Treatment options for patients with relapsed/refractory myeloma who have previously been treated with novel agents and high-dose chemotherapy/autologous stem cell transplant

Abstract

A 64 year-old man with a history of multiple myeloma presents with new back pain. He has a history of International Staging System stage 1, IgG kappa multiple myeloma with normal cytogenetics which was diagnosed 4 years ago when he presented with a pathological fracture of the left humerus. He was initially managed with mechanical stabilization and 4 cycles of bortezomib-dexamethasone, as well as 2 years of bisphosphanates. Following induction therapy he achieved a very good partial response (VGPR). He subsequently received high-dose melphalan and autologous stem cell transplantation (auto-SCT) and achieved a complete reponse (CR) post-transplant. He did not receive maintenance therapy and had been lost-to follow-up for about a year. He now presents 5 years after initial diagnosis with back pain and is noted to have a new lytic lesion with a compression fracture at T8. A serum protein electrophoresis demonstrates reappearance of his original monoclonal protein. After appropriate stabilization he comes to you to discuss additional treatment options.

Treatment of relapsed multiple myeloma depends upon a number of different patient and disease related factors. These include duration of first response, exposure to treatment options, age, performance status, and toxicity associated with previous treatments. More recently, the emergence of novel agent-based therapies has significantly changed the clinical outcome for patients with myeloma at all phases of the disease. It is estimated that the use of agents such as thalidomide, lenalidomide and bortezomib, have improved the overall median overall survival by 50%.¹ While these agents and auto-SCT have clearly improved response rates, their use in the up-front setting has, ironically, created a new challenge: managing patients who relapse after having been exposed to 2 or 3 of these agents as part of their initial therapy. In this review, we discuss an evidence-based strategy for treatment of patients with relapsed or refractory myeloma who have already been treated with novel agents and auto-SCT.

We performed 3 separate literature searches for this review. In studying auto-HCT as a salvage therapy, we queried the PubMed database for all combinations of the terms “transplant” (or “transplantation”), “myeloma,” “second,” “salvage” and “relapsed” with the limitation of English. This yielded 8 results and 2 additional studies were found in the reference sections of the aforementioned 8 articles. Of these, 4 studies were excluded because they were performed before the era of novel therapeutics. For Table 1 we searched the PubMed database using the terms “myeloma” AND “relapsed” with the limitation of “clinical trial,” “human” and “English.” This yielded 127 hits. Of those, 34 studies did not included adequate number of patients with previous exposure to novel agents, 15 studies had equivocal results, 36 studies were not relevant for our clinical question, 10 studies were not relevant to our patient population and 4 studies were updates. This yielded 43 results. In studying early-phase novel therapeutics (Table 2) we performed a search of the most recent oral presentations at the annual American Society of Hematology and American Society of Oncology meetings. We then cross-referenced the cited agents in a search with “myeloma” and “relapsed” in PubMed. This yielded 11 results.

Table 1.

Overview of combination regimens in relapsed/refractory patients with previous exposure to novel agents +/− auto-SCT. ORR= CR+VGPR+PR unless otherwise noted.

Regimen	Overall response rate (ORR)	% of patients previously treated with:
		Thalidomide	Lenalidomide	Bortezomib	Auto- SCT
Bortezomib-lenalidomide-(dexamethasone)17	39%	87	18	55	61 (auto or allo)
Bortezomib-thalidomide-dexamethasone18	47	100	n/a	n/a	11
Bortezomib-PLD-dexamethasone32	80%	n/a	n/a	n/a	12
Bortezomib-PLD-thalidomide33	56%	52	n/a	17	13
Bortezomib-PLD19	44%	43(thal or len)		n/a	54
PLD-bortezomib-thalidomide-dexamethasone34	81%	64	n/a	14	24
Lenalidomide-PLD-dexamethasone21	75%	66	n/a	18
Bortezomib-dexamethasone-cyclophosphamide35	83%	61	n/a	n/a	11
Bortezomib-cyclophosphamide-thalidomide-dexamethasone22	88%	>57	n/a	n/a	19
Bortezomib-cyclophosphamide-prednisone24	68%	38	3	3	78
Bortezomib-dexamethasone-cyclophosphamide25	82%	30	n/a	n/a	80
Cyclophosphamide- lenalidomide dexamethasone23	81%	90	n/a	26	65
Lenalidomide-adriamycin-dexamethasone36	73%	20	n/a	57	84
Bortezomib-doxorubicin-dexamethasone37	92%	75	n/a	27	58
Bortezomib-doxorubicin-dexamethasone then thalidomide-dexamethasone38	84%	33	n/a	n/a	58
Bortezomib-melphalan-dexamethasone26	68%	64	n/a	9	85
Bortezomib-melphalan-dexamethasone-intermittent thalidomide28	66%	55	n/a	10	32
Bortezomib-melphalan-prednisone-intermittent thalidomide30	67%	30	n/a	n/a	67
Bortezomib-melphalan29	50%	55	21	13	37
Lenalidomide-melphalan-prednisone-thalidomide27	75%	23	n/a	20	52 (auto or allo)

Table 2.

Early trial results of novel agents in relapsed/ refractory myeloma. ORR= CR+VGPR+PR unless otherwise noted. MR: Minimal response.

Agent	ORR	Phase
Vorinostat-bortezomib39	42%	I
Vorinostat-bortezomib40	83% (incl MR)	Case series n=6
Vorinostat41	8% with MR	I
Vorinostat-lenalidomide-dexamethsone42	45%	I
Panobinostat-bortezomib43	58%	Ib
Panobinostat-lenalidomide-dexamethasone44	37%	Ib
Carfilzomib45	38%	II
Pomlidomide-dexamethasone46	63%	II
Pomalidomide-dexamethasone (for patients refractory to lenalidomide/bortezomib)47	32%	II
Elotuzumab-bortezomib48	40%	I
Elotuzumab-lenalidomide-dexamethasone49	82%	I/II

In this patient who achieved a CR after auto-SCT and maintained a disease-free interval of approximately 3 years, one could consider another auto-SCT. Available data on second autologous transplants for relapsed patients suggests that these procedures are relatively well-tolerated, with a 100 day mortality of 2-8%^2–5. The more recent studies of second, salvage transplants include a sizeable proportion of patients who have received thalidomide, lenalidomide or bortezomib in the induction setting. The overall response rates (ORR) in studies done in the past 5 years range from 55-69%.^2,3,5,6 Because of the limited number of patients in each of these studies, it has been difficult to determine the most important factors in selecting ideal candidates for a salvage auto-SCT. However, one small study suggests that a relapse-free survival of >18 months after the first auto-SCT is the most reliable predictor of clinical outcome after a second auto-SCT.⁷ Though there are no official guidelines, the general consensus is that a salvage transplant with the intent of inducing long term remission should be offered only to those patients who had a durable response for at least 12-18 months after their first auto-SCT.

When deciding which agents to use in the relapsed/refractory setting, exposure to previous therapy is an important consideration. Among patients who received bortezomib based induction, the use of immunomdulatory (IMiD)-based therapy in early relapse makes logical sense, or the reverse for a patient who received immunomodulatory based induction.^8–13 In addition, updated analyses from the MM-009 and MM-010 studies (lenalidomide-dexamethasone vs. dexamethasone) suggest that the benefit of lenalidomide was maintained despite prior exposure to auto-SCT or thalidomide.^14,15 Similarly, a subgroup analysis from the APEX trial (bortezomib vs. dexamethasone) confirmed that bortezomib was better than dexamethasone regardless of prior treatment with thalidomide or auto-SCT.¹⁶

In addition to the activity of novel agents delivered either alone or in combination with steroids, there is emerging data suggesting that combinations of novel agents -- either with each other or with cytotoxic chemotherapy-- may offer the best chance of response in relapsed/refractory patients. Examples of successful combinations include bortezomib-lenalidomide, ¹⁷ bortezomib-thalidomide,¹⁸ bortezomib or lenalidomide with pegylated liposomal doxorubicin (PLD),^19–21 bortezomib or lenalidomide with cyclophosphamide^22–25 and bortezomib or lenalidomide with melphalan.^26–30 In particular, dedicated subgroup analyses performed in the DOXIL –MMY-3001 study (bortezomib-PLD vs. bortezomib) showed a benefit in the combination arm regardless of prior auto-SCT³¹ or prior IMiD exposure²⁰. As detailed in Table 1, each of the above combinations has yielded promising results in the relapsed/ refractory patient population. These studies are notable because they include patients who, like our patient, had been previously treated with both a novel agent (thalidomide, lenalidomide or bortezomib) and auto-SCT.

In addition to combinations of established anti-myeloma agents, a host of novel agents have recently been studied in the relapsed/refractory setting. Among the most promising are histone deacetylase (HDAC) inhibitors, carfilzomib, pomalidomide and elotuzumab (Table 2). Though the data for most of these drugs are from phase I or II clinical trials, many of the included patients are similar to our patient, with a prior exposure to thalidomide, lenalidomide or bortezomib and/or auto-SCT. The importance of these agents (and their necessary clinical trials) cannot be underscored enough; many of us are utilizing our current “novel” agents much earlier, and in combination with each other. As patients live longer, we will have greater opportunity and need for incorporation of these newborn agents in the post-transplant setting.

Based on available phase III data, our recommendation for the patient described above would be salvage treatment with lenalidomide-dexamethasone (Grade 1B). Of note, both the MM-009 and MM-010 trials included patients who had previously been treated with bortezomib.^9,10 Additionally, given the long duration of response following bortezomib and auto-SCT, it would be reasonable to use bortezomib +/- dexamethasone as salvage therapy (Grade 2B).⁵⁰ If the patient could achieve a PR and had a good performance status, he would be considered for a second, salvage auto-SCT. He would most likely receive lenalidomide maintenance therapy post-transplant, though this would depend on his clinical course and his post-transplant response. If at all possible, a clinical trial should be considered at each of these steps (salvage treatment, salvage transplant conditioning regimen and post-transplant maintenance), as phase III data are still lacking for most of the combinations detailed above.