Autologous stem cell transplantation for multiple myeloma patients whose myeloma-defining event was SLiM.

INTRODUCTION

For decades, the diagnosis of multiple myeloma (MM) required the presence of end‐organ damage attributed to the underlying plasma cell disorder, known as the Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria. 1 The CRAB criteria include increased calcium level, renal dysfunction, anaemia and destructive bone lesions.

In 2014, the diagnostic criteria for MM were updated by the International Myeloma Working Group (IMWG) to include biomarkers in addition to the existing CRAB criteria. 2 The biomarkers included any one or more of the following: clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ration (FLCr) ≥100 (involved FLC must be ≥100 mg/L) and >1 focal lesion on MRI studies (each lesion ≥5 mm). These criteria are called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria and are currently considered a myeloma‐defining event (MDE) that justifies treatment. Currently, the treatment of these patients is similar to that of patients treated with standard CRAB criteria. Whether these patients should be treated differently remains unclear.

Before 2014, patients who met the SLiM criteria were considered smouldering multiple myeloma (SMM) at ultra‐high risk for progression to MM, with a predicted likelihood of 80% in 2 years to progress to MM. The rationale of the updated criteria was that it allows for the treatment of patients who are at ultra‐high risk of progression to symptomatic disease to potentially prevent severe organ damage from occurring. The results of end‐organ damage, especially acute renal failure or pathological fracture, were judged to be unacceptably high, with a risk of substantial long‐term morbidity. Moreover, with the major progress that has occurred in the treatment of MM, and although watchful waiting may have been appropriate in an era of alkylating agents and corticosteroids, intervention seemed justifiable for ultra‐high‐risk patients given the availability of safer and more effective treatments.

The introduction of the SLiM criteria was based on several retrospective studies. A study published by our group showed that patients with SMM reported that having a bone marrow plasma cells (BMPC) of ≥60% had a higher risk of progression to active MM. 3 This population comprised 655 patients who underwent a baseline bone marrow evaluation at the time of diagnosis; in 21 of these patients (3%), the percentage of bone marrow plasma cells was ≥60%. Progression to MM occurred within 2 years of the diagnosis in 95% of the patients with ≥60% bone marrow plasma cells, with a median time to progression of 7 months. Positron emission tomography (PET) scans or total body MRIs were not consistently performed in these patients. These findings were validated by the Greek Myeloma Group in a study that included 96 SMM patients that showed a median time to progression of 15 months in patients with ≥60% bone marrow plasma cells. 4 In a retrospective study that included 586 patients with SMM, 90 patients (15%) had a serum involved/uninvolved FLC ratio ≥100. The risk of progression to MM within the first 2 years in patients with an FLC ratio ≥100 was 72%. The median time to progression in the FLC ratio ≥100 group was 15 months. 5 The Greek Group showed similar results in a study that described outcomes of 96 SMM patients, 7% of which had an FLC ratio ≥100, and almost all progressed within 18 months. 4 Since multimeric light chain aggregates may increase FLC levels and impair renal light chain clearance, our group conducted a retrospective study to assess the association between urine monoclonal protein (uMCP) excretion and the risk of progression. The study included 822 SMM patients without an MDE besides elevated FLCr ( n = 120 with FLCr ≥100, n = 702 with FLCr <100). The 2‐year risk of progression to active MM or AL amyloidosis was 36% in patients with uMCP excretion ≥200 and 13.5% in patients with <200 mg/24 h. 6 Of note, even the group with a high excretion of uMCP did not reach the 80% risk of progression at 2 years that was felt to justify treatment initiation. In a retrospective study that included 149 SMM patients who underwent a total body MRI, 23 (15%) had more than one focal lesion. The median time to progression of this subgroup was 13 months. 7 The Greek Myeloma Group reported on 65 SMM patients who underwent spinal MRI; nine (14%) had more than one focal lesion. The median time to progression (mTTP) of this subgroup was 15 months, and 70% progressed in 2 years. 8 Based on this evidence, the IMWG concluded that a high FLC ratio, BMPC ≥60% and >1 focal lesion per MRI are predictors of imminent progression in SMM, and such patients may be considered candidates for early treatment intervention.

Over the past two decades, there has been great progress in the treatment of MM, with many new medications incorporated into routine treatment. 9 , 10 , 11 , 12 However, whether the current treatment paradigm used for MM applies similarly to patients diagnosed only with SLiM criteria is still unknown. Autologous stem cell transplantation (ASCT) has been an integral part of MM treatment for young and selected fit elderly patients 13 , 14 with a proven progression‐free survival (PFS) benefit 15 and possible OS advantage. 16 To date, there is no data about the response and safety of ASCT in patients treated due to MDE of SLiM.

Herein, we report the outcomes of ASCT in a cohort of MM patients treated due to SLiM or for evolving MM.

METHODS

We conducted a retrospective study of all consecutive MM patients who underwent ASCT due to SLIM criteria at Mayo Clinic, Rochester, Minnesota. The study was approved by the Mayo Clinic Institutional Review Board (IRB). The diagnosis and staging of MM were according to consensus criteria. 2 For risk stratification, we used the international staging system (ISS) and fluorescence in situ hybridization (FISH) in CD 38+‐sorted plasma cells. High‐risk FISH was defined according to IMWG risk stratification criteria 17 and included del 17p, t (4;14), t (14;16), t (14;20) and Gain 1q.

For every patient treated because of SLiM, we matched two patients with CRAB. The matching was done by age, gender, ISS and melphalan dose.

In both cohorts, the eligibility criteria for ASCT were similar

Our current consensus for eligibility of patients with MM undergoing ASCT is assessed up to 30 days before transplant. It includes performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2, no significant comorbidities, adequate liver and renal function, respiratory function studies (FEV1 ≥50%. DLC ≥50%), echocardiography (EF ≥40%), chest X‐ray, sinus X‐ray and a dental evaluation. Plerixafor is used on demand if, on day 4 of GCSF injections, peripheral CD34+ is less than 10 cells/μL.

All patients received conditioning consisting of melphalan 140 or 200 mg/m 2 . Melphalan doses were selected by the treating physician based on clinical judgement. Melphalan was given as a single‐day infusion on day ‐2 with a rest day on day‐1 until the policy changed in February 2018. From February 2018 till February 2019, melphalan was given as a single‐day infusion on day ‐1. After February 2019, the policy was changed again (due to evidence of delayed engraftment when melphalan was given on day ‐1), and patients received melphalan on day ‐2. Supportive care was provided based on Mayo's standard protocol (including prophylaxis with acyclovir, fluconazole, levofloxacin and penicillin).

Neutrophil engraftment was defined by absolute neutrophil count (ANC) ≥ 500/μL for three consecutive days and platelet engraftment by ≥50 000/μL without transfusion support. Bone marrow MRD assessment was done using eight‐colour next‐generation flow cytometry (sensitivity ≥1 × 10 6 ).

The response was assessed at day 60 (high risk) to 100 (standard risk) post‐ASCT according to consensus criteria. 18 A chart review was conducted to assess disease characteristics as well as transplant‐related outcomes. Data on primary indications for hospitalization and duration of hospitalization were collected on all patients. Continuous variables were described as the median and range of observations. Categorical data were described as the median and interquartile range (IQR).

Transplant‐related mortality (TRM) was defined as death from any cause within 100 days of stem cell infusion. The median survival time and the probabilities of overall survival (OS) and progression‐free survival (PFS) were estimated using the Kaplan–Meier method. OS was defined from day zero of bone marrow transplant to death from any cause. PFS was defined as the time from day zero to relapse, assessed by consensus criteria or time to reinitiating therapy or death. Cox regression analysis was used to study the association between studied predictors and OS and PFS. The Wilcoxon rank sum and chi‐squared tests were used to analyse continuous and dichotomous variables respectively. The two‐sided p ‐value <0.05 was considered statistically significant. Statistical analysis was carried out using the JMP 17 (SAS, Cary, NC) statistical software.

RESULTS

Between May 2013 and October 2022, 1886 MM patients underwent ASCT at Mayo Clinic, in 30 of whom the MDE was SLiM criteria or increasing M protein without CRAB. The reasons for treatment initiation were ≥60% bone marrow plasma cells in 12 patients (40%), FLCr ≥ 100 in 14 patients (47%), more than one focal lesion per MRI in one patient (3%) and rapidly rising proteins in two patients (6%). One patient (3%) met both ≥60% bone marrow plasma cells and FLCr ≥ 100.

The baseline characteristics for all 30 patients are listed in Table 1 . The median age at MM diagnosis was 63 (range 46–75). Fifteen patients (50%) were male. The median age at day 0 was 63 (range 46–76); patients aged 70–76 accounted for 20% of the cohort. Seventeen patients (56%) had high‐risk cytogenetic features. Twenty‐five patients received triplet induction with novel agents (listed in Table 1 ), and five patients (17%) received daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) induction.

Transplant‐related data are summarized in Table 2 . The median time from diagnosis to ASCT was 6.5 months (IQR 6–7). For peripheral blood progenitor cell collection, granulocyte colony‐stimulating factors (G‐CSF) were used in all patients. Plerixafor was used in 24 patients (80%) with low peripheral CD34+ at day 4 (<10 cells/μL). The median time to neutrophil engraftment was 15 days (IQR 14–17) and to platelet engraftment (50 000/μL) was 15 days. 14 , 15 , 16

Reduced intensity conditioning (melphalan 140 mg/m 2 ) was administered to one patient (3%) who was aged 75 at day 0. All others (97%) received full‐dose conditioning (melphalan 200 mg/m 2 ). Fourteen patients (47%) had neutropenic fever complicating their transplant course. Bacteraemia was confirmed in seven patients (2 E. coli , 1 Pseudomonas aeruginosa , 2 Staphylococcus epidermidis , 1 Streptococcus , 1 Gemella haemolysans ). Stem cell transplantation at our centre is routinely performed as an outpatient, with patients being hospitalized when deemed clinically necessary upon physician review. Sixteen (53%) patients completed the entire transplant course without hospitalization. Among the 14 patients (47%) that required hospitalization, the median duration of hospital admission was 6 days (IQR 5–14). Reasons for hospitalization included fever or infection (4 patients), diarrhoea, vomiting and nausea (8 patients). Similar hospitalization rates and bacteraemia rates were seen in the control cohort. The SLiM group had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. No differences were seen in the number of cells collected or the use of plerixafor (80% vs. 78%, p = 0.8).

The overall response rate (patients achieving at least a partial response) was 100%, with a complete response or better seen in 30% of patients. MRD assessment was only performed in patients with no morphologic evidence of bone marrow plasma cells at day 60–100. Eighteen patients met these criteria, and nine patients (50% of patients who underwent MRD assessment) achieved MRD‐negative CR (30%). One patient underwent a second ASCT 7.5 years after the first one due to relapsed disease. The median follow‐up for all surviving patients is 55 months (IQR 41–64). Twenty‐eight (93%) of the patients are alive, and two patients died due to progressive MM at 76 and 102 months. None of the patients died within 100 days of transplant, which represented a 0% 100‐day mortality (TRM). Seven patients in the SLiM cohort have progressed during follow‐up, with time ranging from 7 to 69 months from day 0.

The matched cohort consisted of 60 patients, and their baseline characteristics are listed in Table 1 . The median age at MM diagnosis was 62 (range 45–75). Thirty‐one patients (52%) were male. The median age at day 0 was 62 (range 46–75); patients aged 70–76 accounted for 16% of the cohort. Thirty‐one patients (52%) had high‐risk cytogenetic features. As expected, median haemoglobin was lower in the CRAB group (13.1 vs. 12, p = 0.0017). Fifty‐four patients received triplet induction with novel agents (listed in Table 1 ), and six patients (10%) received DVRd induction. More patients in the control group were treated with VRd induction (80% vs. 46%), and fewer were treated with VCd (6% vs. 20%). The overall respose rate (ORR) in the CRAB cohort was 98%, with an MRD negativity rate for the CRAB cohort of 30%, similar to that of the SLiM group. The 36‐month OS was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%–97.42%), with a trend toward longer OS in the SLiM cohort ( p = 0.065) (Figure 1 ). The 36‐month PFS was 91.61% in the SLiM cohort (95% CI 69.93%–97.87%) and 65.95% in the control group (95% CI 52.31%–76.53%). The PFS was comparable between cohorts (HR 0.704, 95% CI 0.30–1.64, p = 0.42) (Figure 2 ).

DISCUSSION

The IMWG reached a consensus that patients with biomarkers associated with roughly an 80% probability of progression to MM within 2 years should be regarded as having MM and offered therapy. Since ASCT with high‐dose melphalan remains a cornerstone of treatment in MM, we were interested in evaluating the outcomes of these patients in terms of response and safety. This is the first report of outcomes of ASCT in 30 patients treated for MM diagnosed by SLIM criteria. Our data show that ASCT can be safely performed in MM patients diagnosed with SLIM criteria, with a TRM in our cohort of 0%. 53% of patients completed the ASCT without requiring hospitalization. The overall response rate was 100%, with 30% of patients achieving CR/sCR and 30% MRD negativity. The 36‐month PFS was 91.61% in the SLiM cohort (95% CI 69.93%–97.87%), and the 36‐month OS was 100%. When comparing our cohort to a matched cohort, the median time to neutrophil and platelet engraftment was significantly shorter in the SLiM cohort. We could not find published data about the response and safety of MM treatments in patients treated solely due to SLIM criteria, and we believe this is an important issue in the pursuit of personalized medicine.

All patients received novel agent‐based induction; 25 patients received triplet induction; and 17% received DVRd induction. All patients achieved ≥PR to induction. With highly effective treatment options existing for newly diagnosed MM and in the era of quadruplet‐based induction therapies, the role of ASCT is less clear. For every treatment we administer, we weigh the response versus toxicity. For our cohort, response rates are high, and toxicity is low. In terms of complication rate, 53% of patients completed the entire course of transplant without hospitalization. Among the 14 patients (47%) that required hospitalization, the median duration of hospital admission was 6 days. We expected a lower complication rate since this cohort is presumed to be fitter than the usual MM cohort that includes symptomatic patients including impaired kidney function and patients with bone disease. However, the hospitalization rate and nature of complications leading to hospitalization are consistent with the control cohort, comprised of patients meeting the CRAB, and with previous literature regarding outpatient ASCT. 19 , 20 None of the patients died within 100 days of transplant, which represented a 0% 100‐day mortality (TRM). This is lower than the TRM that was reported in our institution in a cohort of 716 patients with MM (median age 59) receiving ASCT, 21 but it could be related to a small sample size. None of the patients in our cohort developed a second primary malignancy (SPM). However, the median time from MM diagnosis to developing an SPM is 57 months, 22 so the 0 SPM may be related to short follow‐up. One of the rationales for treating high‐risk smouldering Multiple myeloma is that early intervention in asymptomatic patients would result in a higher rate of MRD negativity when compared to patients in whom therapy is initiated based on symptoms. A comparable hope exists in patients treated with SLiM criteria, that is, a higher MRD negativity rate when intervening in completely asymptomatic patients with high‐risk features. Unfortunately, our MRD negativity rate in patients transplanted because of SLiM criteria in the absence of CRAB criteria was 30%, which is not higher than MRD negativity rates in the control group (30%).

It is interesting to note that mobilization outcomes are not better than the control group. We postulated that, in patients with lower disease burden, we would need to use Plerixafor less often. However, 80% of the cohort received plerixafor, which is used in our centre only if on day 4 of GCSF injections, peripheral CD34+ is less than 10 cells/μL, with rates similar to the CRAB group.

The overall response rate (patients achieving at least a partial response) was 100%, with a complete response or better seen in 30% of patients. The 36‐month PFS was 91.61%, and the 36‐month OS was 100%. Two patients died due to progressive MM at 76 and 102 months. They relapsed 49 and 57 months post‐ASCT, and both were standard genetic risk. The very high response rates may be related to the fact that this cohort is probably fitter since these patients do not have bone disease or renal insufficiency that can cause disability. Moreover, 97% of our cohort received full‐dose melphalan. We generally try to avoid dose reductions, 23 but in one patient, who was 75, we used reduced intensity conditioning to reduce toxicity.

The limitations of our study are its retrospective nature and the small cohort of patients, suggesting that the low TRM and low admission rates should be interpreted with caution. Also, the study was not powered for subgroup analysis. We have relatively short median follow‐up, so we cannot provide data on durability and toxicity.

In conclusion, we demonstrate high response rates to ASCT for patients treated due to SLiM criteria and that ASCT can be safely delivered in the outpatient setting. However, it does not result in higher MRD negativity rates or improved PFS compared to patients transplanted for standard CRAB. The longer PFS is not surprising, given the lower ISS stage of SLiM patients compared to CRAB. The failure to achieve a longer survival compared to CRAB is concerning since one might expect a longer OS given the lead time advantage from SLiM to symptoms, which could be as much as 2 years.

AUTHOR CONTRIBUTIONS

I.V. designed the study, analysed the data, wrote the first draft and approved the final version of the manuscript. S.S. analysed the data. E.M., K.P., S.K., A.D., F.B., D.D., W.G., T.K., R.W., S.S., I.C. and W.H. critically revised the manuscript and approved the final version of the manuscript. M.A.G. designed the study, analysed the data, wrote the first draft and approved the final version of the manuscript. All authors have reviewed the manuscript, agreed with its contents and consent to its submission to BJH.

FUNDING INFORMATION

This work did not receive funding support.

CONFLICT OF INTEREST STATEMENT

Dr. Gertz reports: DSMB AbbVie, DSMB Celgene, Akcea Honoraria and consulting, i3Health educational materials, Prothena consulting, Research to Practice Honoraria, Alnylym consulting, Ambry Genetics honorarium, Amgen honorarium, Janssen Honorarium, Celgene Honorarium, Stock Options Aurora Bio, Ionis Advisory Board, Karyopharm Honorarium, Pfizer honorarium to institution, Sanofi honorarium. Kumar: Research funding for clinical trials to the institution: Abbvie, Amgen, BMS, Carsgen, Janssen, KITE, Merck, Astra‐Zeneca, Novartis, Roche‐Genentech, Takeda, Tenebio, Consulting/Advisory Board participation: (with no personal payments) Abbvie, Amgen, BMS, Janssen, Roche‐Genentech, Takeda, KITE, Astra‐Zeneca, and (with personal payment) Oncopeptides, Beigene, Antagene.

ACKNOWLEDGEMENTS

Open access publishing facilitated by Tel Aviv University.

Vaxman I, Kumar S, Cohen I, Shimony S, Dispenzieri A, Buadi F, et al. Autologous stem cell transplantation for multiple myeloma patients whose myeloma‐defining event was SLiM . Br J Haematol. 2025;206(2):607–614. 10.1111/bjh.19936

[Correction added on 22 January 2025, after first online publication: Fourth author’s surname was corrected.]

[Correction added on 14 February 2025, after first online publication: The subcategory has been changed.]

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Associated Data

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.