Multiple Myeloma


Microenvironment immune reconstitution patterns correlate with outcomes after autologous transplant in multiple myeloma

Harsh Parmar, Morie Gertz, Emilie Anderson, Shaji Kumar, Taxiarchis Kourelis

Early post-ASCT period: a challenge and opportunity

Opportunity: many patients have eradicated most of their disease.

Challenge: more immunosuppressive subsets detrimental to tumor immunosurveillance

Goals: • Identify immune tumor microenvironment (iTME) reconstitution patterns early post-ASCT • Correlate with patient outcomes and clinical characteristics • iTME states associated with a longer remission.

Study: Myeloma patients after SCT (N=58, • ASCT within 12 months from diagnosis ("upfront") • Conditioning with MEL 200 mg/m2 • BM sample (cells and plasma) at day+l00 post ASCT), Identification of immune subsets, Clustering of patients based on immune subsets, immune reconstitution patterns and downstream analyses (FDR corrected p value of <0.05 when multiple comparisons) 

Conclusion and key points:

• 2 major reconstitution patterns of the cellular iTME were identified early after ASCT

• The group of patients with a higher level of naïve and terminally differentiated and exhausted T cells had an inferior hematological response, OS and TTP after ASCT independent of high-risk FISH

• Presence of T-cells at the opposite ends of the T cell differentiation spectrum (naïve and terminally differentiated) are unable to mediate clearance of malignant cells and therefore may lead to inferior outcomes

• CD16-ve NK cells were more often found in male patients. CD16 is a key receptor mediating antibody-dependent cell cytotoxicity required for the efficacy of moabs such as elotuzumab.


• Most patients were male • We did not validate these findings in a separate cohort • Limited number of patients (sample availability, cost) • MRD status was available only in half of patients in CR • 40% patients did not receive maintenance which reflects practice patterns in our institution from 10 years ago. • Cryopreserved samples were used and therefore myeloid cells could not be assessed.


Autologous hematopoietic cell transplantation for relapsed multiple myeloma performed with stem cells re-mobilised following prior auto-HCT - a retrospective study on behalf of EBMT CMWP

Joanna Drozd-Sokolowska

Autologous hematopoietic cell transplantation constitutes the standard of care of multiple myeloma patients eligible for transplantation. Auto-HCT is usually incorporated into the first-line treatment either as single or tandem auto-HCTs. Auto-HCT performed in patients relapsing after the previous auto-HCT may also be beneficial under specific circumstances. If an insufficient number of stored stem cells is available, there is a need to re-mobilize stem cells. Very limited data on the efficacy of remobilization and the safety of salvage auto-HCT performed with remobilized stem cells.

The study aims to analyze the safety (both short- and long-term) and efficacy of salvage auto-HCT performed with cells remobilized after a previous auto-HCT. 

Inclusion criteria: Relapsed multiple myeloma Salvage auto-HCT performed with cells procured during the remobilization after previous auto-HCT (single or double) Time interval from previous auto-HCT to remobilization: >6 months Year of salvage auto-HCT: 2000-2018. 

Primary end-point: Non-relapse mortality (NRM)

Secondary end-points: • timing of recovery • overall survival (OS) • progression-free survival (PFS) • relapse incidence (RI) • the cumulative incidence of t-MDS and t-AML (t-MDS/t-AML Cl) • the cumulative incidence of other than t-MDS/t-AML secondary primary malignancies (SPM Cl).


Salvage auto-HCT performed with stem cells remobilized after a prior auto-HCT is associated with an acceptable NRM and cumulative incidence level of secondary malignancies as expected.

The leading cause of failure is progression of multiple myeloma, which was mostly predicted by the time from the previous auto-HCT to the first relapse and the year of salvage auto-HCT.


Isatuximab plus Carfilzomib and Dexamethasone versus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma Patients who Previously Underwent Transplantation: IKEMA Subgroup Analysis

Thomas G. Martin, Marcelo Capra, Mohamad Mohty, et al.

Isatuximab: Targets a specific epitope on CD38

• Studies have demonstrated prolonged PFS and OS with the use of autologous stem cell transplantation as intensification therapy in patients with NDMM

• However, these patients continuously relapse over lime and require additional, novel therapies2

• Effective treatment options for MM patients who received prior transplant are needed, particularly due to the potential biological nuances of these patients

• Lower expression levels of c-MYC, a known negative prognostic factor in MM, have been reported in MM patients the following transplant

• Recovery of specific immune subpopulations may be associated with improved survival following transplant; however, this may also impact the effects of CD38 monoclonal antibodies, which have been shown to improve outcomes in MM patients via immune-related mechanisms

• RRMM patients with prior transplant who were treated with carfllzomlb-based regimens experienced improved PFS and response rates

• This subgroup analysis examined efficacy and safety in patients from the Phase 3 IKEMA study who received a prior transplant


• Of the302 patients randomized in IKEMA, 185 (61.3%) had received a prior transplant

• Of these 185 patients, 43.2% entered the study with progression following prior transplant In first-line

• The addition of lsatuximab to carfilzomib and dexamethasone (lsa-Kd) improved PFS in patients with relapsed MM and prior transplant (hazard ratio, 0.578; 95% Cl: 0.353-0.945), which was consistent with the hazard ratio in the overall study population

• lsa-Kd also improved PFS in patients with prior transplant and 1 prior line of therapy (hazard ratio, 0.522; 95% Cl: 0.233-1.167)

• lsa-Kd led to high ORR (86.9%) and improved complete response (43.1%) and MRD-negativity rates (31.9%) in patients with prior transplant

• lsa-Kd had a manageable safety profile in patients with prior transplant, consistent with the overall population.


Autologous-allogeneic vs autologous tandem stem cell transplantation and maintenance therapy with thalidomide for patients with multiple myeloma (MM) and age over 60 years: A prospective phase II-study

Nicolaus Kröger

The role of allogeneic SCT in multiple Myeloma remains controversial The role of auto-allo (Auto-Allo) to tandem autologous stem cell transplantation (TSCT) followed by maintenance therapy has not been compared in patients with newly diagnosed multiple myeloma (MM).

Between 2008 and 2014 a total of 210 MM patients 60 years of age were included from 23 German Centers within an open-label, parallel-group, multi-center clinical trial to investigate whether autologous-allogeneic (Auto-Alla) tandem stem cell transplan­tation (TSCT}, compared to autologous-autologous (Auto-Auto) TSCT followed by a 2 year maintenance therapy with thalidomide (100mg/daily) in both arms, has a beneficial effect on progression-free survival.

Patients received autologous peripheral blood stem cell transplantation (PBSCT) followed by allogeneic PBSCT when a matched related or unrelated donor would be available; otherwise, or if they declined allogeneic PBSCT, they received two autologous PBSCTs.

The primary endpoint was relapse/progression-free survival at four years after TSCT between both arms and sample size was calculated on the basis of expected 48-month event rates of 50% for Auto-Allo TSCT and of 70% for Auto-Auto TSCT. 

A total sample size of 185 patients was estimated (n=111 in auto-allo and n=74 in auto-auto) to provide at least 80% power to reject the null hypothesis in a log-rank test model.


This prospective trial showed a 12% difference in PFS at 4 years between auto-allo and auto-auto and thalidomide maintenance (for 2 y) but failed the planned 20% difference.

In contrast to our assumption that about 60% will have suitable donors and proceed to allo, 74% of included patients received allograft and only 26% tandem auto.

A longer follow-up at 8 years showed a difference in PFS of 22%, which however was not significant.

Multivariate analysis showed for PFS and OS improved outcome after thalidomide maintenance, CR after induction chemotherapy, while the worse outcome was seen for high risk defined by del17p and t(4;14).


Allogeneic hematopoietic cell transplantation followed by Bortezomib in Multiple Myeloma: Final Results of a prospective trial highlighting a strong prognostic role of measurable residual disease

Jean Roy

• Despite novel agents, multiple myeloma (MM) remains a lethal disease with a 5-year survival of 54% • Patients with advanced disease (ISS 3), unfavorable cytogenetics such as t(4;14), (14;16), (14;20), 17p-, 1p-, 1q+ and plasma cell leukemia have a shorter survival • Young patients (age 50 years or more) are those with the most significant loss in years of life • Recent data suggest that allogeneic stem cell transplantation (HCT) can overcome the adverse prognosis associated with high-risk cytogenetics.

Allogeneic HCT can cure a subset of newly diagnosed myeloma patients see the following papers:

LeBlanc et al. Profound MRD negativity rates after frontline tandem autologous-allogeneic stem cell transplantation followed by bortezomib maintenance in high-risk or young myeloma patients

Musetti et al. Allogeneic Hematopoietic Transplantation for Multiple Myeloma in the New Drugs Era: A Platform to Cure

Bortezomib: • Significant activity against MM • Is beneficial to patients with high-risk cytogenetics (Neben K, Blood2012) • Has immunomodulatory effects and might improve outcome of allogeneic stem cell transplantation: • Prevents GVHO (Koreth J, J. Clln. 0ncol 2012) • Improves chronic GVHD in relapsed MM patients (Kuroda). Int J Hemato/2010).

Hypothesis: Bortezomib in maintenance after allogeneic hematopoietic cell transplant will: • Decrease the incidence of myeloma relapse • Decrease the incidence and severity of chronic GVHD • Have an acceptable safety profile

Key inclusion criteria: • Newly diagnosed multiple myeloma with measurable disease • Age  65 years or more with any of the following poor prognosis features: • ISS 3 • Plasma cell leukemia • t(4;14) with ISS II or Ill, t(14;16), t(14;20), del(17p13), chromosome 1 abnormalities (10% or more by FISH) • Age 50 years or more regardless of other risk factors • Available 8/8 matched related or unrelated donor.
Median follow-up: 48 months
Median OS: not reached
OS @ 5 years: 80% (95%CI: 58-91)
Median PFS: 49 months (95%CI: 25-NR) PFS@ 5 years: 41% (95%CI: 21-60)
16 progressions
6 deaths: MM progression: 3 GVHD/infections: 2 Sudden death in CR: 1 
  • Tandem auto-allo HCT followed by BTZ maintenance in young and/or high-risk myeloma patients induces high sCR (82%) and negative MRD (79%) rates
  • Low MRD (below 30 abnormal plasma cells) before allo HCT and 4 months after predicts a better outcome and could be used as a landmark for future studies
  • Administration of Bortezomib 1.3 mg/m2 SC every 2 weeks after allogeneic HCT is safe and contributes to decrease both the incidence and severity of chronic GVHD
  • Longer follow-up is needed to evaluate the cure rate in this young/high-risk myeloma population


Acceptable Toxicity and Good Hematological and Renal Response after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency at Transplant: A Prospective SFGM-TC Observational Study

Laurent Garderet, Hafida Ouldjerioual, Mohamed-Amine Bekadja, et al. 


• Primary endpoint: TRM
• Secondary endpoint: 1/ Toxicity of the ASCT 2/ Hematological response at day 100 and 6 months post ASCT 3/ Renal response at 3, 6, and 12 months post ASCT 4/ PFS and OS 
Inclusion criteria: 
1/ Newly diagnosed MM with a creatinine clearance < 40 ml/min (CKD-EPI) at time of ASCT 2/ Age < 66 years 3/ No Cl for ASCT (- LVEF over 50%, - Normal lung functions) 4/ No AL amyloidosis 
Traitement schema
Velcade based - 21 days cycle
Response  PR or better
PBSC collection 3x106/kg or higher - enrollment in observational study
Melphalan 140mg/m2 + ASCT
2 years follow-up 
• We observed one death out of 4 7 patients during the first 100 days post-ASCT, secondary to a septic shock on day 42
• No other patient went into Intensive Care Unit
• The median time to neutrophil engraftment was 12 days (9-68) and to platelet engraftment, 12 days (9-70)
• Median days of hospitalization: 22 (14-42)
Efficacy post ASCT day 100 (Hema) 
  • Hematological response improved in 53%
From PR to VGPR (23%), from PR to CR/sCR (14%) and from VGPR to CR/sCR (16%) 
  • The best response obtained was 9o/o PR, 41 °/o VGPR, 39%CR and 7% sCR with one patient relapsing

Efficacy post ASCT day 100 (Renal)

  • Nine patients (70%) achieved dialysis independence from the time of diagnosis: 13 patients were on dialysis at diagnosis, 6 at the time of ASCT, and 4 three months post-ASCT
  • Renal function improved post-ASCT in 34% of patients, 14%moving from a CrCI of less than 40 ml/min to 60 ml/min and 20% to above 60 ml/min
  • No patient experienced worsened renal function following ASCT


  • In this preliminary analysis, HOM with ASCT proved to be safe and effective in MM patients with RI at transplant.
  • We observed one death among 4 7 patients within the first 3 months post-ASCT
  • Renal function improved in 34% with 2 patients off dialysis and hematological response improved in 53%


COAST (OP-501): First-in-man Phase I multicenter study evaluating OD5 as a myoablative cinditioning regime in relapsed refractory multiple myeloma (RRMM)

Sergio Giralt, Kristine Bäck, Stefan Norin, Francesca Gay

ASCT for patients with MM 

• Conditioning with 200 mg/m2 melphalan is currently considered the standard regimen before ASCT in patients with MM

• However, current HOT is associated with limitations:

• a substantial proportion of patients do not achieve MRD-negativity

• severe non-hematological toxicities, including mucositis and infections

• There is a need for new myeloablative treatments that overcome the limitations of current HDT

Development of OPDS

• OPD5 is a PDC under development as a high-dose conditioning regimen prior to ASCT

• OPD5 is an analogue of melphalan flufenamide (melflufen) and preclinical data indicate similar PK and lipophilic properties, and comparable toxicity profiles

• In contrast to melflufen, OPD5 has been formulated to meet the requirements for high-dose myeloablative therapy

• COAST (OP-501 ): First-in-man Phase I multicenter study evaluating OPD5 as a myeloablative conditioning regimen in RRMM

• Study population: up to 42 patients with RRMM who have received at least 2 prior lines of therapy • Treatment duration: 2 days (high-dose OPDS infusion followed by ASCT the following day)

Key inclusion criteria 

• Measurable MM • Aged 18-70 years (life expectancy 6 months or more) • ECOG PS 1 • At least 2 prior lines of therapy; refractory to a Pl, IMID, and anti-CD38 mAb or CD38-targeted mAb • 2-9 cycles of prior re-Induction therapy • Previous ASCT with progression 24 months or less post-ASCT • Bilirubin 1 .5 X ULN or lower, AST/ALT 3 X ULN or lower, CrCL t45 ml/min or higher

Key exclusion criteria 

• Prior allogeneic or salvage ASCT • Evidence of mucosal bleeding and/or Is platelet transfusion refractory • Previous cytotoxic, biologic, investigational, or corticosteroids therapies 3 weeks or less prior to study treatment • Inadequate cardiac or pulmonary function •Left ventricular ejection fraction below 45% • FEV1 below 50% of the predicted value

COAST {OP-501): dose-escalation schedule

• Single dose of OPD5 is given after 2-9 cycles of re-induction therapy (investigator's choice) • Starting dose OPD5 30 mg/m2 is equivalent to melflufen 55 mg, the highest dose used in RRMM to date • Highest dose OPD5 235 mg/m2 is equimolar to melphalan 142 mg/m2 • MTD: development of Dl Ts in more than one patient in a specific dose cohort indicates that the MTD has been exceeded

COAST {OP-501): Objectives

Primary objective: determine the recommended Phase 2 dose of OP05 by evaluating safety and tolerability 

  • Endpoints include TEAEs until Day 30, clinically significant changes in clinical or laboratory parameters, mucosilis until Day 30, and deaths not related to relapse or progression at Day 100

Secondary objectives: efficacy, PK, myeloablation, and hematologic recovery, assess MRD in patients with suspected CR or VGPR 

  • Efficacy endpoints include best response, overall response rate, duration of response, time to progression, time to next treatment, and progression-free survival

Exploratory objectives: translational biomarkers, DNA damage, the correlation between dose/PK parameters and response 


• HOT followed by ASCT is the current standard of care in transplant-eligible patients with MM and other hematological malignancies

• there is a need for new myeloablative treatments with improved rates and depths of responses and enhanced tolerability versus current HOT options

• OPD5 is a peptide-drug conjugate under development as a high-dose conditioning regimen prior to ASCT

• OPD5 has similar preclinical PK and lipophilic properties as melflufen, with a comparable toxicity profile

• The first-in-man COAST (OP-501) study aims to demonstrate the value of OPD5 as a high-dose myeloablative therapy prior to ASCT in RRMM


Characteristics and Treatment Patterns of Triple-Class Exposed Patients With Relapsed/Refractory Multiple Myeloma Who participated in Clinical Trials of Daratumumab

Katja C. Weisel, Thomas Martin, Kwee Yong, et al.

• Although Pis (eg, bortezomib), IMiDs (eg, lenalidomide), and anti-CD38 mAbs (eg, daratumumab) have improved survival in patients with MM, many patients relapse or become refractory to these therapies • Novel agents are under investigation in patients who have received a Pl, IMiD, and anti-CD38 mAb (ie, triple-class exposed) • Limited data are available characterizing treatment patterns and outcomes in patients with triple-class exposed MM from a global data set with predominantly European patients.

Evaluate subsequent therapies and clinical outcomes in patients with triple-class exposed R/R MM using data from daratumumab global clinical trials

Triple-class exposed patients with R/R MM were identified from 3 trials of the anti-CD38 mAb daratumumab (POLUX (NCT02076009; CASTOR NCT02136134; EQUULEUS NCT01998971)

• After study treatment discontinuation, patients were followed for PFS with therapy subsequent to trial treatment and OS

• Subsequent treatments were per physician choice

Inclusion criteria

• ECOG performance status less than 2 • Received 3 or more prior lines of therapy, including a Pl, IMiD, and anti-CD38 mAb • Receivedone or more subsequent therapy after becoming triple-class exposed • Progressed less than 12 months of last LOT


• This first global analysis of treatment patterns for triple-class exposed patients with R/R MM showed a high subsequent treatment burden

- The majority of patients received regimens containing at least triplets and retreatment with one or more drug that  
   was administered prior to becoming triple-class exposed
- There was no clear standard of care for this population
- Median PFS and OS with subsequent therapy was 5.8 and 15.7 months, respectively

• Consistent with our findings, recent retrospective studies of patients with triple-class exposed MM in the United States reported that this patient population frequently received Pis, IMIDs, and anti-CD38 mAbs as subsequent therapy

• Agents recently approved for this patient population, the BCMA-directed antibody-drug conjugate belantamab mafodotin (US FDA and EMA) and the selective nuclear export Inhibitor selinexor (US FDA) yield low ORR (below 35%) and short PFS (below5 months)

• There is a need for new treatments to improve outcomes in this patient population with a high unmet need.