Managing Newly Diagnosed Multiple Myeloma

Transcription

1 Managing Newly Diagnosed Multiple Myeloma 26 Jan 2018 Alfred Garfall, MD Assistant Professor of Medicine

2 Diagnosis of Multiple Myeloma Traditional criteria: Monoclonal plasma cells + attributable CRAB features Calcium > 1 mg/dl above ULN or 11 mg/dl Hemoglobin >2 g/dl below LLN or <10 g/dl 1 osteolytic lesion CrCl < 40 ml/min or serum Cr >2 mg/dl 2014 Update to IMWG Criteria include the following as myelomadefining events even in absence of CRAB: >60% bone marrow plasma cells Serum free light chain ratio >100 >1 focal lesion on total body MRI

3 Choice of Initial Therapy Regimen Overall RR Len + Dex 72% 75% Studies S0777 (Durie, Lancet, 2016) FIRST (Benboubker, NEJM, 2014) Bort + Dex 73% UPFRONT (Niesvizky JCO 2015) CyBorD 82% EVOLUTION (Kumar Blood 2012) Len + Bort + Dex 82% S0777 (Durie, Lancet, 2016) Car + Cy + Dex 95% Bringhen, Blood, 2014 Car + Len + Dex 98% Jakubowiak, Blood, 2012 Roussel, ASH, 2016 Car + Len + Dex + Dara 100% Jakubowiak, ASCO 2017 More toxic Less convenient Is there a long-term benefit to more intensive up-front therapy?

4 SWOG S0777 RVd (8 x 21 days) (N=230) Rd (6 x 28 days) (N=242) Lenalidomide 25 mg days mg days 1-21 of 28 Bortezomib 1.3 mg/m2 days 1, 4, 8, 11 Dexamethasone 20 mg days 1, 2, 4, 5, 11, mg days 1, 2, 4, 5, 11, 12 44% age >65; 69% intent to transplant; 33% ISS stage 3; CrCl 30 ml/min Collect Stem cells (optional) Maintenance lenalidomide 25 mg days 1-21 of 28 + dex. 40 mg days 1, 8, 15 Median PFS 43 vs. 30 months Median OS 75 vs. 64 months Durie et al., Lancet, 2016

5 FIRST Trial Rd continuous vs. Rd x 18 months vs. MPT for transplant-ineligible MM (N=1623) For patients who cannot tolerate RVd, Rd is an acceptable standard. Rd continuous has clear PFS benefit and trend towards better OS benefit over Rd. Hulin et al., JCO 34:3609, 2016

6 Summary: Initial therapy Based on S0777 results, RVD is our standard first-line therapy Standard regimen is twice-weekly Velcade, 21-day cycles Consider once weekly Velcade, 28-day cycles Carfilzomib does not yet have long-term comparative data for up-front usage Mayo guidelines recommend this for high-risk patients ECOG E1A11: phase 3 study KRd vs VRd for transplant ineligible, standard-risk patients. Special populations Renal insufficiency (CrCl <30): CyBorD (or Vd if frail) Very elderly, frail: Rd x 18+ months Coming soon All oral regimens (ixazomib, lenalidomide, dexamethasone) If renal impairment is severe, consider starting with: - Cyclophosphamide 500 mg/m2 - Twice weekly Velcade Moreau et al., ASH 2016, abstract #674

7 Important outstanding questions Should we further intensify front-line therapy ECOG E1A11: Randomized carfilzomib vs bortezomib with len/dex Daratumumab based regimens CAR T cells (Penn trial for high-risk patients opening in upcoming months) Can we personalize up-front therapy Intensify therapy only for patients who fail to achieve MRD-negative response? Incorporate subgroup-specific therapies (e.g., venetoclax for t(11;14))

8 High-dose Melphalan + ASCT HDM + ASCT remains standard-of-care even in era of novel agents. Rd induction MPR vs. ASCT x2 (Palumbo NEJM 2014) 98/156 (63%) in MPR group got MEL200 SCT at relapse

9 High-dose Melphalan + ASCT HDM + ASCT remains standard-of-care even in era of novel agents. Rd induction MPR vs. ASCT x2 (Palumbo NEJM 2014) PFS/OS benefit of transplant extends across all examined subgroups PFS OS Palumbo NEJM 2014

10 High-dose Melphalan + ASCT What about with RVD induction? DFCI/IFM-2009 study 79% of non-transplant arm received transplant later MRD PFS OS Attal et al., NEJM 2017

11 High-dose Melphalan + ASCT No difference between RVD and ASCT if MRD negative What about with RVD induction? DFCI/IFM-2009 study 79% of non-transplant arm received transplant later MRD Avet-Loiseau ASH 2017

12 Post-transplant Minimal Residual Disease Associated with PFS/OS IMWG 2016 response criteria Flow cytometry, IgH sequencing Integrate MRD & immune monitoring? More mature B cell phenotype distribution OS among CRs by MRD Munshi et al., JAMA Oncology, 2017 Paiva et al., Blood, 2016 MRD+ with favorable immune reconstitution may do as well as MRD- patients.

13 Tandem ASCT and post-asct consolidation BMT CTN 0702 N=750 pts (250 in each arm) Lenalidomide Maintenance ** N=257 Register and Randomize MEL 200mg/m 2 VRD x 4* N=254 Lenalidomide Maintenance MEL 200mg/m 2 N=247 Lenalidomide Maintenance

14 Primary Endpoint: Progression-free Survival Probability, % Month Estimate and 95% CI Auto/Auto: 56.5 (49.4, 62.9) Auto/RVD: 56.7 (50.0, 62.8) Auto/Maint: 52.2 (45.4, 58.6) Months from Randomization N at risk Auto/Auto Auto/RVD Auto/Maint Stadtmauer et al., ASH 2016, LBA #1

15 Melphalan + busulfan N=204 single-center RCT (MD Anderson) Bu 130 mg/m2/d x 4 + Mel 70 mg/m2/d x 2 vs Mel 200 mg/m2 Median PFS 64.7 vs 34.4 months (P=0.013) More mucositis, LFT elevation, and neutropenic fever w/ Mel/Bu but no excess TRM. Qazilbash ASH 2017

16 High-dose Melphalan + ASCT in Renal Insufficiency CIBMTR Retrospective analysis egfr N %MEL200 > % % < % 35 on dialysis No significant differences in: duration of hospital stay Engraftment day 100 response, PFS, or OS Day 100 TRM was 0% among mod/sev renal impairment groups 34/35 dialysis patients achieved independence from dialysis Mahindra et al., Bone Marrow Transplantation, Sept y PFS by melphalan dose and renal fxn: < mg/m 2 18% 25% 200 mg/m 2 46% 32% P=0.009 P=0.37

17 Important outstanding questions Overall survival implications of delayed vs up-front transplant Do MRD-negative patients benefit from transplant? Role of busulfan/melphalan conditioning

18 RCTs of lenalidomide maintenance CALGB (McCarthy et al. NEJM 2012) 10 mg daily, to 15 mg if tolerated, vs. placebo Indefinite duration crossover after interim analysis IFM (Attal et al. NEJM 2012) 2 x 28d cycles of len. 25 mg + dex maintenance [as above] vs placebo Indefinite duration stopped early due to d 2 nd malignancies (119 pts) GIMEMA RV-MM-PI-209 (Palumbo et al. NEJM 2014) Lenalidomide 10 mg days 1-21 of 28 days vs observation Indefinite duration

19 Meta-analysis of maintenance studies - PFS 1208 patients, median f/u 79.5 months McCarthy et al., JCO, 2017

20 Meta-analysis of maintenance studies Overall Survival P=0.001 McCarthy et al., JCO, 2017

21 Second Primary Malignancies Deaths due to SPM Lenalidomide Observation Pre-PD Post-PD Total Pre-PD Post-PD Total Heme SPM 5.3% 0.8% 6.1% 0.8% 2.0% 2.8% Solid SPM 5.8% 1.5% 7.3% 2.0% 2.2% 4.2% McCarthy et al., JCO, 2017

22 Conclusions Post-ASCT lenalidomide maintenance prolongs PFS and overall survival. PFS/OS benefit is apparent across subgroups with possible exception of high-risk subjects. Increased risk of second malignancies with lenalidomide, but not more death due to second malignancies Required duration of therapy is uncertain; DFCI/IFM 09 studies and ECOG E1A11 study may address this.

23 Important outstanding questions Role of augmented maintenance PD-1 inhibitor + lenalidomide (Pawarode ASH 2017) Ixazomib + lenalidomide (Patel ASH 2017) Elotuzumab + lenalidomide (Thomas ASH 2017) Duration of therapy

24 Management of myeloma bone disease Q4W vs Q12W zoledronic acid, randomized non-inferiority study (Himelstein JAMA 2017) Breast/Pancreas/Myeloma N # with SREs Q4W (68%) Noninferiority Q12W (68%) P<0.001 Myeloma only N # with SREs Q4W (60%) Noninferiority Q12W (55%) P=0.14 Cr increase vs baseline 19.9% (Q4W) vs 15.5% (Q12W) (P=0.02)

25 Management of myeloma bone disease Denosumab vs zoledronic acid placebo-controlled, randomized noninferiority study (Raje ASCO 2017) Slide credit: Clinical Care Options

26 Management of myeloma bone disease Denosumab vs zoledronic acid placebo-controlled, randomized noninferiority study (Raje ASCO 2017) *P<0.001, P<0.05 Denosumab is now FDA approved for multiple myeloma. Advantages: Less renal insufficiency, PFS (but no OS) benefit, convenient Disadvantages: Possibly more ONJ, expensive, hypocalcemia Slide credit: Clinical Care Options

27 Outstanding questions What is the optimal duration of therapy? Is there benefit in patients with no lytic bone disease or osteopenia/osteoporosis? Use of bone metabolism biomarkers to guide therapy? Recently published ASCO guideline (Anderson JCO 2018): No strong position on bisphosphonate vs denosumab Therapy is recommended in all patients Consider less frequent dosing in patients responsive/stable disease Duration: up to two years, resume with relapse or new bone lesions Monitor albuminuria on bisphosphonate, discontinue if >500 mg/24h, resume cautiously Dental precautions

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