Short-course lenalidomide plus low-dose dexamethasone in the treatment of newly diagnosed multiple myeloma — a single-centre pragmatic study

Purpose We assessed response to treatment, toxicity, time to progression, progression-free survival, and overall survival in patients newly diagnosed with multiple myeloma who were ineligible for or unwilling to undergo transplantation and who were treated with a combination of lenalidomide and low-dose dexamethasone for a fixed 6 cycles in a resource-constrained environment. Methods This pragmatic study, conducted in a single tertiary cancer centre in South India, enrolled patients from May 2009 till April 2011. Treatment included lenalidomide 25 mg daily for 21 days, with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle, for 6 cycles. Response was evaluated after the 3rd and 6th cycles of treatment. All patients were followed for 5 years. Results The study enrolled 51 patients. Median age in the group was 61 years (range: 38–76 years). Immunoglobulin G or A myeloma constituted 70.6% of the diagnoses, and light-chain myeloma constituted 29.4%. Stages i, ii, and iii (International Staging System) disease constituted 21.4%, 28.6%, and 50% of the diagnoses respectively. All patients were transplantation-eligible, but 34 (66.7%) refused for economic reasons. After treatment, 19.6% of the patients achieved a stringent complete response; 35.3%, a complete response; 5.9%, a very good partial response; and 29.4%, a partial response, for an overall response rate of 90.2%. Stable disease was seen in 3.9% of patients, and progressive disease, in 5.9%. Grade 3 or greater nonhematologic and hematologic toxicity occurred in 35.2% and 11.7% of patients respectively. Pulmonary embolism occurred in 1 patient. No patient experienced deep-vein thrombosis or peripheral neuropathy. The median follow-up duration was 66 months. All patients experienced disease progression. Median progression-free survival was 16 months. In 10 patients, re-challenge with lenalidomide and dexamethasone achieved a second complete response. At the time of writing, 19 patients had died. The overall survival rate at 5 years was 62.74%. Median overall survival is not yet reached. Conclusions In a resource-constrained setting, lenalidomide with low-dose dexamethasone is an effective treatment with acceptable toxicity in patients newly diagnosed with multiple myeloma and not planned for transplantation. Complete responses were significantly more frequent than reported in the Western literature. Occurrence of clinical deep-vein thrombosis was rare, but hyperglycemia was common. An abbreviated course of treatment is suboptimal in multiple myeloma. Maintenance regimens should be advocated.


INTRODUCTION
Multiple myeloma is a clonal plasma-cell disorder that accounts for slightly more than 10% of all hematologic cancers 1 .According to hospital-maintained data, the reported incidence of multiple myeloma in India is 0.5-1.2 per 100,000 population 2 .
For many years, melphalan-prednisolone was the standard therapy for this disease 3 .To maintain patient eligibility for stem-cell transplantation, non-alkylatorbased induction therapy with vincristine-doxorubicindexamethasone was introduced 4 .Nearly a decade after that, combination thalidomide-dexamethasone emerged as an alternative to vincristine-doxorubicin-dexamethasone in newly diagnosed multiple myeloma 5 .However, grade 3 or greater nonhematologic toxicities were significantly higher with standard-dose thalidomide.Lenalidomide, a derivative of thalidomide and a second-generation immunomodulatory drug, was found to be less toxic and more potent than thalidomide.Responses were observed even in patients for whom thalidomide treatment had previously failed 6 .Lenalidomide has shown significant activity in combination with dexamethasone, with fewer nonhematologic side effects than are seen with thalidomide 7 .
Compa red w it h t ha lidom ide -dexa met hasone, lenalidomide-dexamethasone is now accepted as a safer and more effective alternative in newly diagnosed myeloma.The use of lenalidomide for treating newly diagnosed multiple myeloma is not novel, but its use in a resourceconstrained Indian scenario is underreported.
The treatment of myeloma is becoming ever more expensive as the years roll on.The per-capita gross domestic product in India was last recorded at 77,524 Indian rupees (US$1750.60) in 2015 8 .With more than 70% of Indian patients paying out of pocket for medical expenses, expensive myeloma treatment-including stem-cell transplantation-is generally unaffordable 9 .Lenalidomide has become less expensive over the years because of the availability of generic versions.
The present study of lenalidomide and low-dose dexamethasone was a logical extension of our institutional phase ii study of thalidomide plus low-dose dexamethasone by Thomas et al. 10 , which reported 57% complete responses (crs) and 21% partial responses (prs), for an overall response rate of 78%-significantly higher than the response rates reported in the literature.
In a developing nation such as India, where sustaining long-term treatment is a challenge, there is a need to assess whether an abbreviated course of treatment for 6 months would be effective.The present study assessed an abbre viated 6-cycle course of treatment with lenalidomidedexamethasone in patients not planned for transplantation.

METHODS
This single-institution prospective pragmatic study had an enrolment period of May 2009 to April 2011.The study included patients above the age of 18 years who had untreated symptomatic multiple myeloma, measureable disease, and an Eastern Cooperative Oncology Group performance status of 0-2.
Multiple myeloma was diagnosed on the basis of 10% or more clonal bone marrow plasma cells, the presence of serum or urinary monoclonal protein (except in patients with true non-secretory multiple myeloma), and evidence of end-organ damage attributable to underlying plasmacell proliferative disorder-specifically, hypercalcemia; renal insufficiency; anemia; and lytic bone lesions, severe osteopenia, or pathologic fracture.
All patients were either ineligible for (>65 years of age) or unwilling to undergo autologous stem-cell transplantation, because the aim was to assess response in non-transplanted people, which is generally the norm in most Indian centres.
The investigations were limited to those that were mandatory.For diagnostic purposes, all consenting patients with suspected myeloma underwent serum and urine electrophoresis, bone marrow aspiration and trephine biopsy, skeletal survey, quantitative serum immunoglobulins (G, A, and M) and free light-chain assay (kappa, lambda), and β 2 -microglobulin, in addition to routine investigations such as complete blood count, peripheral blood smear, kidney and liver function tests, serum calcium, and lactate dehydrogenase.Immunofixation was not used in view of lack of local availability and cost concerns.Because of resource constraints, bone marrow conventional karyotyping was performed only in patients who separately consented for the same.Reassessment evaluations were performed after the 3rd and 6th cycles.
A cr was defined as normal serum electrophoresis, normal quantitative serum immunoglobulins and free light-chains, disappearance of any soft-tissue plasmacytomas, and fewer than 5% plasma cells in bone marrow.A stringent cr (scr) was defined as (in addition to cr criteria) a normal free light-chain ratio and absence of clonal cells in bone marrow by immunohistochemistry.A very good partial response (vgpr) was defined as a 90% or greater reduction in serum quantitative immunoglobulins.A pr was defined as a 50% or greater reduction in the abovementioned features.
The protocol was reviewed and approved by the institutional review board.All patients provided written informed consent before being enrolled in the trial in accordance with the Declaration of Helsinki.
Patients were treated with oral lenalidomide 25 mg daily for 21 days of a 28-day cycle, and dexamethasone 40 mg orally on days 1, 8, 15, 22 of the cycle.Standard dose modification guidelines were followed for grades 3 and 4 neutropenia and thrombocytopenia.Patients received adjunct treatment with radiation therapy to painful skeletal lesions, acetylsalicylic acid 75 mg for thromboprophylaxis, and bisphosphonates.Antibiotic and antiviral prophylaxes were not administered.Treatment was discontinued after 6 cycles of treatment for all patients other than those with progressive disease.Patients who progressed during or after completion of the proposed 6 cycles were treated according to their physician's discretion.All patients who relapsed after achieving at least a pr were advised to try re-treatment with lenalidomide-dexamethasone; however, patients who could not afford the drug were allowed to proceed with treatment according to the treating physician's discretion.

Endpoints
The primary endpoint was progression-free survival (pfs) with abbreviated lenalidomide-dexamethasone.Secondary endpoints included overall survival (os), overall response rate, time to response, time to second-line antimyeloma therapy, and safety.

RESULTS
This study recruited 51 eligible patients over the 2-year study period.All patients were prospectively followed for a period of 5 years.Median follow-up was 66 months (range: 60-74 months), with 4 patients being lost to follow-up.
Median age in the group was 61 years (range: 38-75 years).Of the 51 patients, 17 (33.3%)were more than 65 years of age and therefore transplantation-ineligible.The 34 transplant-eligible patients (66.7%) were counselled for autologous stem-cell transplantation, but all declined for economic reasons.
The overall male-to-female ratio was 1.04:1.Median age at diagnosis was about 6 years less in the women than in the men (58 years vs. 64 years).More than 50% of the women were less than 60 years of age; only 25% of the men were less than 60 years of age.The median duration of symptoms before diagnosis was 6 months (range: 1-28 months).The median delay in diagnosis, defined as the time since the patient presented to a physician for the first time, was 2 months (range: 1-5 months).
Table i presents comparative clinical features for patients reported from Indian, Mayo Clinic, and Asian centres.
She was morbidly obese.The remaining toxicities were all grades 1-2 and included constipation, anxiety, rash, respiratory infection, agitation, nausea, dyspepsia, anorexia, and stomatitis.No patient experienced transaminasemia, dizziness, or confusion.Among the patients with hyperglycemia secondary to dexamethasone, none developed ketoacidosis.
Table ii presents a comparison of toxicities in the E4A03 trial and in our study.
Of the 2 patients taken off study (3.9%), the first withdrew consent (cycle 1), and the second experienced pulmonary embolism (cycle 2).No early deaths occurred.The remaining 49 patients (96.1%) completed the intended 6 cycles of treatment.No dose reductions were required.
The median pfs was 16 months (range: 2-62 months).During the course of follow-up, all patients experienced biochemical relapse.At that point, re-treatment was offered.Median time to biochemical progression was 8 months.Of the 51 patients, 36 (70.6%) who, because of lack of clinical symptoms, refused re-treatment at the time of biochemical relapse were kept on regular follow-up.Subsequently, in the 6-8 months after biochemical relapse, those patients developed clinical symptoms including bone pain, anemia, and worsening renal parameters.Median time to second-line anti-myeloma therapy was 14 months.In all 10 patients (19.6%) whose relapse occurred more than 12 months after primary therapy, re-challenge with the same schedule of lenalidomide-dexamethasone achieved a second response within 3 months.After achieving a second response, patients were continued on lenalidomide 10 mg as maintenance therapy; at the time of writing, a continued response was observed in 7 of those patients.The remaining patients were treated with other anti-myeloma agents including thalidomide, bortezomib, cyclophosphamide, melphalan, and vincristine-doxorubicin-dexamethasone according to the treating physician's discretion.
The os rate at 5 years was 62.74%.At the time of writing, the median os was not yet reached.
At the time of data cut-off, 19 patients (37.3%) had died: 8 because of disease progression; 1 each because of domestic accident, suicide, and colon cancer; and 8 because of age-related comorbidities.No direct relation was observed between either relapse or survival and the initial depth of response to treatment.

DISCUSSION
Our study was intended to assess the utility of fixed-duration treatment with lenalidomide-dexamethasone for newly diagnosed multiple myeloma in patients who were either transplantation-ineligible or -unwilling in a resourceconstrained Indian setting.In our cohort, 66.7% of the patients were transplant-eligible, but were unwilling to proceed because of financial constraints.In a large retrospective analysis of Asian data spanning 25 years (1986-2011) e364 Current Oncology, Vol. 24, No. 5, October 2017 © 2017 Multimed Inc.
by the Asian Myeloma Network, only 19.8% of patients underwent autologous transplantation, suggesting that, in community practice, bone-marrow transplantation is still an unaffordable treatment for many in developing nations 11 .
In our patients, the overall response rate was a little above 90%, which is similar to the 91% reported in the Mayo Clinic experience of lenalidomide-dexamethasone in newly diagnosed myeloma 12 ; however, the cr rate was significantly higher in our study.In the Mayo Clinic study, 6% of patients had a cr, and 32% had a vgpr or near-cr.In 2006, at a median follow-up duration of 36 months, the Mayo Clinic experience was updated 13 .The cr rate had improved to 18%, and the vgpr rate was 38%, for a cr +vgpr rate of 56% at 4 months, which further increased to 67% in patients who continued to receive lenalidomide-dexamethasone as primary therapy beyond the stipulated 4-month period.In our study, reassessment at 6 months showed a 60.7% scr + cr + vgpr rate and an overall response rate of 90.2%.Because treatment was stopped after 6 months in our study (unlike in the Mayo Clinic study), we are unable to assess any increasing depth of response with prolonged treatment.Our results are similar to those in a study by Nair et al. 14 from northern India, who also reported a significantly higher cr rate (30% near-cr + cr) and an overall response rate of 95% in newly diagnosed patients with multiple myeloma treated with lenalidomide-dexamethasone.
At the time of our study, most Western studies had also assessed response to a fixed duration of treatment.In 2014, Benboubker et al. 15 of the first trial, which evaluated lenalidomide-dexamethasone for fixed duration of 18 weeks compared with the same treatment until progression, reported durable responses with continuous treatment.Similarly in the Multiple Myeloma 015 trial, patients in the arm with continuous use of lenalidomide experienced a better pfs even though os was similar 16 .
In our study, the median pfs with 6 cycles of treatment was 16 months (range: 2-62 months).That duration is inferior to the 20.7 months reported in the 18-cycle lenalidomide-dexamethasone arm of the first trial.However, the 5-year os rate in our study population was 62.74%, which is marginally better than the 56% os rate reported for the 18-cycle lenalidomide-dexamethasone arm in the first trial.In the present study, median os had not yet been reached at the time of reporting.
The median time to second-line anti-myeloma therapy was 14 months in our study, which is again inferior to the 28.5 months reported for the 18-month lenalidomidedexamethasone arm and the 39.1 months reported for the continuous lenalidomide arm in the first trial.
It was easy to achieve a second response w it h lenalidomide-dexamethasone rescue therapy in patients who had previously achieved a cr.That observation echoes results in the first trial, in which patients on the 18-cycle lenalidomide-dexamethasone arm achieved a second remission with more ease.The 35.3% grade 3 and greater nonhematologic toxicities in our study contrast with the 48% reported in the Mayo Clinic series 17 .The most common grade 3 toxicities included hyperglycemia (23.5%), fatigue (17.8%), and hypocalcemia (3.9%).
In 1 female patient who was morbidly obese, a pulmonary thromboembolism (proven by computed tomography angiography) developed and had to be lysed, resulting in improvement.We believe that the morbid obesity would have contributed to the occurrence of thromboembolism in this patient.No other patient experienced deep-vein thrombosis or pulmonary embolism.That finding is in stark contrast to the high (up to 17%) reported incidence of venous thromboembolism in patients with myeloma on lenalidomide-dexamethasone therapy 14 .Pooled data from 6 studies involving 1125 adult patients with newly diagnosed or relapsed multiple myeloma reported that the risk of venous thromboembolism in patients on acetylsalicylic acid was 1.5 per 100 patient-cycles, with a total risk of venous thromboembolism of 10.7% 18 .The low risk of thromboembolic phenomena in our Indian patients is corroborated by the study reported by Nair et al. 14 , in which, of a cohort of 41 patients treated with lenalidomidedexamethasone and routine acetylsalicylic acid prophylaxis, none developed deep-vein thrombosis.
Grade 3 hy perglycemia (fast ing blood glucose ≥ 250 mg/dL) occurred nearly 4 times as often in our study as in results from the Eastern Cooperative Oncology Group (23.5% vs. 6.0%).Many epidemiology studies in urban and rural Indian populations have found a very high prevalence (up to 21.1%) and incidence (20.2 per 1000 person-years) of impaired glucose tolerance and impaired fasting glucose.This glucose intolerance is unmasked very easily by introduction of steroids for therapeutic purposes in various diseases including in multiple myeloma.That unmasking is the most likely cause for a different hyperglycemia profile in our patients.
The rate of grade 3 and greater infection was lower in our patient cohort, although the reason for that finding is not very clear.We assume that it might be attributable to herd immunity against common pathogens in the Indian subcontinent, considering the socioeconomic and living circumstances.
The reasons for a higher response rate and a different toxicity profile in our patient cohort cannot alone be explained on the basis of simple clinical variables such as age, stage, performance status, and so on.It probably is more likely attributable to tumour biology or genetic variations, or both.
Myeloma karyotypes are complex, and cytogenetic abnormalities are known to predict poor response in the patients carrying them.Areas of common recurrent and nonrandom changes that have been noted with multiple myeloma include the 14q32 region (involving the immunoglobulin H gene) and chromosomes 1q and 13.Detection of partial or complete deletions of chromosome 13 at diagnosis or after high-dose cyclophosphamide therapy for peripheral stem-cell mobilization, followed by two autografts, has been found to portend a poor prognosis 19 .In our study, conventional karyotyping, which was available as an in-house facility, was carried out.Because of resource constraints, plasma-cell enrichment and fluorescence in situ hybridization (fish) studies were not done.Lack of the latter tests would be a limitation to our interpretation of the cytogenetic data because, using standard metaphase analysis, abnormal karyotypes are seen in only 18%-30% of samples 20 .With conventional karyotyping, 62.5% of patients showed an abnormal karyotype, the most common abnormalities being trisomy and monosomy of chromosome 15.Other anomalies included aneuploidy, polyploidy, and trisomy 22. None of our patients had a chromosome 1, 3, 13, or 14 abnormality.That finding contrasts with results from an Asian Myeloma Network study that reported only 32.5% abnormal cytogenetics 11 .Hyperdiploidy in myeloma is known to be associated with good prognosis and is characterized by trisomies of chromosomes 3, 5-7, 9, 11, 15, 17, 19, and 21 by both metaphase cytogenetics and fish 21 .
The limitations of our study are twofold.Both relate to economics and logistics.The first limitation is the lack of immunofixation studies, which are the basis for assessing response in both the International Myeloma Working Group and the European Group for Blood and Marrow Transplantation criteria.In our study, response was instead assessed by quantitative serum immunoglobulin levels and serum free light-chain estimations.Those measures are definitely cruder than immunofixation methods and might be responsible for the higher response rates reported in our study.The second limitation is the use of conventional karyotyping and the lack of fish studies.At the time of the study, immunofixation and fish analyses were scarcely available and carried an exorbitant cost for the average Indian patient.
Because this trial was designed before the advent of the routine use of maintenance therapy, we cannot comment on the survival benefits of maintenance lenalidomide.

CONCLUSIONS
Lenalidomide-dexamethasone is an effective first-line treatment for patients who, in an economically constrained environment, are newly diagnosed with multiple myeloma and are not candidates for transplantation.However, shortduration treatment is suboptimal, and patients should be advised to take continuous treatment with these agents.

TABLE I
Comparative data from Indian, Japanese, pan-Asian, and Western studies