A Prospective Study of Lenalidomide Monotherapy for Relapse After Allogeneic Stem Cell Transplant for Multiple Myeloma

Abstract

Allogeneic stem cell transplantation (Allo-SCT) can result in long-term remissions in patients with multiple myeloma (MM), although its overall role in disease management remains controversial. We evaluated lenalidomide monotherapy response and tolerability among patients with MM who progressed (PD) or relapsed after Allo-SCT. Eighteen patients, enrolled a median of 12 months (range 3–104) following transplant. Treatment duration of lenalidomide was 8 months (range 1–57). Ten patients required dose reductions from 25 mg to 5–20 mg at a median of 3 cycles (range 1–12); 8 for neutropenia; 1 for thrombocytopenia, and 1 for myalgias and weakness. Serious adverse events N=5, included H1N1 influenza (2), bacterial pneumonia (2), and fever, myalgia and hypoxia. Two patients died at 3 and 5 months of gastrointestinal or hepatic GVHD occurring within 1 month of dosing. Responses included CR (5), VGPR (2), PR (3), MR (1) and SD (2) for an overall response rate (≥PR) of 56%. Ten patients discontinued therapy for PD a median of 8.5 (1–43) months. Six patients died from PD. Five patients remain on therapy at 39 months (range 14–57), 4 in CR. Lenalidomide for relapse of MM after Allo-SCT can result in extended disease control (>12 months) in 50% of patients.

Introduction

There has been enormous progress in the treatment of multiple myeloma (MM) due to the development of new drugs and the widespread use of high dose therapy and autologous stem cell transplant (SCT).^1,2 Median overall survival has improved from 3 to 5 years and patients diagnosed before age 50, without high risk features, may expect to live more than 10 years.^2,3 Despite these improvements, MM remains incurable for the large majority of patients who will eventually die of recurrent disease. Myeloablative allogeneic SCT was the first therapy demonstrated to produce durable, long term remissions in some patients with MM. High rates of transplant related mortality, however, have limited it use to relatively few, younger patients.^4–6 The development of non-myeloablative, reduced intensity conditioning regimens with improved early mortality led to wider application and several trials comparing autologous SCT with reduced intensity allogeneic SCT. These trials have produced inconsistent results with several trials demonstrating improved overall survival for allogeneic SCT while others have shown equivalent outcomes.^7–12 Thus, the role of allogeneic SCT in the overall management of MM remains controversial.

Few studies have examined treatment outcomes for patients who receive allogeneic SCT and develop recurrent disease. The most widely reported treatment, donor lymphocyte infusions (DLI), results in complete response rates of approximately 20% in which remissions may be durable in select patients but with an increased risk of GVHD.^12–14 Lenalidomide is a second generation “immunomodulatory” drug with substantial activity in newly diagnosed and relapsed multiple myeloma. In the relapsed setting, response rates as monotherapy are approximately 25%.¹⁵ Allogeneic SCT results in an entirely new immune effector mechanism for graft recipients and has the potential for improved response to immunomodulatory agents. One report using lenalidomide as maintenance therapy after allogeneic SCT observed an intolerable rate of GVHD and it was concluded that the drug could not be used in this setting.¹⁶ Other reports have demonstrated activity in patients with MM who relapse after allogeneic SCT.^17,18 To address this question we designed a prospective trial to examine the activity and toxicity of lenalidomide monotherapy in patients with relapsed setting after allogeneic SCT.

Materials and Methods

This prospective study opened in March 2008, with the final patient enrolled in December 2011. The trial enrolled patients with MM who had received a prior allogeneic SCT, either ablative or non-myeloablative, from either a related or unrelated donor, and who subsequently experienced disease progression or relapse at any time following transplant. Eligibility included progression according to European Group for Bone Marrow Transplantation Criteria which included a 25% increase in monoclonal protein, or a 50% increase in urinary protein, new or increased bone lesions or hypercalcemia.¹⁹ Patients must have discontinued all cancer related therapy, except for corticosteroids or immunosuppressive therapy for GVHD at least 4 weeks prior to beginning lenalidomide. Patients had to have an ECOG status ≤2, meet minimum organ function requirements including blood counts ; absolute neutrophils of 1.5 × 109/L, and platelets 50 × 108/L, creatinine ≤2 mg/dL, bilirubin ≤1.5 mg/dL, SGOT and SGPT ≤2 times upper limit of normal. Females could not be pregnant, and patients were required to comply with RevASSIST program. Exclusions included prior malignancy within 5 years of diagnosis, acute GVHD grades 3–4, known hypersensitivity to thalidomide or lenalidomide and known positivity to HIV or hepatitis viruses.

The trial’s primary objective was to determine the overall response rate, with secondary objectives of determining safety, progression-free and overall survival.

The starting dose of lenalidomide monotherapy was 25 mg orally days 1–21 every 28 days as monotherapy. Dose reductions at 5 mg increments were allowed after cycle 1 for neutropenia, thrombocytopenia or non-hematologic toxicities. Patients received aspirin 81 or 325 mg for thromboprophylaxis. The trial was designed to enroll 18 patients.

Results

Eighteen patients were enrolled in the trial during the 3 year, 9 month interval. Their characteristics are shown in table 1. Patients were a median age of 54.5 years (range 33–66). They had received a median of 2.5 lines of prior therapy (range 1–6). Sixteen of the patients had received a prior autologous transplant as part of a tandem autologous-allogeneic transplant approach. Five patients had relapsed after a prior autologous transplant and received a second autologous transplant as part of the tandem approach. One patient had 2 non-ablative transplants without a prior autograft while one patient received only a single ablative allograft using a busulfan, melphalan preparative regimen. All patients received mobilized peripheral blood stem cells from either matched siblings(N=11), matched unrelated donors(N=6) or a C locus, mismatched unrelated donor (N=1). Six donors were sex mismatched with their recipient. Eight patients developed acute GVHD, grade 2. Eight patients developed chronic GVHD requiring treatment. Fourteen patients responded after allogeneic transplant; 10 CR, 4 PR. Eight patients had received lenalidomide prior to their allogeneic transplant. Disease relapse, progression and trial enrollment occurred 2–101 months, median 12 months, following allogeneic transplant. Four patients relapsed after receiving 2 or more doses of bortezomib dose 1.3 mg/m2 given every other week as maintenance after the allogeneic stem cell transplant.

Table 1.

Patient and Donor Characteristics

Pt #	Age	Sex	Tx Type	Donor/Sex	#Auto	Prior Len	GVHD Acute Gr.	GVHD Chronic	Response
1	48	M	NA	MR/M	1	N	2	Y	CR
2	33	M	BuMel	MR/F	0	Y	0	Y	PR
3	63	M	NA	MU/M	2	Y	2	Y	PR
4	61	F	NA	MR/F	2	Y	2	NE	PD
5	49	M	NA	MU/M	2	Y	0	Y	PR
6	66	M	NA	MMU/M	2	Y	2	Y	CR
7	60	M	NAx2	MR/F	0	N	0	N	CR
8	59	M	NA	MR/M	1	N	0	N	CR
9	48	F	NA	MR/F	1	N	2	Y	CR
10	57	M	NA	MR/M	1	N	0	Y	CR
11	53	M	NA	MR/M	1	N	0	N	CR
12	43	M	NA	MU/M	1	Y	2	Y	PR
13	60	M	NA	MU/F	2	N	0	N	CR
14	48	M	NA	MR/F	1	N	0	N	PD
15	48	M	NA	MR/F	1	N	2	N	PD
16	59	F	NA	MU/M	1	Y	0	N	PD
17	48	F	NA	MU/F	1	Y	2	N	CR
18	56	F	NA	MR/F	1	N	0	N	CR

TxType NA=nonablative, BuMel=Busulfan, melphalan

Donor MR=matched related, MU= matched unrelated, MMU=mismatched unrelated

Response after allogeneic transplant (but prior to subsequent relapse)

The duration of lenalidomide therapy was a median of 12 months (range 0.5 to 57+ months). (Table 2) Responses were complete n=5, very good n=2, or partial n=3 for an overall response rate of 56%. Two additional patients had a minimal response or stable disease.

Table 2.

Response and Outcome

Pt #	Time (mo)	Time on Therapy (mo)	Response	Reason for Discontinuation	Final Dose (mg)	Died (mo)
1	62	12	MR	PD	5	44
2	3	57+	CR		10
3	4	2.5	PR	PD	25	12
4	2	0.7	NE	GVHD	25	6
5	12	0.5	NE	GVHD	25	3
6	26	43	CR	PD	15
7	45	1.5	PD	PD	15	2
8	101	39+	CR		20
9	50	39+	CR		10
10	82	15	SD	PD	10
11	12	1.2	PD	PD	25	30
12	20	28	PR	PD	10
13	38	9	PR	PD	25
14	4	1.3	NE	toxicity	10	2
15	8	1.5	PD	PD	25	9
16	6	8	VGPR	PD	25
17	8	17+	CR		10
18	8	14+	VGPR		10

Time=interval from allogeneic transplant to start of lenalidomide (months)

Time on therapy= months from the start of lenalidomide therapy

Response to lenalidomide, CR=complete, VGPR=very good partial, PR=partial, MR=minimal, SD=stable disease, PD=progressive disease

Common adverse events, grades 1–2, were constipation 28%, diarrhea 17%, fatigue 17%, myalgia 17%, nausea 11%, neuropathy 11%, rash 11%, and thrombocytopenia 11%. Grade 3 adverse events were pneumonia 17%, H1N1 influenza 11%, and fever, hypoxia, neuropathy 6% and myalgias 6%. Eight patients required dose reductions to 20–10 mg for grade 3 neutropenia. One patient required dose reduction to 15 mg for neuropathy.

Three patients received steroids during lenalidomide. Two were on a prednisone taper during the first 2 months of therapy. A third patient had dexamethasone 20 mg added for a rising monoclonal protein after 1 year of monotherapy and had stable disease for another year before disease progression. Ten patients discontinued therapy due to progressive disease after a median of 8.5 months (range 1.2–43) of therapy. One patient discontinued therapy after 1.3 months due to toxicity characterized as myalgias, weakness and fevers despite dose reduction to 10mg. Two patients received only 14 and 19 days of lenalidomide at 25 mg/day; discontinuing due to the development of GVHD, 1 in the setting of a rapid taper of immunosuppression. In retrospect, 1 of these 2 patients had normal liver function tests at the time of trial registration but abnormal tests 10 days later, immediately prior to the start of lenalidomide. Both patients died due to complications of GVHD, 3 and 5 months following trial initiation. Eight patients have died 2–44 months after beginning lenalidomide, 6 of disease progression and 2 of GVHD. Ten patients are surviving a median of 35 months (range 14–57) with 5 still on therapy a median of 39 months (range 14–57).

Discussion

This prospective study confirms the efficacy of lenalidomide monotherapy in 18 patients who experienced disease progression after undergoing an allogeneic SCT. Overall lenalidomide was well tolerated with only 3 patients discontinuing therapy for toxicity or GVHD related issues. About one-half of patients required dose reductions of lenalidomide, primarily for neutropenia and 1 patient for neuropathy, occurring 4–24 months after the start of therapy.

Overall response rates in this heavily pretreated population were encouraging at 56%. This is superior to the historical 26% response rate reported for lenalidomide monotherapy among patients who had not undergone allogeneic transplant.¹⁵ Ten patients experienced disease control for at least 1 year, range 12–57+ months. Steroids were used in 3 patients on our study, 2 were finishing a prednisone taper (on 20 mg daily or alternate day prednisone) and 1 had dexamethasone added for a rising monoclonal protein after 1 year of monotherapy. The improved response rate and extended disease control suggest that lenalidomide may augment the donor immune response against myeloma in the post transplant setting. An increase in the frequency of CD4+Foxp3+ T cells has been demonstrated in response to lenalidomide administration.¹⁷ Other groups have observed an increase in the anti-myeloma activity of NK cells among patients on lenalidomide.²⁰

After allogeneic transplant, lenalidomide has been used both as maintenance therapy and as a form of consolidation to upgrade responses in combination with DLI.²¹ Unlike the HOVON group which reported a 47% incidence of acute GVHD with a 10 mg dose only 2 patients developed GVHD in our study.¹⁶ This reduced incidence could relate to the timing of administration after the transplant; 12 months in our trial versus 3 months in the trial using it for maintenance. Another trial of lenalidomide maintenance in high risk patients started between days 100–180 after allogeneic transplant, observed a 38% incidence of GVHD which led to discontinuance in 29%of patients.²⁰ Lenalidomide 10 mg has also been given with DLI beyond day 100 and after all immunosuppression was finished, without an apparent increase in GVHD.²¹ Thus the timing of lenalidomide administration after allografting is likely an important factor relating to the risk of exacerbating GVHD. One study preemptively utilized a combination of 1–3 DLI infusions plus either thalidomide, lenalidomide or bortezomib in patients with myeloma who were beyond 100 days from an alloSCT and had not achieved a CR. They observed a 59% rate of CR without excessive GVHD.²²

One report of 16 patients who relapsed after allogeneic transplant gave lenalidomide with dexamethasone (n=8) found an 87% response rate, but only 46% with lenalidomide monotherapy.¹⁷ Some of these patients were given DLI in close proximity to lenalidomide. GVHD grades 2–4 occurred in 5/16 patients. A retrospective study from a French consortium reported on 52 patients who received lenalidomide 25mg + dexamethasone (77%) started a median of 24 months after transplant for relapsed disease, found an 83% response rate.¹⁸ About 1/3 of patients experienced an exacerbation of GVHD. GVHD was more frequent in patients receiving lenalidomide as first line salvage and in patients who had recently discontinued immunosuppression. In our own study 1 of the 2 cases of ultimately fatal GVHD occurred in the setting of lenalidomide therapy initiated while immunosuppression was rapidly tapered. Taken together these studies suggest that lenalidomide is better tolerated beyond the 3 month period from an allogeneic transplant and when immunosuppression is finished without the development of GVHD.

In summary our prospective study suggests that lenalidomide monotherapy can be given safely to most patients who relapse after allogeneic SCT for myeloma. Furthermore lenalidomide appears to be highly effective in this setting, resulting in a significant response rate and prolonged disease control in some patients.