Selected Novel Agents in Development for Multiple Myeloma



Syed Abutalib, MD

Syed Abutalib, MD

Here are several abstracts selected from the proceedings of the 2016 America Society of Hematology (ASH) Annual Meeting & Exposition, highlighting newer therapeutics for the development for patients with relapsed or refractory multiple myeloma. For full details of these study abstracts, visit http://www.bloodjournal.org/content/128/22.

Abstract 488: Phase I study (n = 66) of venetoclax monotherapy for relapsed/refractory multiple myeloma1

Study Endpoints: Study objectives were to assess safety, pharmacokinetics, maximum tolerated dose, recommended phase II dose, objective response rate, time to disease progression, and duration of response to venetoclax (Venclexta).

Abstract Conclusion: Grade 3 and 4 adverse events in ≥ 10% of patients were thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cell count (12%). Serious adverse events in at least two patients were pneumonia (n = 5); sepsis (n =3); and pain, pyrexia, cough, and hypotension (n= 2 each). Two patients experienced dose-limiting toxicities at 600 mg, with the development of abdominal pain and nausea. 

Novel Agents in Development for Multiple Myeloma

Agents currently being studied for use in multiple myeloma include:

  • The BCL-2 inhibitor venetoclax, as monotherapy, and in combination with bortzomib and dexamethasone
  • The HIV protease inhibitor nelfinavir in combination with bortezomib and dexamethasone
  • The oral selective inhibitor of nuclear export (SINE) compound selinexor in combination with low-dose dexamethasone

Agents currently being studied for use in multiple myeloma include:

  • Selinexor in combination with pomalidomide and low-dose dexamethasone
  • Pembrolizumab in combination with pomalidomide and dexamethasone

The objective response rate for all patients on venetoclax monotherapy was 21%, and 15% of the patients achieved at least a very good partial response. The median duration of response and time to disease progression were 9.7 and 2.6 months, respectively. Most objective responses (12/14 [86%]) were reported in the subset of patients with t(11;14) abnormality. In this group, the objective response rate was 40%, and 27% of patients achieved at least a very good partial response; the median duration of response for patients with t(11;14) was 9.7 months. For two patients with response in the non-t(11;14)/undetermined group, 1 had a translocation of chromosome 14 with an unidentified partner, and the other had no cytogenetic data available.

Clinical Implications: Venetoclax monotherapy has an acceptable safety profile and clear antimyeloma activity in relapsed/refractory multiple myeloma, primarily in patients with t(11;14) having a high BCL-2, low BCL-XL, and low MCL-1 expression levels (assessed by immunohistochemistry method).

Abstract 975: Venetoclax combined with bortezomib and dexamethasone (VBD) in patients (n = 65) with relapsed/refractory multiple myeloma2

Study Endpoints: The objectives of the study were to assess the safety, pharmacokinetics, maximum tolerated dose, recommended phase II dose, objective response rate, time to disease progression, and duration of response to combination therapy.

Abstract Conclusion: The median number of prior therapies was 3 (range: 1–13), and 21 patients (32%) were refractory to bortezomib (Velcade), 37 patients (56%) were refractory to lenalidomide (Revlimid), and 41 patients (62%) had prior autologous transplant. A total of 33 patients discontinued therapy due to disease progression. Grade 2 to 4 adverse events in ≥ 10% of patients included thrombocytopenia (29%), anemia (15%), and neutropenia (14%). One dose-limiting toxicity (venetoclax at a dose of 1,200 mg) of lower abdominal pain was reported.

The objective response rate for all evaluable patients was 68%, and 40% of the patients achieved at least a very good partial response. For all patients, the median duration of response was 8.8 months (95% confidence interval [CI]: 7.2–15.8 months), and time to disease progression was 8.6 months (95% CI: 5.7–10.2), with a median follow-up of 4.9 months (range: 0.03–26.7).

The 31 patients who were nonrefractory to bortezomib and had 1 to 3 prior therapies had an objective response rate of 94% (29/31), 68% (21/31) with at least a very good partial response; the median duration of response was 10.6 months, and time to disease progression was 11.3 months for this subgroup. Moreover, patients who were bortezomib-naive and had 1 to 3 prior lines of therapy had an objective response rate of 100% (12/12), and the median duration of response was 15.8 months, and time to disease progression was 17.1 months.

In patients who were nonrefractory to prior bortezomib but who were refractory to lenalidomide, the objective response rate was 86% (19/22), as compared with 91% (20/22) in those who were nonrefractory to lenalidomide. Clinical responses were comparable in patients with and without t(11;14); the objective response rate with the translocation was 78% (7 of 9 patients) and without, 66% (37 of 56 patients). In the t(11;14) group, 3 patients were bortezomib-refractory, and 2 of them achieved a partial response as best response. Also, four patients had more than three prior lines, with three of them achieving a partial response.

Clinical Implications: The VBD regimen has an acceptable safety profile in patients with relapsed or refractory multiple myeloma. These data support the ongoing phase III trial with this regimen (ClinicalTrials.gov identifier NCT02755597).

Abstract 487: The HIV protease inhibitor nelfinavir in combination with bortezomib and dexamethasone (NBd) has excellent activity in patients with advanced, proteasome inhibitor–refractory multiple myeloma.3

Study Endpoint: Activity of added nelfinavir (2,500 mg days 1–14 twice a day) to bortezomib and dexamethasone (NVd) in patients (n = 34) with proteasome inhibitor–refractory multiple myeloma. Also, 26 patients (76%) were lenalidomide-refractory (double-refractory).

Abstract Conclusion: A total of 22 patients achieved an objective response with at least a partial response, resulting in an objective response rate of 65% (90% CI: 49.2%–75.7%). In double-refractory patients, the objective response rate was 69%; in patients with poor-prognosis cytogenetic abnormalities, it was 77%. The objective response was independent from the number of prior therapy lines (objective response rate 69% with < 5 prior therapy lines; objective response rate 61% with ≥ 5 prior lines). Most frequent > grade 2 adverse events were anemia, thrombocytopenia, infections, hyperglycemia, and fatigue.

Clinical Implications: This is a provocative data set. The NVd regimen showed unfolded protein response activation in vivo and strong signals of activity in bortezomib-refractory multiple myeloma in the SAKK 65/08 phase I trial.4 In this phase II study,3 the objective response rate of 65% in an advanced, heavily pretreated, mostly dual-refractory patient population is exceptional. These results warrant further investigation.

Abstract 491: Selinexor [a first-in-class, oral selective inhibitor of nuclear export, or SINE compound, which inhibits XPO1-mediated nuclear export, resulting in nuclear retention of major tumor-suppressor proteins and subsequently in cancer cell death] and low-dose dexamethasone (Sd) in patients (n = 79) with lenalidomide, pomalidomide (Pomalyst), bortezomib, carfilzomib (Kyprolis), and anti–CD38 antibody-refractory multiple myeloma: Phase II, STORM study5

Study Endpoints: Objective response rate and duration of response with selinexor in quad-refractory and penta-refractory (includes also patients refractory to anti-CD38 antibody)

Abstract Conclusion: The objective response rate was 21% and 20% for quad-refractory (n = 48) and penta-refractory (n = 31) patients with multiple myeloma. Median overall survival was 9.3 months for all patients, > 11 months (median not reached) for responders (≥ partial response), and 5.7 months for nonresponders. The median duration of response in responding patients was 5 months, and the median progression-free survival in all patients was 2.1 months.

The main toxicities of the Sd regimen were thrombocytopenia, nausea, anorexia, and fatigue. Seventy patients discontinued therapy due to progressive disease (73%), adverse events (17%), physician or patient preference (1%), and death (9%). In all, six patients died, with one case related to selinexor (intracranial bleed from grade 4 thrombocytopenia).

Clinical Implications: The oral regimen Sd is active in heavily pretreated patients with refractory multiple myeloma, including those with high-risk cytogenetic abnormalities, with a manageable toxicity profile.

Abstract 3330: Selinexor shows synergy in combination with pomalidomide and low-dose dexamethasone (SPd) in patients (n = 11) with relapsed or refractory multiple myeloma6

Study Endpoints: In this phase Ib and II dose-escalation study, the study objectives were to determine the tolerability, maximum tolerated dose, recommended phase II dose, and preliminary efficacy of SPd.

Study Conclusion: For the once-weekly selinexor cohort, the 80-mg dose level has been cleared, and the 100-mg dose level is ongoing. For the twice-weekly cohort, the 60-mg dose level has been cleared, and the 80-mg dose level is ongoing. No dose-limiting toxicities have been observed, and the maximum tolerated dose has not been reached.

Ten patients were evaluable for response, including one complete response, fve partial responses, three minor responses, and one stable disease. The objective response rate is 60%, with a clinical benefit rate of 90% (objective response rate plus minor responses). Responses were rapid in onset, with at least minor responses achieved by cycle number 2 on day 1.

Five patients were refractory to both lenalidomide and bortezomib; eight patients were refractory to lenalidomide alone; and seven patients were refractory to bortezomib alone. In lenalidomide- and bortezomib-refractory patients, the objective response rate was 50%. Grade 3 and 4 adverse events included neutropenia (73%), thrombocytopenia (36%), and leukopenia (27%).

Clinical Implications: This novel treatment regimen holds promise for patients with multiple myeloma who are refractory to immunomodulatory agents and proteasome inhibitors.

Abstract 2119: Pembrolizumab in combination with pomalidomide and dexamethasone for pomalidomide-exposed relapsed or refractory multiple myeloma7

Study Endpoint: Activity of pembrolizumab (Keytruda; 2 mg/kg every 2–3 weeks) with pomalidomide and dexamethasone in previously pomalidomide- and lenalidomide-exposed patients (n = 9)

Study Conclusion: All patients had been treated with at least five prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and alkylating agents (including high-dose melphalan and autologous hematopoietic cell transplantation). Prior to therapy, 89% had significant anemia, 78% had lytic bone lesions, and two patients had significant renal insufficiency (creatinine: 2.32 and 3.32 mg/dL, respectively), although neither one was on dialysis. All patients progressed after prior lenalidomide, and eight of nine patients progressed on previous pomalidomide (the other one had stable disease).

The objective response rate of this regimen was 33%. A total of 88% of patients achieved a clinical benefit. Median progression-free survival was 57 days (0–85 days). There were no observed discontinuations of treatment or deaths attributed to drug toxicity, and no pneumonitis was seen. Two patients experienced noninfectious colitis, which responded to prednisone. The overall survival at 6 months for the 9 patients was 56%. Four patients have died of progressive disease.

Clinical Implications: These are retrospective data. This regimen has activity in relapsed or refractory multiple myeloma, with acceptable toxicity, even in a heavily treated immunomodulatory drug–exposed patients.

Abstract 490: Pembrolizumab (200 mg every 2 weeks) in combination with pomalidomide and dexamethasone for relapsed or refractory multiple myeloma: A single center phase II study8

Study Endpoints: Safety and activity profile of this regimen in patients (n = 48) with relapsed or refractory multiple myeloma

Study Conclusion: Patients had a median of three lines of prior therapy; all patients had received immunomodulatory agents and proteasome inhibitors, and 70% had a prior autologous hematopoietic cell transplantation. Eighty-percent of patients were double-refractory to both immunomodulatory agents (lenalidomide) and proteasome inhibitors [bortezomib (n = 18) or carfilzomib (n = 20)], and an additional 20% of the patients were refractory to lenalidomide. Six patients had soft-tissue extramedullary plasmacytomas.

There were no infusion-related reactions. Autoimmune-mediated events included interstitial pneumonitis (13%), hypothyroidism (10%), transaminitis (6%), adrenal insufficiency (4%), and vitiligo (2%). At a median follow-up of 10 months (range: 2–18 months), 25 patients continued on the study, and 23 patients discontinued therapy due to progressive disease (n = 15), side effects (n = 7), or protocol violation (n = 1). Five patients died while on study due to progressive disease (n = 3), sepsis (n = 1), or cardiac event (n = 1). Three additional patients died off therapy. 

On intent-to-treat analysis, the objective response rate was 56%, with at least a partial response observed in of 27 of 48 patients. Of 38 double-refractory patients, the objective response rate was 55%. The median duration of response for responding patients was 8.8 months and for patients with at least a very good partial response, the duration of response was 10.7 months.

Clinical Implications: This regimen shows reassuring therapeutic activity with autoimmune-mediated side effects, which would require careful assessment and monitoring. ■

Disclosure: Dr. Abutalib reported no conflicts of interest.

Dr. Abutalib is Assistant Director in the Stem Cell Transplant & Cell Therapy Program at Cancer Treatment Centers of America in Chicago.

References

1. Kumar S, Vij R, Kaufman JL, et al: Venetoclax monotherapy for relapsed/refractory multiple myeloma: Safety and efficacy results from a phase I study. 2016 ASH Annual Meeting. Abstract 488. Presented December 4, 2016.

2. Moreau P, Chanan-Khan AA, Roberts AW, et al: Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. 2016 ASH Annual Meeting. Abstract 975. Presented December 5, 2016.

3. Driessen C, Müller R, Novak U, et al: The HIV protease inhibitor nelfinavir in combination with bortezomib and dexamethasone has excellent activity in patients with advanced, proteasome inhibitor–refractory multiple myeloma: A multicenter phase II trial (SAKK 39/13). 2016 ASH Annual Meeting. Abstract 487. Presented December 4, 2016.

4. Driessen C, Kraus M, Joerger M, et al: Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: A phase I trial (SAKK 65/08). Haematologica 101:346-355, 2016.

5. Vogl DT, Dingli D, Cornell RF, et al: Selinexor and low dose dexamethasone in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma: STORM study. 2016 ASH Annual Meeting. Abstract 491. Presented December 4, 2016.

6. Chen C, Kotb R, Sebag M, et al: Selinexor shows synergy in combination with pomalidomide and low dose dexamethasone in patients with relapsed/refractory multiple myeloma. 2016 ASH Annual Meeting. Abstract 3330. Presented December 4, 2016.

7. Wilson L, Cohen AD, Weiss BM, et al: Pembrolizumab in combination with pomalidomide and dexamethasone for pomalidomide exposed relapsed or refractory multiple myeloma. 2016 ASH Annual Meeting. Abstract 2119. Presented December 3, 2016.

8. Badros AZ, Hyjek E, Ma N, et al: Pembrolizumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma. 2016 ASH Annual Meeting. Abstract 490. Presented December 4, 2016.



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