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Ixazomib, pomalidomide and dexamethasone in triple-class
exposed multiple myeloma patients - a phase II study
by Tamir Shragai, Noa Lavi, Iuliana Vaxman, Moshe E. Gatt, Evgeni Chubar, Chezi Ganzel, Hila Magen,
Efrat Luttwak, Moshe Mittelman, Svetlana Trestman, Eyal Lebel, Revital Saban, Vladimir Vainstein,
Tsila Zuckerman, Netanel Horowitz, Inna Tzoran, Nurit Horesh, Noa Lowenton-Spier, Natan Melamed,
Ilana Pereg, Irit Avivi and Yael C. Cohen
Received: April 14, 2026.
Accepted: August 31, 2026.
Citation: Tamir Shragai, Noa Lavi, Iuliana Vaxman, Moshe E. Gatt, Evgeni Chubar, Chezi Ganzel, Hila Magen,
Efrat Luttwak, Moshe Mittelman, Svetlana Trestman, Eyal Lebel, Revital Saban, Vladimir Vainstein,
Tsila Zuckerman, Netanel Horowitz, Inna Tzoran, Nurit Horesh, Noa Lowenton-Spier, Natan Melamed,
Ilana Pereg, Irit Avivi and Yael C. Cohen. Ixazomib, pomalidomide and dexamethasone in triple-class
exposed multiple myeloma patients - a phase II study.
Haematologica. 2026 Sept 10. doi: 10.3324/haematol.2026.301067 [Epub ahead of print]
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1
Ixazomib, pomalidomide and dexamethasone in triple-class exposed
multiple myeloma patients - a phase II study
Tamir Shragai1,2, Noa Lavi3,4, Iuliana Vaxman 1,5, Moshe E. Gatt6,7, Evgeni Chubar8, Chezi
Ganzel6,9, Hila Magen1,10, Efrat Luttwak1,2,11, Moshe Mittelman1,2, Svetlana Trestman2, Eyal
Lebel6,7, Revital Saban6,7, Vladimir Vainstein6,7, Tsila Zuckerman3,4 , Netanel Horowitz3,4, Inna
Tzoran3,4, Nurit Horesh3,4, Noa Lowenton-Spier2, Natan Melamed2, Ilana Pereg2, Irit Avivi1,2
and Yael C. Cohen1,2
1) Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2) Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
3) Department of Hematology, Rambam Health Care Campus, Haifa, Israel
4) Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
5) Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
6) Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
7) Department of Hematology, Hadassah University Hospital, Jerusalem, Israel
8) Department of Hematology, HaEmek Medical Center, Afula, Israel
9) Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
10) Department of Hematology, Tel-Hashomer, Chaim Sheba Medical Center, Ramat-Gan,
Israel
11) Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center,
New York
Clinical trial registration:
Clinicaltrials.gov identifier: (NCT04790474).
Acknowledgments: The authors acknowledge Takeda pharmaceuticals for
providing Ixazomib (Ninlaro®) and supporting this study through a research grant.
The authors also wish to thank Irit Segalovich and Ella Krayzler from the Clinical
trial units, Tel-Aviv sourasky medical center, for their support with coordination
and monitoring.
Contribution: Y.C.C, N.L.S and T.S designed the study and wrote the protocol;
T.S, Y.C.C, N.L, I.V, M.E.G, E.C, C.G, H.M, E.L, M.M, S.T, E.L. R.S, V.V, N.H,
T.Z, I.T, N.H, and I.A enrolled the patients and conducted the study; T.S, Y.C.C
and N.M analyzed the data; N.M performed the statistics; I.P monitored data at all
sites; T.S, Y.C.C and N.M wrote the manuscript; I.A, I.V and N.L critically
reviewed the manuscript; All authors read and approved the submitted version of
the manuscript.
Conflict-of-interest disclosure:
T.S: Consulting & advisory role: GSK, Takeda; honoraria: J&J;
Y.C.C: Consulting & advisory role: J&J, Sanofi, BMS, Takeda, Pfizer, GSK;
Speaker’s Bureau: GSK, J&J; Research Funding: J&J, Takeda
All other co-authors declare no conflict of interest
2
Data-sharing statement
The data supporting the findings of this study are available from the
corresponding author upon reasonable request.
Correspondence: Tamir Shragai, Department of hematology, Tel-Aviv sourasky
medical center, Tel-Aviv, Israel; e-mail: tamirsh@tlvmc.gov.il.
3
Abstract:
Multi-class upfront regimens for multiple myeloma (MM) have improved
outcomes, yet many patients become either triple-class exposed (TCE) or
refractory (TCR) early in their disease course. This is a phase II, investigator
initiated, open-label, single-arm, prospective, multicenter study evaluating all-oral
Ixazomib-pomalidomide- dexamethasone (IPd) regimen for TCE RRMM patients.
Sixty-one patients were enrolled between March 1st 2021 and March 17th 2024.
The median age was 74 (range: 53-89) years; 25 (41%) were ≥75 years old. Fifty-
seven percent had high-risk cytogenetics (t(4;14), t(14;16), +1q21, del17p(.
Twenty-six (43%) patients were frail. Refractoriness rates to bortezomib,
lenalidomide and daratumumab were 51%, 85% and 96% respectively. Triple-
class refractory (TCR) rate was 39%. Ninety-seven percent of the patients had ≥1
treatment emergent adverse event (TEAE) and 67% had a TEAE grade ≥3. The
rate of Gr ≥3 AE was not increased in frail vs. non-frail patients (p=0.43). Overall
response rate (ORR) was 58% (22% very good partial response or better). TCR
patients had an ORR of 46% vs. 68% for non-TCR patients (p=0.12). The median
progression-free survival was 8.1 (95% CI 3.9-12.3) months and the median
overall survival was 30.4 (95% CI 21.5-39.4) months. To conclude, the all-oral
IPd regimen for TCE RRMM patients showed high response rates and a
manageable safety profile, in a cohort enriched with TCR, elderly and frail
patients. (NCT04790474).
4
Introduction:
Progress in the treatment paradigm of multiple myeloma (MM) in recent years
has resulted in marked improvements in patients' outcomes. The introduction of
triplet and quadruplet regimens in the frontline setting resulted in improved
progression-free survival (PFS) and higher minimal residual disease (MRD)
negativity rates, both for transplant eligible(1–3) and transplant ineligible(4–7)
patients. In recent years, due to incorporation of quadruplet regimens in the front-
line setting, many patients are triple-class exposed (TCE) - that is, exposed to
proteasome inhibitor (PI), immunomodulatory drug (IMiD) and CD38 monoclonal
antibody (MoAb) at their 1st relapse - and almost all patients are TCE at their 2nd
relapse. TCE patients exhibited unfavorable treatment outcomes, with PFS and
overall survival (OS) of 4.6 months and 9.2 to 13.8 months, respectively, in real-
world studies(8,9), prior to the introduction of T-cell redirectional therapy. While
novel immunotherapies, mainly chimeric antigen receptor T-cell (CART) and
bispecific antibodies, show promising efficacy in the early relapse setting(10–12),
their use is sometimes challenged by toxicity, financial costs and logistic
complexity.
Ixazomib is an oral 2nd generation PI, with proven efficacy as a part of
combination regimens in newly diagnosed(13), and relapsed refractory (RR)
MM(14).
Pomalidomide is an oral third generation IMiD with single-drug activity in RRMM
patients (15). Adding pomalidomide to the PI bortezomib improved PFS in
lenalidomide exposed RRMM patients(16). Pomalidomide was also used in
various single arm trials for RRMM(15–18).
5
Ixazomib-pomalidomide-dexamethasone (IPd) combination is an all-oral triplet for
TCE patients, which could be particularly suitable for older patients. Therefore,
we designed a prospective trial to explore the safety and efficacy of this
combination in patients with TCE myeloma.
Methods:
Ethics approval and consent to participate:
The IPOD-790 study is a phase II investigator-initiated study. It was conducted in
7 Israeli centers and was approved by Institutional Review Boards at each
institution. All subjects signed informed consent prior to screening. Ixazomib was
supplied by Takeda Inc. Pomalidomide was supplied by patients' health plan.
This trial is registered at www.clinicaltrials.gov (NCT04790474).
Eligibility:
Patients ≥ 18 years of age with RRMM according to the international myeloma
working group (IMWG) criteria(19). Patients had to have measurable disease and
be triple-class exposed or refractory. Exposure was defined as receiving at least
1 full cycle of a drug; Refractoriness was defined as documented progression
while receiving, or within 60 days of last dose of anti-myeloma drug(20). Patients
had to have adequate bone marrow reserve (hemoglobin ≥8 gr/dl, platelet count
≥75×109/L and neutrophil count ≥1.0 ×109/L), creatinine clearance (using the
MDRD(20) equation) >15 mL/min, and Eastern Cooperative Oncology Group
(ECOG) score of 2 or less. The full inclusion/exclusion criteria are provided in the
supplementary materials.
Treatment plan:
6
Eligible patients received ixazomib 3 mg (days 1,4,8,11), pomalidomide 4 mg
(days 1-14), and dexamethasone 20 mg (days 1,2, 8,9, 15 and 16) every 21 days
for 3 cycles (cycles 1-3), followed by 28-days cycles of ixazomib 4 mg (days 1,8
and 15), pomalidomide 4 mg (days 1-21) and dexamethasone 20 mg (days 1,2,
8,9, 15, 16, 22 and 23) every 28 days, for additional 21 cycles (cycles 4-24)
(Figure S1). The initial doses of pomalidomide and dexamethasone could be
decreased (to 3 and 10 mg, respectively) in patients older than 75 and/or with
renal impairment (creatinine clearance of 15-50 mL/min), according to physician
discretion. Doses may have been subsequently increased if the regimen was well
tolerated. After completion of 24 treatment cycles, patients continued
pomalidomide and dexamethasone as standard of care until progression or
unacceptable toxicity. Mandatory supportive care included prophylactic antiviral
therapy against varicella zoster virus and prophylactic anticoagulation (or
antiplatelet therapy). The cut-off date for database lock was May 1st, 2025.
Definitions:
Revised international staging system (R-ISS) was calculated according to serum
levels of albumin, beta2 microglobulin, lactate dehydrogenase and the presence
of del(17p), t(4;14) or t(14;16)(21). Patients were considered to have high-risk
(HR) cytogenetics if they had one of these alterations or +1q gain/amplification,
as detected by fluorescence in situ hybridization (FISH) since diagnosis. Frailty
score was calculated according to the modified IFM frailty score, based on age,
ECOG and Charlson comorbidity score(22) according to Facon et al(23). Double
refractory patients were defined as patients whose disease was refractory to both
bortezomib and lenalidomide. Bortezomib-free interval and lenalidomide-free
7
interval were defined as time (in months) from last administration of the drug as a
part of previous line to C1D1.
Endpoints:
The primary endpoint was PFS. Secondary endpoints included the safety profile
of the regimen using the National Cancer Institute Common Terminology Criteria
for Adverse Events (version 4.0) (24), the response rates according to IMWG
criteria(25), duration of response (DOR; defined as time from 1st documented
response to progression of disease [PD]), time to next treatment (TTNT; defined
as time from 1st dose of study regimen to first dose of subsequent regimen), and
OS.
Statistics:
Sample size determination: Assuming a PFS of at least 8 months in our study
with IPd regimen , a sample size of 61 patients, enrolled over 24 months with an
additional follow-up of 18 months, will allow to detect superiority over the
historical control group(26) (POM/dex arm - PFS 4.7 months) with a power of 0.8
and type 1 error of 5%.
The estimation of median time-to-event data for PFS, OS, DOR and TTNT was
done using the Kaplan-Meier method. Cox regression was used to model the
relationship between predictor variables and time-to-event data. Association
between categorical variables was determined using Chi-square or Fisher's exact
test, depending on sample size. All the statistics were performed using IBM
SPSS Statistics for Windows, version 29 (IBM Corporation, 2022).
8
Results:
Sixty-one patients (35 [57%] males) were enrolled between March 1st 2021 and
March 17th 2024. The median age was 74 (range: 53-89); 13 patients (21%) were
80 years or older. The R-ISS score was I/II/III for 29%, 55% and 16%,
respectively; 57% had high-risk cytogenetics. Twenty-six (43%) patients were frail
according to simplified myeloma frailty score(23); Ten patients (16%) had a
glomerular filtration rate ≤40 ml/min. All patients were exposed to bortezomib and
lenalidomide and were included in the safety cohort. Sixty (98%) were DARA
exposed and were included in the efficacy cohort (one DARA-naïve patient was
excluded from the efficacy cohort). Refractoriness rates to bortezomib,
lenalidomide and daratumumab were 51%, 85% and 96%, respectively. Thirty-
nine percent of the patients were Triple-class refractory (all double-refractory
patients were also triple refractory). Thirty percent had undergone autologous
stem-cell transplantation. Median time from diagnosis to enrollment was 45
[interquartile range 28-74] months, median prior lines of therapy was 2 (range 1-
4) (Table 1). The initial dose of pomalidomide was 4 mg in 50 (82.0%) patients.
Eleven (18.0%) patients had reduced initial dose at physician discretion (3 mg in
10 patients and 2 mg in 1 patient). Thirty-five (57%) patients received anti-platelet
therapy, 20 (33%) received anticoagulation therapy, 4 (7%) received both anti-
coagulation and anti-platelet therapy and 2 patients (3%) did not receive anti-
platelet nor anti-coagulation therapy.
At data cut-off date (May 1st, 2025), two patients (3%) remained on study
treatment and 7 patients (11%) completed 2 years of study regimen and
continued pomalidomide monotherapy as standard of care, as prespecified in the
9
protocol. Study regimen discontinuation occurred in 52 patients (85%): 34 (56%)
due to (d/t) PD, 14 (23%) d/t AE, 3 (5%) withdrew consent and 1 (2%) d/t
investigator decision. Seven (11%) patients died on treatment (see details below)
(Figure 1).
Safety:
Fifty-nine patients (97%) had ≥1 treatment emergent adverse event (TEAE) and
41 (67%) had a TEAE grade (Gr) 3 and above. Common (occurring in ≥15% of
patients) TEAEs related to study regimen included neutropenia (39%, Gr≥3:
30%), fatigue (33%, Gr≥3: 2%), pneumonia (30%, Gr≥3: 26%, including 3% Gr 5),
thrombocytopenia (31%, Gr≥3: 18%), gastrointestinal (GI) toxicity (33%, Gr≥3:
3%; including diarrhea 30%, Gr≥3: 3%; nausea and vomiting 13%, Gr≥3: 0%),
anemia (30%, Gr≥3: 5%), peripheral edema (26%, Gr≥3: 2%), pain (23%, Gr≥3:
3%), rash (20%, Gr≥3: 0%), peripheral neuropathy (18%, Gr≥3: 2%) and
COVID19 infection (15%, Gr≥3: 3%)(Table 2). Thirty-two patients (52%) had a
dose reduction: pomalidomide, ixazomib and dexamethasone doses were
reduced in 18 (30%), 14 (23%) and 17 (28%) of patients, respectively. The
reasons for ixazomib dose reductions were neutropenia (6 patients),
thrombocytopenia (5 patients), peripheral neuropathy (2 patients) and
constipation, nausea and urinary tract infection (UTI) (1 patient each). The
reasons for pomalidomide dose reductions were: neutropenia (6 patients), rash (5
patients), anemia, thrombocytopenia (4 patients each), Sweet/ suspected Sweet
syndrome (2 patients), deterioration in kidney function (2 patients), neuropathy,
disequilibrium, fatigue, constipation, edema, UTI, pneumonia (1 patient each). For
both drugs, some patients had multiple reasons for dose reductions. Twenty-two
(36%) patients had at least one serious adverse event (SAE), mainly infectious
10
(28%, including pneumonia in 18%, febrile neutropenia 5% and bacterial
meningitis 1.6%). Other SAEs included acute renal injury, acute febrile
neutrophilic dermatosis and ischemic cerebrovascular accident (1.6% each).
As mentioned above, 7 (11%) patients died while still on treatment: 1 d/t PD, and
6 (10%) patients died from AEs: one from CVA, and 5 (8%) patients died from
infections: 3 pneumonia, 1 COVID19 infection and 1 septic shock. Three of these
patients died during the first 3 cycles of therapy, without achieving response. Two
died 6 and 12 months from treatment initiation, one in VGPR and one in stable
disease (SD). Three of them had dose reduction prior to their death. All 6
patients who died from AEs were frail. Eight (13%) patients (2 frail, 6 non-frail)
discontinued treatment d/t AEs. Six (10%) were potentially related to the study
regimen: pneumonia, thrombocytopenia, meningitis, renal failure, blepharitis and
upper GI bleeding. Two of them had a dose reduction (both had pomalidomide
dose reduction, and one of them additionally had ixazomib dose reduction) prior
to permanent discontinuation of the study protocol. Two (3%) patients
discontinued protocol because of AEs deemed by investigator to be unrelated to
treatment: adenocarcinoma of GI tract and dementia. No venous thromboembolic
events were observed.
Efficacy:
Sixty patients were eligible for response assessment (one patient was not
exposed to DARA and therefore excluded from the efficacy cohort). Overall
response rate (ORR) was 58%. Complete response (CR), very good partial
response (VGPR) and partial response (PR) rates were 7% (stringent CR in 2%),
15% and 36%, respectively.
11
The median follow-up time was 32 (95% CI 28.8-35.2) months. The median PFS
was 8.1 (95% CI 3.9 – 12.3) months (Figure 2A). The median DOR and TTNT
were 10.7 (95% CI 8-13.5) and 11.7 (95% CI 8.5-14.9) months, respectively.
Patients achieving VGPR or better had a median PFS and median DOR of 25.6
(95% CI 3-48.2) and 24.9 (95% CI 2.2-47.6) months, respectively. The median
OS was 30.4 (95% CI 21.5-39.4) months (Figure 2A). Response to treatment
(achieving PR or better) was not significantly associated with OS in a time-
dependent Cox regression model adjusted for age and sex, but a trend toward
improved survival was observed (HR 0.46; 95% CI 0.20-1.05; p=0.065). Patients
with high-risk cytogenetics had similar ORR as patients with standard risk
cytogenetics, 59% vs. 60%, respectively (p=0.96), but shorter PFS and DOR (7.9
vs 13.8 months, p=0.036; 8.6 vs 13.1 months, p= 0.05) (Figure 2B).
Impact of drug-refractoriness:
Single-class refractoriness: ORR rates were 52% and 66% for bortezomib
refractory and non-refractory patients, respectively (p=0.31). Similarly, ORR was
56% and 75% for lenalidomide refractory and non-refractory patients, respectively
(p=0.45). PFS and DOR did not differ significantly between bortezomib-refractory
and bortezomib-sensitive patients (PFS: 7.1 vs 9.8 months, p=0.98; DOR: 11.5 vs
9.5 months, p=0.85) (Figure 3A). Lenalidomide-refractory patients had shorter
PFS and DOR compared to patients who were lenalidomide-sensitive (PFS: 6.2
vs 16.6 months, p=0.156; DOR: 9.1 vs 24.9 months, p=0.017) (Figure 3B).
Lenalidomide-free interval and bortezomib-free interval had no impact on ORR,
PFS and DOR (appendix Table S1).
Triple refractoriness: ORR was numerically lower for patients who were refractory
to bortezomib, lenalidomide and daratumumab: 46% vs. 68% for patients who
12
were not triple-refractory, p=0.12. Median PFS and DOR in triple-refractory
patients (4.0 and 7.4 months, respectively) were not significantly different from
those in non-triple-refractory patients (Figure 3C). OS of triple-refractory patients
was shorter than that of non-triple-refractory patients (26.6 vs. 37.2 months),
although at the time of data cut-off this did not reach statistical significance
(p=0.09).
Impact of frailty:
Twenty-six (43%) of the study population had a frailty score of 2 or more
according to the simplified frailty score(23). Frail patients had no increase in all
AEs, Gr≥3 AEs, all infections, Gr≥3 infections, Gr≥3 anemia, renal failure and
stroke (appendix Table S2), but, as mentioned above, had a significantly higher
rate of fatal AEs compared to non-frail (6 vs none, p=0.001). Gr≥3
thrombocytopenia was higher in frail patients (46% vs. 17%, p=0.014), leading to
treatment discontinuation in one patient only.
ORR of frail patients was 50% vs 65% for non-frail (p=0.30). Frail patients had
numerically but not statistically significant shorter PFS (6.2 vs 9.8 months,
p=0.14) (Figure 2C) and DOR (7.6 vs 11.5 months, p=0.13). A trend towards
shorter OS in frail patients was noticed: median OS of 22.5 months vs 34.7 in
the non-frail patients, p=0.065.
Combined effect of frailty and refractoriness:
Almost all frail patients were lenalidomide refractory (24/26, 92%). Half (13/26) of
the frail patients were bortezomib-refractory and 38% (10/26) were TCR.
Bortezomib-refractory and TCR frail patients had consistently numerically lower
ORR and shorter PFS and DOR (appendix Table S3). None of these
comparisons was statistically significant, except for DOR for TCR frail patients
13
compared to non-TCR frail patients: 3.3 months (95% CI 0.0-7.7) vs 10.7 months
(95% CI 6.5-14.9), p=0.02.
Discussion:
In this phase II multi-site study of triple-exposed RRMM patients, an all-oral
regimen of ixazomib-pomalidomide-dexamethasone resulted in a response rate
of 58% and median DOR of 10.7 months. A twice-weekly ixazomib administration
was used in the first three cycles, aiming to increase dose intensity in order to
improve initial disease control in these hard-to-treat TCE patients. To date, three
published prospective trials evaluated the combination of IPd for RRMM. The
participants were younger and less frail than in our cohort, and most patients
were not TCE: Krishan et al.(27) published a phase I/II trial of 32 bortezomib
exposed, lenalidomide refractory patients. The median age was 62 (38-84) years,
and the median number of previous lines was 2 (1-5). ORR was 48%, with a
median PFS and DOR of 8.6 and 9.2 months, respectively. None of the patients
was reported to be DARA exposed. The IFM 2014 trial was a multicenter, open-
label, single arm, phase II study of IPd in 26 lenalidomide refractory MM patients
with adverse genomic abnormalities, defined as t (4;14) and/or del 17p at 1st or
2nd relapse(28). Ixazomib was given twice weekly (3 mg on days 1,4,8,11 every
21 days) for 17 cycles and then switched to weekly administration (4 mg days
1,8, 15 every 28 days). Less than half of the patients were DARA exposed. The
median age was 72 and 12 patients were 75 or older. ORR was 60%, DOR was
10.0 months and median OS was 23.7 months. Safety profile was manageable
and demonstrated the tolerability of twice weekly 3 mg ixazomib
administration(28). The ALLIANCE 061202(29) was a phase II randomized trial
comparing IPd to pomalidomide-dexamethasone (Pd) in 1st relapse for
14
lenalidomide refractory, but PIs naïve or sensitive, MM patients. None of them
were DARA exposed. Seventy-seven patients were randomized in a 1:1 ratio.
The median age was 65 (with only 6 patients older than 75 in the IPd arm). The
ORR for the IPd arm was 63% with median DOR of 23 months, both numerically
better than the control arm but differences were not statistically significant.
Patients in the IPd arm had significantly higher rate of deep responses (VGPR or
better) - 29% vs. 5% (p<0.00). There was no difference in OS. Hematological and
GI gr≥ 3 AEs were higher in the IPd arm. Thus, the abovementioned studies
reported ORR rates and DOR similar to our cohort. The longer DOR reported in
the ALLIANCE 061202 trial(29) likely reflecting patient populations with lesser
disease resistance, as TCE patients were not included. Other studies used
different pomalidomide combinations for TCE patients: The SELECT(18) trial
investigated the carfilzomib-pomalidomide combination in 52 RRMM patients.
Sixty-seven percent were TCE and 37% were TCR. ORR was similar to ours with
58%, but responses were more durable: median PFS was 11.1 and median DOR
was 20.3 months. The ALGONQUIN trial enrolled patients after a median of 3
(range 1-6) previous lines of therapy to receive belantamab mafodotin in
combination with pomalidomide(30). In a post-hoc subgroup analysis of 69 TCE
patients(31) ORR was 86% (with 64% VGPR or better). The median DOR was 22
months. Both studies included younger patients (median age 67-68) compared to
our cohort.
Indeed, the unmet need among TCE patients was shown in recent real-world
studies preceding the introduction of novel immunotherapies, including
Mammoth(8) and Locommotion(9) that reported inferior results in this population,
with ORR of 29-30%, and median PFS and OS of 4 and 12 months, respectively.
15
Our study population is highly enriched with elderly and frail patients, which would
have precluded their enrollment in most interventional studies. Rates of TEAE
related discontinuation and on-study death (23% and 11%, respectively) were in
accordance with other early-relapse, non-immunotherapy trials with similar age
distribution(18,32). Although response rates of frail patients were not significantly
lower compared to the non-frail patients (50% vs. 65%, respectively, p=0.30) a
trend towards shorter DOR and OS was noted, probably attributed to 6 frail
patients who died without achieving response, thus uncontrolled myeloma could
have also contributed to their death.
The ORR was lower among TCR patients, suggesting potential class-wide drug
resistance. Of note, all double refractory patients in our efficacy cohort were also
triple-refractory (as daratumumab is typically continued until progression, and
discontinuation d/t AEs is uncommon). Nevertheless, nearly half of the TCR
patients responded, and maintained response for more than 7 months (almost
double than DOR for triple-class refractory patients in the Locommotion study(9)).
The recent introduction of T-cell redirectional therapy and anti B-cell maturation
antigen (BCMA) CART significantly improved outcomes of TCE patients. Initial
studies of novel immunotherapies enrolled TCE RRMM patients in late relapse
(after 3 or more lines of therapy). These studies have demonstrated encouraging
results: ORR was 63-98% and median DOR was 7.8-33 months(33–37). Novel
Immunotherapy outcomes are superior to those in our IPd cohort and will likely
change the treatment paradigm for relapsed TCE myeloma in the coming years.
Combination studies may further improve efficacy outcomes(11,31,38) as may
the introduction of novel immunotherapies in earlier treatment lines.
The place of IPd regimen nowadays needs to be considered in the context of
these remarkable results. Nevertheless, the IPd regimen, being an all-oral
16
therapy, represents an alternative option for some of the TCE RRMM population,
with a manageable safety and tolerability profile, no need for hospitalizations d/t
risk of CRS and no hypogammaglobulinemia requiring IVIG administration (as
opposed to immunotherapy), and no keratopathy (associated with belantamab-
mafodotin). It may also be considered in between immunotherapy regimens, to
allow for T cell recovery. An all-oral combination can potentially overcome social
and mobility challenges that may interfere with adherence. However, frail patients
did suffer from considerable toxicity, including fatalities, underscoring the need for
careful patient selection and monitoring.
The response rate of 58% which we report in this study is encouraging in this
TCE population, enriched with high-risk cytogenetics (57%), elderly (41% >75
years) and frail (43%) patients, which closely resembles “real-world” patients.
However, most responses were not deep (22% VGPR or better), translating to a
median duration of response (DOR) of 10.7 months. While still surpassing
expectations for this cohort, these results remain inferior to immunotherapy or
BPd regimens(10,31). Whether extending ixazomib biweekly administration
beyond three cycles could lead to deeper and more durable responses remains
unknown. In the IFM 2014 trial, twice weekly ixazomib for 17 cycles did not yield
a longer DOR (median 10.0 months); notably, the study only included patients
with high-risk cytogenetic aberrations. The more frequent administration did not
result in added toxicity(28).
Limitations of this study include the small sample size and single arm design. The
absence of pharmacokinetic samples, particularly during cycles with biweekly
ixazomib administration, precluded determination of the optimal dosing schedule.
Frailty was assessed using the simplified IFM frailty score, as the variables
required for this tool were consistently available in our dataset, whereas more
17
comprehensive validated scores such as the IMWG frailty score were not
assessed in our trial.
In conclusion, our study demonstrated the efficacy and safety of the all oral
combination therapy of IPd in TCE and relapsed myeloma patients. The efficacy,
safety and tolerability demonstrated in a cohort relatively enriched with elderly
and frail patients, which are typically underrepresented in clinical trials, provide an
alternative for patients who are not candidates for more intensive treatments.
18
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22
Table 1: Baseline Demographic and Clinical Characteristics of the Study
Population (N=61)
n* %
Age, years:
<65
65-75
≥75
11
25
25
18
41
41
Sex
Male 35 57
Female 26 43
ECOG
0 25 41
1 31 51
2 5 8
Frail† 26 43
eGFR‡
>60 31 51
30-60 25 41
<30 5 8
Myeloma type (n=55)
IgG 26 47
IgA 9 16
Light chain only 20 36
ISS (n=48) I / II / III 20 / 12 / 16 42 / 25 / 33
R-ISS (n=44) I / II / III 13 / 24 / 7 29 / 55 / 16
FISH Cytogenetics§ (n=47)
Any high-risk FISH 27 57
Double-hit myeloma 4 9
true EMD at study baseline (n=59) 3 7
Prior Drug Exposure and Resistance
Prior lines of therapy
1 6 10
2 44 72
3-4 11 18
Bortezomib – Exposed (E) / Refractory
)R) (R)
61 / 31 100 / 51
Daratumumab - E / R 60 / 59 98 / 96
Lenalidomide - E / R 61 / 52 100 / 85
Carfilzomib - E / R 3 / 2 5 / 3
Post-ASCT 18 30
Triple-class refractory
(DARA+PI+IMiD)e 5– R
24 39
* n=61 Unless otherwise specified
23
† Frailty status was determined using the simplified IFM frailty score based on
age, ECOG, and Charlson Comorbidity Index according to Facon et al(23)
‡ eGFR was calculated using the MDRD equation(20)
§ High-risk cytogenetics defines as the presence of del(17p), t(4;14), t(14;16) or
+1q gain/amplification. Double-hit myeloma was defined as the presence of two
or more of these aberrations.
24
Table 2: Common Treatment Emergent Adverse Events (≥15%)
AEs All grade GR ≥3
n % n %
Neutropenia 24 39 18 30
Fatigue 20 33 1 2
Pneumonia 19 31 16 26
Thrombocytopenia 19 31 11 18
Anemia 18 30 3 5
Diarrhea 18 30 2 3
Peripheral edema 16 26 1 2
Pain 14 23 2 3
Rash 12 20 0 0
Peripheral neuropathy 11 18 1 2
COVID-19 infection 9 15 2 3
25
Figure 1: CONSORT diagram of patient's disposition
Consort flow diagram for the IPoD study.
Figure 2: Progression-free and overall survival
(A) Progression-Free Survival (PFS) and Overall Survival (OS) (B) PFS
by Cytogenetics: Patients with high-risk cytogenetics (HR FISH), defined as:
t(4:14), t(14:16), +1q21, or del17p) compared to standard -risk patients (C)
PFS by Frailty Status: Frail patients (frailty score ≥2) compared to non-frail
patients
Figure 3: Progression-free survival according to prior refractoriness
PFS according to bortezomib (A), lenalidomide (B) and triple-class
refractoriness status (C).
Table S1: Impact of bortezomib and lenalidomide-free intervals on efficacy:
HR (95% CI) p-value
Bortezomib-free interval:
ORR
PFS
DOR
1.022 (0.998-1.048)
0.992 (0.981-1.002)
0.998 (0.975-1.002)
0.075
0.113
0.094
Lenalidomide-free
interval:
ORR
PFS
DOR
1.030 (0.978-1.085)
0.989 (0.966-1.013)
0.979 (0.949-1.009)
0.261
0.378
0.168
Supplementary
Table S2: Comparison of TEAEs between frail and non-frail patients:
Frail
n (%)
Non frail
n (%) P value
Any TEAE 26 (100) 33 (94) 0.503
TEAE GR 3-5 18 (69) 23 (66) 0.772
Common TEAEs in frail
patients:
Thrombocytopenia
Thrombocytopenia GR≥3
Diarrhea
Neutropenia
Neutropenia GR≥3
Anemia
Anemia GR≥3
Peripheral edema
Rash
Pneumonia
AKI
Stroke
All infections
10 (39)
6 (23)
12 (46)
8 (31)
6 (23)
7 (27)
1 (4)
7 (27)
5 (19)
8 (31)
3 (12)
1 (4)
17 (65)
9 (26)
5 (14)
6 (17)
16 (46)
12 (34)
11 (31)
2 (6)
9 (26)
7 (20)
11 (31)
1 (3)
2 (6)
25 (71)
0.29
0.50
0.014
0.24
0.34
0.70
1
0.92
0.94
0.96
0.30
1
0.6
Table S3: Refractoriness status in frail patients:
Refractory Non refractory p-value
Bortezomib n=13 (50.0%) n=13 (50.0%)
ORR (%) 38.5% 61.5% 0.24
PFS (months):
median (95% CI) 6.23 (2.60-9.87) 9.77 (0.00-21.82) 0.53
DOR (months):
median (95% CI) 5.53 (0.67-10.40) 9.30 (2.69-15.90) 0.28
Lenalidomide n=24 (92.31%) n=2 (7.69%)
ORR (%) 50.0% 50.0% 1
PFS (months)
median (95% CI) 5.70 (1.98-9.42) 7.90 (N/A) 0.22
DOR (months)
median (95% CI) 5.97 (2.40-9.53) N/A N/A
Triple-Class n=10 (38.46%) n=16 (61.54%)
ORR (%) 40.0% 56.3% 0.420
PFS (months)
median (95% CI) 4.47 (0.95-7.98) 7.90 (0.00-15.87) 0.243
DOR (months)
median (95% CI) 3.27 (0.00-7.74) 10.73 (6.54-14.92) 0.022
Study Population:
Adult patients with a confirmed diagnosis of symptomatic and relapsed and/or
refractory MM, after receiving bortezomib, lenalidomide and daratumumab during
first and second lines, will be eligible to be enrolled in this study.
For the purposes of this study, refractory disease is defined as disease progression
on treatment or progression within 60 days after the last dose of a given therapy.
Inclusion criteria:
Patients must meet all of the following inclusion criteria:
1. Male or female patients, 18 years of age or older.
2. Multiple myeloma diagnosed according to standard IMWG criteria
3. Patients must have measurable disease defined by at least one of the following
five
measurements:
• Serum M-protein >1 g/dL (>10 g/L).
• Urine M-protein >200 mg/24 hours.
• Serum free light chain assay: involved free light chain level at least 100 mg/L),
provided that the serum free light chain ratio is abnormal.
• A biopsy proven evaulble plasmacytoma
• Bone marrow plasmacytosis > 30% of total marrow cells
4. Patients received one or two prior lines of therapy which must have included
bortezomib, lenalidomide-and daratumumab.
NOTE: A line of therapy is defined as one or more cycles of a planned treatment
program. This may consist of one or more planned cycles of single-agent therapy or
combination therapy, as well as a sequence of treatments administered in a
planned manner. For example, a planned treatment approach of induction therapy
followed by autologous stem cell transplantation, followed by maintenance is
considered one line of therapy. Autologous transplants are permitted.
5. Patients must meet the following clinical laboratory criteria:
• Absolute neutrophil count (ANC) ≥1,000/mm3 and platelet count≥75,000/mm3.
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3
days of enrollment.
• Total bilirubin ≤1.5 the upper limit of the normal range (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 ULN.
• Calculated creatinine clearance ≥15 mL/min
NOTE: Patients with creatinine clearance of 15-50 mL/min will receive
pomalidomide at a reduced dose (3 mg), which may subsequently be increased if
well tolerated.
6. ECOG performance status of 0, 1 or 2.
7. Female patients who:
• Are postmenopausal for at least 24 months before the screening visit, OR
• Are surgically sterile, OR
• Who are of childbearing potential, and agree to practice two effective methods of
contraception (1 highly effective method and 1 additional effective method) AT THE
SAME TIME, from the time of signing the informed consent through 90 days after the
last dose of study treatment, OR agree to completely abstain from heterosexual
intercourse, AND
• Must also adhere to the guidelines of the pomalidomide pregnancy prevention
program
Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 days of
initiation of Cycle 1 and again within 24 hours of starting Cycle 1. FCBP must also
agree to ongoing pregnancy testing. All patients must be counseled at a minimum of
every 28 days about pregnancy precautions and risks of fetal exposure.
8. Male patients, even if surgically sterilized (i.e., status postvasectomy), who:
• Agree to completely abstain from heterosexual intercourse, OR
• Agree to practice effective barrier contraception (i.e., latex condom) during sexual
contact with a FCBP, even if they have had a successful vasectomy, throughout the
entire study treatment period and through 4 months after the last dose of study
treatment AND
• Must also adhere to the guidelines of the pomalidomide pregnancy prevention
program.
9. Must be able to take concurrent aspirin 100mg daily (or enoxaparin 40 mg
subcutaneously daily [or its equivalent] if allergic to aspirin) as prophylactic
anticoagulation.
NOTE: For patients with prior history of deep-vein thrombosis, low molecular weight
heparin (LMWH) or alternative anticoagulation (coumadine / NOAC) according to
physician discretion, is advised.
10. Voluntary written consent must be given before performance of any study-
related procedure not part of standard medical care, with the understanding that
consent may be withdrawn by the patient at any time without prejudice to future
medical care.
11. Patient is willing and able to adhere to the study visit schedule and other
protocol requirements.
Exclusion criteria:
Patients meeting any of the following exclusion criteria are not eligible to participate
in the study:
1. Patient underwent an allogeneic transplantation
2. Female patients who are lactating or pregnant.
3. Major surgery within 14 days before enrollment.
4. Central nervous system involvement
5. Concomitant use of any other antineoplastic treatment with activity against MM
(with the exception of ≤40 mg Dexamethasone per day or equivalent for no longer
than 4 days).
6. Infection requiring systemic antibiotic therapy or other serious infection within 14
days before enrollment
7. Diagnosis of Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)
syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome,
or myeloproliferative syndrome.
8. Evidence of current uncontrolled cardiovascular conditions, including
uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic
congestive heart failure, unstable angina, or myocardial infarction within the past 6
months.
9. Anti-myeloma therapy as follows prior to screening bone marrow aspiration:
• Targeted therapy, epigenetic therapy, within 14 days or at least 5 half-
lives,whichever is less;
• Monoclonal antibody treatment for multiple myeloma within 21 days;
• Cytotoxic therapy within 14 days;
• Proteasome inhibitor therapy within 14 days;
• Immunomodulatory agent therapy within 7 days.
• Radiotherapy within 14 days (with the exception of radiotehrapy for spinal cord
compression or for pain control that should be discussed and approved by the
sponsor- investigator prior to study enrollment). However, if the radiation portal
covered ≤5% of the bone marrow reserve, the subject is eligible irrespective of the
end date of radiotherapy.
10. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin,
ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin,
itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before
enrollment in the study.
11. Ongoing or active systemic infection, active hepatitis B virus infection, active
hepatitis C infection, or known human immunodeficiency virus (HIV) positive.
12. Comorbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into this
study or interfere significantly with the proper assessment of safety and toxicity of
the prescribed regimens.
13. Psychiatric illness/social situation that would limit compliance with study
requirements.
14. Known allergy to any of the study medications, their analogues, or excipients in
the various formulations of any agent.
15. Inability to swallow oral medication, inability or unwillingness to comply with the
drug administration requirements, or known GI disease or planned gastrointestinal
(GI) procedure that could interfere with the oral absorption or tolerance of
treatment.
16. Diagnosed or treated for another malignancy within 2 years before enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type
are not excluded if they have undergone complete resection.
17. Failure to have fully recovered (ie,
Grade 1 toxicity) from the reversible effects
of prior chemotherapy.
18. Patient has
Grade 3 peripheral neuropathy during the screening period.
19. Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial.
20. Patients that have previously been treated with ixazomib or pomalidomide