Transplant in

Lymphoma and
Multiple Myeloma
ANTHONY BETBADAL
Learning Points
Transplant eligibility
Stem cell mobilization and collection
Conditioning regimens
The transplantation process
Regimens for relapsed DLBCL
Single vs tandem transplant in multiple myeloma
Maintenance therapy in lymphoma and multiple myeloma
Transplant Eligibility
Age – typically less than 75 but can evaluate on a case-by-case basis
Cardiac function – LVEF >40%, preferably by echo with strain but MUGA acceptable
◦ If using higher dose cyclophosphamide for conditioning, >50% LVEF

Pulmonary function – DLCO >40%

Liver function – no frank cirrhosis
Renal function – Cr <2mg/dL for lymphoma, no restrictions on myeloma
Social support
Financial support
Transplant Eligibility
Chronic HIV, HepC, and HepB do not change eligibility
◦ Change pre-transplant and post-transplant care with focus on viral suppression
◦ Higher rates of cytopenias and infectious complications in HIV+ patients

History of Chagas disease – must be treated with documented clearance

Compliance history
Disease chemosensitivity – discussed later in presentation
CNS disease
Timing of Transplant
Lymphoma should be offered transplant at first relapse if eligible
Up-front transplant and delayed transplant for myeloma have similar OS based on IFM2007 trial
◦ Up-front transplant had better rates of CR, MRD negativity, and PFS
◦ Patients could be salvaged at relapse with similar outcomes

With high-risk myeloma, want to achieve CR due to chemoresistance as disease evolves

◦ Should be offered up-front transplant if eligible
Stem Cell Mobilization
Peripheral blood is typically used over bone marrow harvest
◦ In autologous transplant, PBSC (peripheral blood stem cells) lead to better engraftment and lower cost
with similar survival

Much lower rates of CD34+ stem cells in peripheral blood – must increase presence with
mobilization
◦ Can increase presence by >1000 fold, depending on method
G-CSF
Backbone to all mobilization regimen – superior to GM-CSF in head to head trial
10mcg/kg subQ once daily (or 5mcg/kg BID) rounded to nearest vial x5 days
On fifth day, pheresis catheter is placed and cells are obtained
◦ Can collect for 2-3 days to attain goal

Minimum collection of 2x10^6/kg CD34+ stem cells, optimally 3x10^6/kg CD34+ for single
transplant or 6x10^6/kg for tandem
Cyclophosphamide
Adding cyclophosphamide improves mobilization 3x greater than G-CSF alone
◦ Increases toxicity including nausea, stomatitis, neutropenia, and cystitis

3g/m2 on day 1 (with 3g IV MESNA) added to conditioning for patients at risk for poor
mobilization
◦ Relapsed lymphoma
◦ Relapsed multiple myeloma
◦ Multiple myeloma after more than 6 cycles of lenalidomide or any melphalan up-front
◦ Decrease to 1.5g/m2 in ESRD patients
Plerixafor
Used in patients that fail to mobilize with G-CSF +/- cyclophosphamide
60-70% successful in patients that failed previously
Given as 240mcg/kg on evening of day 4 with collection on day 5
◦ If failing to collect, can repeat for 2-3 days in total and collect each day

Diarrhea and cost are major side effects – 15% of patients

Purifying Product
Malignant cells present in pheresed product
Decontamination can be attempted two ways
◦ Positively by selecting for CD34+ cells
◦ Negatively by selecting out BCMA or CD20+ cells

No difference in multiple myeloma and unclear benefit in lymphoma

◦ Some institutions add rituximab 375mg/m2 x1 to mobilization, we do not
Storing Product
Product cryopreserved in DMSO (dimethyl sulfoxide) 10%
◦ Prevents ice crystals from puncturing stem cell membranes

Patients must recover from pheresis (about 10-14 days) before being admitted for conditioning
and transplant
Extra cells can be stored for several years in DMSO cryopreservation
BEAM Conditioning Regimen
BEAM or BCNU/etoposide/Cy are considered standards for lymphoma induction – BEAM is used
at Indiana University
BCNU causes jaw pain and headaches with infusion – opioids should be made available
No clear benefit to rituximab – possibly increase infectious complications so omitted from
conditioning
Chemotherapeutic Schedule
BCNU 300mg/m2 Day -6
Etoposide 200mg/m2 IV daily Day -5 through Day -2
Cytarabine 200mg/m2 IV BID Day -5 through Day -2
Melphalan 140mg/m2 Day -1
High Dose Melphalan
For multiple myeloma and amyloidosis
Unique toxicity is “melphalan blues” – patients feel depressed or apathetic starting 1 week after
transplant, lasting 1-2 weeks
Typically given as 200mg/m2 day before transplant
◦ Can do 100mg/m2 for 2 days alternatively
◦ Compared to 100mg/m2, better response rates and longer PFS post transplant with higher toxicity but
same treatment related mortality

Dose reduce to 140mg/m2 with Cr >2mg/dL or in patients ≥70 years old

◦ Higher toxicity leading to higher pulmonary toxicity and mucositis in ESRD patients
◦ Similar OS between 200mg/m2 and 140mg/m2 in ESRD patients
Conditioning Regimens
Both regimens are highly emetogenic
For melphalan, give dexamethasone 8mg day of chemotherapy and 4mg for 3 days, ondansetron
16mg day of, fosaprepitant 150mg day of, and olanzapine 5mg qHS for 5 days
For BEAM, dexamethasone is given 8mg daily, ondansetron 16mg daily, and olanzapine 5mg qHS
Transplantation
Quite anticlimactic…
Cryopreserved cells are thawed and infused like a blood transfusion
◦ Pretreated with APAP 650mg and diphenhydramine 50mg

Unusual toxicities with infusion

◦ Most patients have an odd taste in their mouths – like tomato soup or garlic
◦ Dry cough occurs in 70% of patients
◦ Can have flushing, wheezing, hypotension
Transplant Complications
Universal neutropenia and thrombocytopenia
◦ Neutropenic fever in 40% of patients
◦ Need for platelet transfusion in 60% of patients

Grade 3 mucositis in 30% of patients

Chemotherapy induced nausea / vomiting
Diarrhea
Treatment related mortality – 1-2% at IU
Engraftment and Discharge
Engraftment is defined as ANC >500, plt ct >10k, Hgb >7g/dL
◦ Neutrophil recovery on average day +11, platelets day +18
◦ Monocyte count going up indicates impending neutrophil recovery

Prophylactic fluconazole 400mg, ciprofloxacin 500mg continued until ANC >500

G-CSF is not typically given to hasten recovery – shortens neutropenia by 1 day without
difference in TRM (treatment related mortality)
Patients can be discharged safely if eating / drinking, vomiting and diarrhea have subsided, and
ANC >500
◦ Typical hospital stay is until day +13-17
Post-Transplant Care
Acyclovir 400mg BID is continued for 1 year after transplant
Starting at 6 months, patients start on vaccination schedule
◦ Hepatitis B, polio, meningitis, PCV13 x2 then Pneumovax, HiB, DTaP
◦ Live vaccines at 2 years (MMR if seronegative)
◦ Can receive influenza vaccination at 4 months (IM only)
◦ https://bethematchclinical.org/post-transplant-care/vaccinations/
Relapsed DLBCL
Transplant is the only definitive curative option for DLBCL
◦ This may change as we continue to gather data on CAR T-cells

Several platinum based regimens available with similar responses – 30-65%

I prefer rituximab / gemcitabine / dexamethasone / cisplatin
◦ Compared to R-ESHAP, R-DHAP, R-ICE can be done as an outpatient
◦ Avoid additional etoposide exposure – risk for secondary malignancy
◦ 3 week cycles x2 - Rituximab 375mg/m2, gemcitabine 1g/m2 day 1 & 8, cisplatin 75mg/m2 day 1, and
dexamethasone 40mg day 1-4
◦ High emetogenicity – use 5HT3RA, olanzapine, and NK-1 antagonist
Alternative Regimens
R-DHAP – rituximab 375mg/m2 day 1, cisplatin 100mg/m2 infused over 24 hours, cytarabine
2g/m2 BID on day 2, dexamethasone 40mg day 1-4 every 21 days
◦ Higher dose of Ara-C so may have better CNS penetration

R-ESHAP - rituximab 375mg/m2 day 1, etoposide 40mg/m2 day 1-4, cisplatin 25mg/m2/day
continuous infusion x4 days, cytarabine 2g/m2 after completing cisplatin, methylprednisolone
500mg IV day 1-5 every 28 days
R-ICE – rituximab 375mg/m2 day 1, ifosfamide 5g/m2 continuous infusion over 24hr day 4,
MESNA 5g/m2 day 4, carboplatin AUC 5 (max dose 800mg) day 4, etoposide 100mg/m2 day 3-5
every 14 days
◦ No NK-1 antagonist with ifosfamide, must use olanzapine
Chemosensitivity
Chemosensitivity is predictive and prognostic in DLBCL
Imaging obtained prior to chemotherapy and after 2 cycles
◦ Ideally should see a CR to move forward with transplant
◦ Can consider transplant in select cases with PR (50% reduction in volume at least) or opting for a 3 rd
cycle and re-imaging
◦ ½ of chemosensitive patients can be cured with transplant

Patients with chemoresistant disease should move to clinical trials or alternative therapies
◦ Ibrutinib or lenalidomide in ABC subtype
◦ Double-hit / triple-hit lymphomas should go for clinical trial
◦ Polatuzumab
◦ CAR T-cell
CAR T-Cells
CAR T-cells are genetically engineered T-cells through lentiviral vectors creating a novel antigen
receptor, in this case pertinent to the disease managed
CD19 chosen in leukemia / lymphoma due to ubiquity of cellular antigen and well-known
management of B-cell aplasia
BCMA is widely expressed by maturing B-lymphocytes and a key antigen in myeloma evolution
Must lymphodeplete prior to infusion with cyclophosphamide 300-500mg/m2 and fludarabine
30mg/m2 daily over 3 days
CAR T-Cells

CH June, M Sadelain. N Engl J Med 2018;379:64-73.

CAR T-Cells
In DLBCL, CR rates have been 40-50% in heavily pretreated patients with durable responses at 18
months and beyond
In myeloma, the recent update to CARTITUDE-1 had 100% ORR with 76% stringent CR
◦ At 6 months, 26/29 had no progression and 16 evaluable patients were MRD negative

KarMMa trial in myeloma, however, showed median PFS of 11.3 months

◦ This product is being updated with PI3K inhibitor ex-vivo enrichment

Major toxicity is cytokine release syndrome, neutropenia (100% of patients with anti-BCMA CAR
T-cells), and thrombocytopenia
Relapsed Hodgkin’s Disease
Unlike DLBCL, chemosensitivity is prognostic but not predictive
Can move directly to transplant in low volume disease vs cytoreduction for symptomatic bulky
disease
Similar protocols to DLBCL (GDP, ESHAP, DHAP, ICE) for salvage therapy
Non-transplant candidates should be given pembrolizumab over brentuximab (PFS of 13.2
months vs 8.3 months)
 Relapsed Hodgkin’s Disease
Risk stratification pre-transplant

Risk Factor Point Value

Karnofsky Performance Status < 90 1
Chemoresistant Disease 1
Extranodal Disease 2
>3 Prior Chemotherapy Regimens 2

• Low risk (0) – 4 year PFS 71%

• Intermediate risk (1-3) – 4 year PFS 60%
• High risk (4-6) – 4 year PFS 42%
Single vs Tandem Transplant
No role for tandem transplant in DLBCL or Hodgkin’s disease based on uncontrolled trials
suggesting no benefit
Role of tandem transplant in myeloma is still debated with current regimens
◦ STaMINA trial randomizing patients post-autologous transplant to second transplant, consolidation
chemotherapy, or maintenance lenalidomide had no differences in PFS or OS
◦ This contrary to EMN02 / H095 trial where secondary randomization with subgroup analysis of high risk
disease showed 3 year PFS of 69% vs 40%
◦ Guidelines also exist for tandem transplant in patients not achieving VGPR
Post-Transplant Evaluation
For DLBCL and Hodgkin’s disease, imaging done post-transplant if patient didn’t have CR prior to
transplant at 3 months
For multiple myeloma, check SPEP, free light chains, and bone marrow biopsy at day 100
◦ BM used for MRD status by high sensitivity flow cytometry
◦ MRD negative patients have longer PFS (~71 months) and OS – prospective trials at reducing
maintenance in MRD negative patients are pending
Relapse and Repeat Transplant
If no maintenance is given for myeloma, a repeat transplant can be considered if patient does
not relapse within 18 months
If maintenance is given, a repeat transplant can be considered if patient does not relapse within
36 months
Role of repeat transplant is becoming more limited with newer agents
Relapse before these times suggests chemoresistance and a poor prognosis
Allogeneic Transplant
Limited role in lymphoma and multiple myeloma
Can be considered in select cases with lymphoma in primary refractory disease, chemoresistant
disease, or second relapse
◦ CAR T-cell may be more appropriate at this time

When compared to autologous transplant in myeloma, relapse rates were similar but higher
TRM in allogeneic transplant
◦ Role is currently limited to clinical trials only
Maintenance Rituximab
No role for maintenance rituximab in DLBCL post transplant based on CORAL trial
Maintenance rituximab should be used post-transplant in mantle cell lymphoma if given
conventional immunochemotherapy
◦ 375mg/m2 every 2 months for 3 years after transplant
◦ Per LYSA trial, improved 4 year PFS and OS (83% vs 64%, 89% vs 80% respectively)
Maintenance Brentuximab
Based on AETHERA trial, 1.8mg/kg every 3 weeks for 16 cycles (10 cycles if given brentuximab
for relapsed disease)
Only given if high risk defined as:
◦ Primary refractory cHL
◦ Relapse within 12 months of completing up-front therapy
◦ Relapse at extra-nodal site

While no OS benefit due to large trial crossover, improved 5 year PFS from 11% to 59%
◦ Suggests patients that relapsed can be salvaged after relapse
Maintenance Pembrolizumab
With recent evidence suggesting pembrolizumab’s superiority over brentuximab at relapse,
interest in maintenance post-transplant has piqued
Limited trial with 30 patients given 8 cycles of maintenance
◦ 90% high risk per prior criteria
◦ 40% with immune related side effects
◦ PFS at 18 months was 82% with 100% OS
◦ Pending further evaluation
Maintenance in Multiple Myeloma
Extends PFS and OS after transplant – starts on day +100
For standard risk, lenalidomide is used 10mg once daily
◦ Improved median PFS to 53 vs 24 months, 7 year OS improved to 62% from 50%
◦ No survival benefit seen in high risk disease
◦ Debate ongoing for duration of therapy, 2 years seems to be concensus

For high risk, bortezomib 1.3mg/m2 subQ q2 weeks for 2 years

◦ Based on French trial comparing thalidomide to bortezomib maintenance
◦ Largest benefit seen in high risk disease, improving PFS to 54 months vs 24 months
Maintenance in Multiple Myeloma
Ixazomib was trialed but had modest improvement in PFS in standard risk (27 vs 21 months) and
non-significant improvement in high risk
◦ Long term OS data is immature but PFS is not convincing

Thalidomide 50mg remains an alternative when these agents are not available for 2 years