscosity if M-protein>5g/dl FISH for del 13, del 17, t(4:14), t(11:14), t(14:16), 1q21 amplification Page 1 of 7

2 ** MRI spine and PET-CT are also useful. B. Diagnostic criteria: 1) MGUS: M- protein < 3 g/dl, BM myeloma cells < 10%, No end-organ damage. 2) Smoldering MM: M-protein 3 g/dl, BM myeloma cells 10-30%, No end-organ damage. 3) Symptomatic MM: M-protein (no true cut-off), BM myeloma cells 10%, or plasmacytoma on tissue biopsy, and end-organ damage (hypercalcemia, renal failure, anemia, lytic bone lesions). 4) Free light chain assay: An involved/uninvolved FLC > 100 has a risk of progression to end organ damage in the next two years of approximately 80%. In these patients, if the absolute involved FLC level was also increased at 100 mg/dl (1000 mg/l) or more, the risk of progression in the next two years increased to 93%. Given the high rate of progression, an FLC ratio of 100 or more is now considered diagnostic of MM. C. Classification: 1) Multiple Myeloma: IgG (50%), IgA (20%), IgD (2%) Light chain only (20%): incidence of renal failure. Non-secretory (3%): need BM for diagnosis. Solitary plasmacytoma: at bone or soft tissure (extramedullary). 2) Waldenstrom's Macroglobulinemia: 3) Systemic AL Amyloidosis: + amyloid staining, M-spike or clonal plasma cells in the bone marrow. 4) POEMS: VEGF P (peripheral neuropathy), O (organomegaly), E (endocrinopathy,excluding DM or hypothyroidism), M (multiple myeloma), S (skin changes). PATHOLOGY: A) M-Spike: IgG ( 52%), IgA (21%), κ or λ light chain only (Bence Jones) (16%), IgD ( 2%), Biclonal (2%), IgM (0.5%), Negative ( 6.5%) B) IHC Charicteristic: CD19, CD Normal PC + - Myeloma C) Staging: Page 2 of 7

3 1) Durie-Salman Staging: cubersome reflect tumor burden Stage I. must have all of the following: * Hb >10 g/dl * Ca <12 * Low M-spike (IgG <5 g/dl, IgA <3, Bence Jones protein <4g/24hr) * Negative or solitary plasmacytoma * Myeloma cell mass: <0.6 (low) Stage II: neither I or II Stage III: any one of following * Hb <8.5 * Ca >12 * High M-spike (IgG >7, IgA > 5, Bence-Jones protein >12g/24hrs) * Multiple lytic bone lesions * Myeloma cell mass: >1.2 (high) ** Subtype A: Cr <2, B: Cr >2 2) International Stage System (ISS): used only after the MM dx'd prognosis. Overall Survival Stage I: β2m <3.5, Alb >3.5, 62 months Stage II: neither stage I nor III, 44months Stage III: β2m >5.5, 29months * β2-microglobulin: reflect tumor burdon * Albumin: negatively reflect body response PREDICTION AND PROGNOSIS: Risk Stratification for Therapy: A. High-Risk: OS 2-3 yrs; require intensitive therapy or clinical trial FISH: Del 17, t(14:16), t(14:20) GEP defined high-risk B. Intermediate-Risk: OS 2-3 yrs; require intensive therapy, Hypodipoidy FISH: t(4;14) (response to bortezonib) Cytogenetics: del (13). Note: FISH del 13 also intermediate-risk PCLI: >3% C. Standard-Risk: OS >6-7 yrs. Majority (67%) Page 3 of 7

4 No high risk features above, including * Hyperdipoidy * t(11:14), t(6:14) *** The detection of trisomies by FISH predicts good prognosis. TREATMENT RECOMMENDATION: A) General Consderation: 1. Does this patient need therapy? 2. Is the patent a transplant candidate? B) Monoclonal gammopathy of unknown significance (MGUS): Does not require therapy, 1% annual risk of progressing into multiple myeloma. 1) Risk Group: assessed by M-protein >1.5g/dl, Non-IgG MGUS (i.e. IgA, IgD, IgM), abnormal FLC ratio (κ/λ) <0.26, or >1.65. * 3 factors high-risk, 58% risk over 20 years * 2 factors high-intermediate, 37% risk over 20 years * 1 factor low-intermediate, 21% risk over 20 years * 0 factor low-risk, 5% risk over 20 years 2) Management: H&P, SPEP/UPEP, CBC, BUN/Cr, Ca at 6 months after diagnosis, then If low-risk (M-protein<1.5, IgG subtype, normal FLC ratio), then follow-up with H&P alone will suffice. For all other MGUS, follow-up with every 6-12 months SPEP/UPEP, CBC, Cr, Ca. MGUS has risk for osteoporosis and thromboembolism, annual DEXA for osteoporosis. Start bisphosphonate at osteoporosis diagnosis, plus calcium and vit D. C) Smouldering multiiple myeloma (SMM): Does not require therapy, higher annual risk (10%) than MGUS of progressing into multiple myeloma. Oberve and labs at q 3-6 months (QI, SPEP/UPEP, CBC, BUN/Cr, Ca), and skeletal survey annually or as indicated. Bone marrow biopsy, serum FLC assay, MRI/PET as clinically indicated. Start therapy at the time of disease progression. Median time from SMM to symptomatic MM is 7 months without therapy. D) My Approach to Newly Diagnosed MM: E) Initial therapy for multiple myeloma: 1) Non-transplant candidate: Page 4 of 7

5 1.1. Criteria for NOT a candidate for transplant Age > 77 Direct billirubin >2 Serum Cr >2.5 ECOG 3-4 New York Heart Association Class III or IV Standard Procedure: Initial induction: based on risk factors * Standard Risk: Rd * Intermediate Risk: VCd * High Risk: VRd (most intensive) Duration of treatment: 1-2 yrs or until plateau, then observe. Maintenance treatment is NOT recommended for non-transplant patients. 2) Transplant candidate: 2.1. Initial induction: Avoid melphalan, Harvest stem cells enough for two transplants after 2-4 cycles of treatment. Risk-adapted therapy: * Standard-risk: Rd or Vd, rather than Thalidomide/Dex. * High-Risk/Light chain MM/Standard risk MM with extensive bone diseases: Bortezomib-based regimen (3-drug), VRd and VTd are most commonly used Stem cell transplant (SCT): perform immediate 1st autologous SCT after 4 cycles of induction therapy. Important advances: * Autologous-SCT: Induction chemo, followed by auto-sct prolong surival compared to standard therapy alone (Mayo Clinic Trial 1996). Whether the use of novel agents can eliminate the need for auto-sct remains to be studied. * Upfront vs delayed transplantation (at disease progression): no difference in survival (MAG study, SWOG study). BUT, early auto-sct is preferred. * Tandem auto-sct: Double transplant superior to single transplant in OS (IFM 94 trial). In practice, 2nd auto-sct is often NOT needed, and only indicated for patients who did not achieve at least VGPR after initial SCT, or at the time of disease progression. * Allo-SCT is NOT a standard care and should be used only in clinical trial setting Maintenance therapy: Who gets maintenance? * Stardard-risk patients who achieved complete remission (CR) or VGPR after first auto-sct, observation, rather than maintenance therapy. * High-risk patients or standard-risk patients who do not achieve at least VGPR after first auto- SCT, initiate maintenance therapy. Page 5 of 7

6 Maintenance regimen: * Lenalidomide (10mg/day) until disease progression: improve PFS but not OS; more neutropenic fever and higher risk of second malignancies. * Thalidomide maintenance (category 1): prolong PFS by 10 month, may prolong OS. Long-term toxicity associated with peripheral neuropathy and thromboembolism. * Bortezomib: Hovon trial F) Treatment for Relapse or Refractory Multiple Myeloma: 1) General consideration: If patients with relapse or refractory MM had no prior auto-sct, then repeat previous therapy (if relapse >6 months) or 2nd line therapy (if relapse < 6 months, followed by high dose chemotherapy and auto-sct. If patients with relapse or refractory MM had prior auto-sct, then consider repeat transplant (2nd transplant). 2) Newly FDA approved therapy for relapse or refractory multiple myeloma: Daratumumab/bortezomib/dexamethasone (DVd): preferred Daratumumab/lenalidomide/dexamethasone (DRd): preferred Carfizomid/lenalidomide/dexamethasone (KRd): preferred Ixazomib/lenalidomide/dexamethasone Elotumumab/lenalidomide/dexamethasone Pomalidomide/Carfizomid/dexamethasone Pomalidomide/Bortezomid/dexamethasone G) Solitary Plasmacytoma: Osseous plasmacytoma: radiation (45Gy or more), curative Extraosseous plasmacytoma: radiation, followed by surgery if necessary. Follow-up: q 4 wks initially until complete dissappearance of the paraprotein, then q3-6 months (SPEP/UPEP, SIFE, FLC) or as clinically indicated (BM, MRI, CT, PET). H) Adjuct Therapy for Multiple Myeloma: 1) Bisphosphonates or Xgeva monthly indicated for: Patients with lytic lesion. Patients who do not have lytic lesions but have osteopenia or osteoporosis on DEXA. NOT indicated for smodering MM or MGUS Duration of treatment is two yrs. Bisphosphonate can be resumed when new skeletal events occur. Common side-effecta: nephrotic syndrome, renal insufficiency, hypocalcemia, and osteonecrosis (avascular necrosis) of the jaw. * Pamidronate: focal collapsing segmental glomerulosclerosis, azotemia often proceeded by albuminuria. Page 6 of 7

7 * Zoledronic acid: tubular dysfunction (interstitial nephreitis, etc), renal failure. * Risk factors for side effects: - Older age at diagnosis - Longer duration of bisphosponate therapy - Recent dental extraction - Sequential therapy with pamidronate followed by zoledronic - Zolendronic > Pamidronate - Concomitant use of thalidomide and an increased number of bisphosphonate infusions also increases the risk for ONJ. FOLLOW-UP: A. Response criteria (International myeloma working group): Stringent complete response (scr): no M-protein by IFE, normal FLC ratio, no clonal cells in BM. Complete response (CR): no M-protein by IFE, <5% clonal cells in BM. Very good partial response (VGPR): >90% reduction in serum M-protein but still positive by IFE. Partial response (PR): > 50% reduction in serum M-protein Stable disease (SD): does not meat above criteria. Progressive disease (PD): >25% increase from the lowest response value in any of following (serum M-protein, urine M-protein, BM, FLC). CHEMOTHERAPY AND REGIMEN: 1). Thalidomide: throboembolism ( when used with glucocorticoids or ESA), neuropathy, constipation, sedation, rash 2) Lenalidomide: Neuropathy, Thrombocytopenia, Rash 3). Bortezomib: IV twice weekly and weekly are equal efficacy. Weekly has less neuropathy. Dose adj for PN (neuropathy): Grade 1 (pain) or 2 (interfere function), dose to 1.0 from 1.3 mg/m2 Grade 2 with pain or 3 (interfere daily living), hold the dose and re-start at 0.7mg/m2 after symptoms resolved. Bortezomib a/w incidence of herpes zoster. Rx anti-viral prophylasix for all patients receiving bortezomib. Acyclovir 400mg po bid or valacyclovir 500mg daily Peripheral neuropathy (pain, etc), cytopenia, diarrhea, and zoster reaction. 4) Bisphosphonate: Clodronate: PO Zoledronate: IV 4mg over 30 min q 4weeks; contraindicated when Cr >3, GFR<30 Page 7 of 7

8 Pamidronate: IV 90mg over 2hrs q 4weeks: dose reduction when Cr >3, GFR<30 Page 8 of 7