Allogeneic stem cell transplant for multiple myeloma & myelofibrosis with split-dose busulfan, fludarabine & cyclophosphamide

Abstract

Allogeneic stem cell transplant can have high morbidity and mortality in patients with myelofibrosis (MF) and multiple myeloma (MM). This phase 2 study used a novel myeloablative regimen of split-dose busulfan, fludarabine, and then post-transplant cyclophosphamide. Four patients with MF and 2 with MM were enrolled. At 1 year, non-relapse mortality was 33.3%, and overall survival was 50%. Incidence of acute and chronic GVHD was 33.3% and 16.7%, respectively. Those surviving beyond 1 year (MF = 1, MM = 2) had durable remissions with a median follow-up of 42 months. This small study demonstrates relative safety & favorable key outcomes using this novel approach.

1. Background

Multiple myeloma (MM) and myelofibrosis (MF) are two distinct hematologic malignancies for which allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as a potential treatment option [1]. For MM, allo-HSCT may be considered in younger patients with early relapse after primary therapy including autograft, and/or for high-risk disease based on cytogenetics, presence of extramedullary disease, or plasma cell leukemia [2]. High risk cytogenetics include hyodiploidy, chromosome 1 abnormalities, t(4;14), t(14;16), t(14;20), and del17p. Prior studies have investigated the role of allo-HSCT in multiple myeloma and suggest some efficacy; however, its success has been hindered by transplant-related mortality (TRM) [3]. MF patients with intermediate 2 or high-risk disease based on the Dynamic International Prognostic Symptom Score (DIPSS) are also eligible for allo-HSCT [4,5]. Similarly, allo-HSCT in MF is historically associated with substantial morbidity and high rates of TRM [6]. Given the historical issues with allo-HSCT in high-risk MM and MF, our group conducted a phase 2 trial investigating an alternative regimen (NCT03303950).

2. Materials & methods

A conditioning regimen consisting of myeloablative doses of busulfan and cyclophosphamide prior to stem cell infusion has been one of the most successful regimens in the treatment of MM [7]. To improve safety, efficacy, and reduce graft-versus-host disease (GVHD), we split the regimen so that cyclophosphamide was given after stem cell infusion on days 3 and 4, similar to the currently used strategy in haploidentical transplantation [8]. To further minimize toxicity, we used pharmacokinetic-directed high-dose busulfan and added a moderate dose of fludarabine to further improve engraftment of donor cells. For our phase II study, the final regimen consisted of busulfan (3.2 mg/kg/dose) with an AUC target of 76.8–86.4 mg x h/L and fludarabine (30 mg/m²/day) administered on days −5 – −2 before stem cell infusion. GVHD prophylaxis consisted of post-transplant cyclophosphamide (PTCY) 50 mg/kg on days +3 and +4 and tacrolimus and mycophenolate mofetil beginning on day +5 [9]. The primary endpoint was non-relapse mortality (NRM) at day +100. Secondary endpoints were NRM at day +365, incidence of acute and chronic GVHD at day +365, overall survival (OS) and disease-free survival (DFS) at day +365, and clinical and molecular response at day +365. Patients were consented in accordance with the Helsinki declaration, and the protocol was approved by the Huntsman Cancer Institute at the University of Utah Institutional Review Board (IRB).

3. Results & discussion

The study sought to enroll 24 patients but was terminated early due to slow accrual. A total of 6 patients [MF (n = 4); MM (n = 2)] were enrolled between the years of 2018 and 2020. All patients were Caucasian, with a median age of 55 years, and included one 69-year-old patient (Table 1). Five of the 6 patients (83.3%) were female.

Table 1.

Patient characteristics, disease characteristics, and key outcomes. Abbreviations: MF, myelofibrosis; MM, multiple myeloma; HSCT, hematopoietic stem cell transplant; MRD, minimal residual disease; KPS, Karnofsky performance scale; HCT-CI; hematopoietic cell transplantation specific comorbidity index; MSD, matched sibling donor; UD, unrelated donor; MUD, matched unrelated donor; CR, complete response; SD, stable disease; VGPR, very good partial response; sCR, stringent complete response; GVHD, graft-versus-host disease; N/A, not applicable.

Patient number
Age (years)	1	2	3	4	5	6
	50	56	69	58	51	53
Disease	MF	MF	MF	MM	MF	MM
Disease Status at HSCT	MRD positive	MRD positive	MRD positive	VGPR	MRD positive	Stringent CR3
KPS	90	70	80	90	90	90
HCT-CI	0	5	3	0	0	4
Donor Type	MSD 10/10	MSD 10/10	UD 9/10	MSD 10/10	MUD 10/10	MSD 10/10
Days to Neutrophil Engraftment	20	N/A	25	19	20	16
Days to Platelet Engraftment	15	N/A	51	14	33	10
Clinical Best Response	CR	Not evaluable	SD	VGPR	CR	sCR
Molecular Best Response	MRD negative	Not evaluable	MRD negative	MRD negative	MRD negative	MRD negative
Acute GVHD?	No	No	Yes	Yes	No	No
Chronic GVHD?	No	No	No	Yes	No	No
Day of Death	+347	+29	+179	Alive	Alive	Alive
Cause of Death	Relapse	Sepsis, respiratory failure	Severe pneumonia	N/A	N/A	N/A

MRD-negative status was achieved in all 5 evaluable patients (100%) at any time post-transplant. In terms of clinical response up to day +365, one MM patient achieved stringent complete response (sCR) and the other a very good partial response (VGPR). Of the three evaluable MF patients, two (66.7%) achieved complete remission (CR), while the other one (33.3%) had stable disease (SD). The incidence of acute and chronic GVHD by day +365 was 33.3% and 16.7%, respectively.

Grade 3 and higher adverse events were as expected in this study, affecting 4/6 (66.7%) of patients. The most common SAE was lung infection in 33.3% (2/6) of patients, with three episodes of respiratory failure. Other lower-grade adverse events (AE) generally included those common in allo-HSCT.

The NRM rate at day +100 was 16.7% (1 of 6 patients). This patient failed to engraft and died on day +30 due to sepsis. The cumulative NRM rate at day +365 was 33.3% (2 of 6 patients), with the second death due to severe pneumonia. A third patient died after disease relapse and progression to acute leukemia. The 3 patients alive at day +365 were disease-free. All three deaths which occurred by 1 year were in patients with myelofibrosis. Taken together, 1-year OS was 50% (Fig. 1).

Fig. 1.

Overall survival of patients with MM and MF undergoing allo-HSCT. [separate document].

The three patients who were alive at one year had durable long-term responses. All three patients were still alive at a median follow up time of 42 months. Only one of the three patients had chronic GVHD, manifesting as a mild skin maculopapular rash. Importantly, none of these patients experienced relapse of their disease. The two MM patients were placed on maintenance therapy with pomalidomide 1–2 mg daily every 21 days starting shortly after day +100 and have tolerated treatment well.

The treatment landscape for MM has changed dramatically in the last 3 years, particularly for those with higher-risk disease. Chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibodies, other immunotherapies, and novel induction and maintenance combinational regimens have provided more efficacious and less toxic options to patients with MM when compared to allo-HSCT. Although the two MM patients on this trial maintained durable remissions at 1-year post-transplant, a larger study population would be needed to validate this finding, as well as explore the role of novel maintenance strategies, like pomalidomide, following alloHSCT.

Although the rate of SAEs was high, the vast majority occurred in the single patient who failed to engraft and died on day +30. The remaining three patients who had SAEs experienced either a single SAE, or two events of the same SAE. Despite this, the numbers seen here are higher than those found by prior studies with more conventional myeloablative preparative regimens, attributable to our small study population [10,11].

The recent increased use of PTCY has greatly reduced the incidence of GVHD, particularly in patients receiving a haploidentical graft [8,12]. Utilization of this drug in our regimen showed a rate of aGVHD of 33.3%, consistent with typically observed rates. However, our rate for cGVHD (16.7%) was lower than the historical rate of 40–50%. However, this study is limited by a small sample size.

4. Conclusion

Our preparative regimen of busulfan and fludarabine followed by PTCY did demonstrate notable SAEs, but important outcomes such as disease-free survival were favorable in long-term survivors, particularly in MM patients who were subsequently placed on maintenance therapy. Future endeavors to optimize allo-HSCT conditioning regimens in patients with MM and MF remains an area of active and much-needed investigation.

CRediT authorship contribution statement

Andrew D. Trunk: Data curation, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. Sagar S. Patel: Data curation, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. Josef T. Prchal: Investigation, Methodology, Validation, Visualization, Writing – review & editing. Douglas W. Sborov: Investigation, Methodology, Validation, Visualization, Writing – review & editing. Axel R. Zander: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing. Catherine J. Lee: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

Declaration of Competing Interest

None.