High-dose BCNU/Melphalan conditioning regimen before autologous stem cell transplantation in newly diagnosed multiple myeloma.
Bone Marrow Transplant. 2018 Jan;53(1):34-38.
Sivaraj D, Bacon W, Long GD, Rizzieri DA, Horwitz ME, Sullivan KM, Kang Y, Li Z, Chao NJ, Gasparetto C.
The standard conditioning regimen for autologous stem cell transplants in patients with multiple myeloma has been single agent high-dose melphalan, usually 200 mg/m2. In this retrospective study, 104 patients received a combination of high-dose melphalan and carmustine (BCNU), another alkylating agent. These transplants were done between 1997 and 2002, and the results were compared to those of 103 patients who received high-dose melphalan alone, between 2001 and 2008. The outcomes were better in the group treated with melphalan-carmustine: the median progression-free survival was 40.4 vs 20.5 months (p<0.001), and the median overall survival was 88.4 vs 67.2 months (but the difference was not statistically significant: p=0.07). Transplant-related mortality was similar: 2.9% vs 3.9%).

Modified HyperCVAD Versus Bortezomib-HyperCAD in Patients With Relapsed/Refractory Multiple Myeloma.
Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84.
Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E.

Safety and efficacy of pomalidomide, dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma.
Br J Haematol. 2018 Jan;180(1):60-70
Cohen A, Spektor TM, Stampleman L, Bessudo A, Rosen PJ, Klein LM, Woliver T, Flam M, Eshaghian S, Nassir Y, Maluso T, Swift RA, Vescio R, Berenson JR.

Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders.
Br J Haematol. 2018 Jan;180(1):71-81.
Foulk B, Schaffer M, Gross S, Rao C, Smirnov D, Connelly MC, Chaturvedi S, Reddy M, Brittingham G, Mata M, Repollet M, Rojas C, Auclair D, DeRome M; MMRF CoMMpass Network, Weiss B, Sasser AK.
The authors describe an automated assay to enumerate and characterize circulating myeloma cells, and tested it in over 1000 patient samples (including MGUS, smoldering myeloma, newly diagnosed symptomatic myeloma, and relapsed/refractory disease). The specimen consisted of 4 mL of peripheral blood, and numbers of circulating myeloma cells were considered high if >100/4 mL. Of note, results obtained by FISH correlated well with those seen in the bone marrow aspirates. There was a good correlation between number of circulating myeloma cells and multiple clinical parameters, for example ISS stage at baseline in newly diagnosed patients, response to therapy, remission, relapse, and survival. This assay represents not only a useful research tool, but it can be a non-invasive method to monitor the status and clinical behavior of plasma cell disorders.

Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance.
N Engl J Med. 2018 Jan 18;378(3):241-249.
Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, Rajkumar SV.
This is a study of 1384 patients residing in Minnesota and diagnosed in the Mayo Clinic between 1960 and 1994. After a median follow-up of 34 years, progression to a hematologic malignancy occurred in 147 patients (11%). Excluding unrelated deaths, rate of progression was 10% at 10 years, 18% at 20 years, 28% at 30 years, and 36% at 40 years. Risk of progression was higher in patients with IgM MGUS. Of note, patients with MGUS had shorter median overall survival than the matched control population (8.1 vs. 12.4 years, p<0.001).



A case control study of syngeneic transplantation versus autologous transplantation for multiple myeloma: two decades of experiences from a single center.
Leuk Lymphoma. 2018 Feb;59(2):515-518.
Mohyuddin GR, Faisal MS, Badar T, Shah N, Bashir Q, Patel KK, Hosing C, Popat UR, Rondon G, Delgado R, Shah JJ, Weber DM, Thomas SK, Manasanch EE, Orlowski RZ, Champlin RE, Qazilbash MH.
This is a retrospective study comparing outcomes of 10 patients with myeloma who underwent a syngeneic stem cell transplant, vs 48 matched control represented by 48 patients who underwent an autologous transplant. The outcomes were superior with the syngeneic transplant. The authors believe that one of the reason for the difference may be the contamination of the graft by malignant plasma cells with the autologous transplant. In laternative, there may be a subclinical GVHD with the syngeneic transplant.

Surgery for vertebral involvement in multiple myeloma.
J Neurosurg Sci. 2018 Feb;62(1):10-15.
Donnarumma P, Tarantino R, Rullo M, Grisaro A, Petrucci MT, Santoro A, Delfini R.
Retrospective review of 120 patients with multiple myeloma who underwent spinal surgery.

Is the revised International staging system for myeloma valid in a real world population?
Br J Haematol. 2018 Feb;180(3):451-454.
Walker I, Coady A, Neat M, Ladon D, Benjamin R, El-Najjar I, Kazmi M, Schey S, Streetly M.
The R-ISS staging system for multiple myeloma, introduced in 2015, was modeled on 3060 newly diagnosed patients enrolled in 11 clinical trials, from 2005 to 2012. However, the population in clinical trials may not reflect outcomes in the real world, because patients in clinical trials are usually younger and healthier. Therefore, these authors have retrospectively assessed the validity of the R-ISS in 345 unselected myeloma patients in the U.K. Their analysis showed that R-ISS maintains its an accurate and powerful prognostic relevance even in the real world. Of note, 48% of patients did not have an LDH level available at baseline, and 13% did not have available FISH results, and therefore they could not  be staged by R-ISS. This reflects the limitations of current medical practice, because failure to obtain LDH and FISH at baseline prevented the classification of about half patients.

Efficacy of VDT PACE-like regimens in treatment of relapsed/refractory multiple myeloma.
Am J Hematol. 2018 Feb;93(2):179-186.
Lakshman A, Singh PP, Rajkumar SV, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Dingli D, Hwa YL, Fonder AL, Hobbs M, Hayman SR, Zeldenrust SR, Lust JA, Russell SJ, Leung N, Kapoor P, Go RS, Lin Y, Gonsalves WI, Kourelis T, Warsame R, Kyle RA, Kumar SK.
VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) is an aggressive combination chemotherapy which was used, along with tandem transplants, in the Total Therapy protocols designed by Dr. Barlogie at the University of Arkansas. This regimen is widely adopted outside those protocols, particularly in patients with very aggressive myeloma, when the disease becomes refractory to novel agents such as IMiDs and proteasome inhibitors. However, efficacy and overall impact on the disease course have not be precisely defined in the "real world", i.e., off protocol. These authors administered VDT-PACE-like chemotherapy regimens in in 141 patients with relapsed/refractory myeloma between 2006 and 2017. Of note, these patients were heavily pretreated, with a median number of prior therapies of 4 (range 1-14), and 67% of them had a stem cell transplant. 52% of them had high-risk cytogenetics. Median number of cycles was 1 (range 1-9). Results:
  - Response rate: 54%, with VGPR/CR in 10% of cases
  - Median progression-free survival: 3.1 months
  - Median overall survival: 8.1 months

Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens.
Biol Blood Marrow Transplant. 2018 Feb;24(2):276-281.
Oyekunle A, Shumilov E, Kostrewa P, Burchert A, Trümper L, Wuchter P, Wulf G, Bacher U, Kröger N.
The strategy for collecting the autologous stem cells is not standardized, and varies among transplant centers. Some of them use only growth factors, typically G-CSF, other add mobilization chemotherapy, typically cyclophosphamide. The benefit of adding cyclophosphamide has been questioned by some experts, because the novel agents IMiDs and proteasome inhibitors in the induction therapy achieve a depth of response that may not be increased by the mobilization chemotherapy. Adding to the controversy, mobilization chemotherapy has the benefit of increasing the collection yield, but the risk of morbidity, in terms of neutropenic fever and other side effects. These authors reviewed the medical records of 236 consecutive MM patients "mobilized" between 2009 and 2016. About 90% of them were already in PR or better after the induction therapy. They underwent mobilization chemotherapy with either cyclophosphamide-based (93%) or etoposide-based (7%) regimens. Results:
  - The changes in the tumor markers, i.e., the paraprotein levels detected by SPEP and/or FLC, were found to be clinically insignificant
  - The depth of remission was improved in only 7 of 236 patients (3%)
  - Chemotherapy-related complications (mainly neutropenic fever and sepsis) were observed in 67 patients (28%)
  - Hospitalization was required in 4% of cases

Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma.
N Engl J Med. 2018 Feb 8;378(6):518-528.
Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators.
In this trial, 706 patients with multiple myeloma ineligible for stem cell transplant were randomized in two groups: the first (354 patients, control group) were treated with VMP:
  - Bortezomib 1.3 mg/m2 SC twice a week on weeks 1, 2, 4, and 5 of cycle 1, and once a week on weeks 1, 2, 4, and 5 of cycles 2-9
  - Melphalan 9 mg/m2 PO on days 1-4
  - Prednisone 60 mg/m2 on days 1-4
Cycles were repeated every 42 days x9.
The second group (350 patients, Dara-VMP group) was treated with VMP and daratumumab, 16 mg/Kg IV once a week in cycle 1, and every 3 weeks in cycles 2-9, then every 4 weeks.
The dara-VMP group has better results:
  - Response rate: 74% with VMP, and 91% with Dara-VMP (CR/sCR: 24% with VMP, and 43% with Dara-VMP)
  - Progression-free survival at 18 months: 50% with VMP, and 72% with Dara-VMP (p<0.01)

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia.
Blood. 2018 Feb 22;131(8):855-863.

Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N, Baz R, Mau-Sorensen M, Berdeja JG, Savona M, Savoie L, Trudel S, Areethamsirikul N, Unger TJ, Rashal T, Hanke T, Kauffman M, Shacham S, Reece D.


MARCH 2018

Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.
Lancet Oncol. 2018 Mar;19(3):370-381.
Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, Legieć W, Krejčí M, Laribi K, Zhu L, Cheng P, Warner D, Roodman GD.
This is a double-blind placebo-controlled randomized study which involved 259 medical centers in 29 countries. Between 2012 and 2016, 1718 patients with newly diagnosed multiple myeloma and at least 1 bone lesion (by x-rays, CT, or MRI) received either zoledronic acid 4 mg IV or denosumab 120 mg SC, every 4 weeks. Each group consisted of 859 patients. The chemotherapy was chosen by the individual investigators. Inclusion criteria required patients to have a creatinine clearance of at least 30 mL/min. Skeletal surveys were obtained every 12 weeks. The primary endpoint of the study was the time to skeletal-related events, defined as compression fractures, spinal cord compression, and surgery or radiation to the bones. The median time on study was 17 months. Denosumab showed to be non-inferior to zoledronic acid: the median time to first skeletal-related event was 24 months with zoledronic acid, and 23 months with denosumab (hazard ratio was 0.98, p=0.01). Overall survival was similar in the two groups. Median progression-free survival was greater with denosumab: about 35 months with zoledronic acid, and about 46 with denosumab (p=0.036). In terms of specific side effects, the study showed the following:
  - Hypocalcemia was seen in 17% of patients treated with zoledronic acid, and 12% with denosumab
  - Renal toxicity was seen in 17% of patients treated with zoledronic acid, and 10% with denosumab
  - Osteonecrosis of the jaw had a similar incidence: 3% with zoledronic acid and 4% with denosumab (p=0.14)
Based on the results of this clinical trial, the FDA approved the use of denosumab in patients with multiple myeloma.

A systematic classification of death causes in multiple myeloma.
Mai EK, Haas EM, Lücke S, Löpprich M, Kunz C, Pritsch M, Knaup-Gregori P, Raab MS, Schlenzka J, Bertsch U, Hillengass J, Goldschmidt H.
Blood Cancer J. 2018 Mar 8;8(3):30.

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results.
Br J Haematol. 2018 Mar;180(6):821-830.
Richardson PG, Bensinger WI, Huff CA, Costello CL, Lendvai N, Berdeja JG, Anderson LD Jr., Siegel DS, Lebovic D, Jagannath S, Laubach JP, Stockerl-Goldstein KE, Kwei L, Clow F, Elias L, Salman Z, Graef T, Bilotti E, Vij R.

In this clinical trial, 92 patients with relapsed/refractory myeloma received dexamethasone 40 mg once a week, and ibrutinib once a day at various doses. Patients were heavily pretreated, because they received a median of 4 prior chemotherapy regimens. Clinical benefit, defined as at least a minor response, was observed in 28% of patients receiving ibrutinib 840 mg daily. Median progression-free survival was 4.6 months (range, 0.4-17.3).

Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma.
J Clin Oncol. 2018 Mar 20;36(9):859-866.
Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, Zonder J, Baz R, Nooka A, Richter J, Cole C, Vij R, Jakubowiak A, Abonour R, Schiller G, Parker TL, Costa LJ, Kaminetzky D, Hoffman JE, Yee AJ, Chari A, Siegel D, Fonseca R, Van Wier S, Ahmann G, Lopez I, Kauffman M, Shacham S, Saint-Martin JR, Picklesimer CD, Choe-Juliak C, Stewart AK.

Selinexor is a selective inhibitor of exportin 1 (XPO1), a protein found in the nucleus of cancer cells. It induces apoptosis of cancer cells through the retention of tumor suppressor proteins and the glucocorticoid receptor in the nucleus. Selinexor also reduces the expression of oncogenes such as c-myc and bcl-2. In this trial, 79 patients with relapsed myeloma received selinexor 80 mg and dexamethasone 20 mg, both orally and twice a week. Patients were heavily pretreated: they received a median of 7 prior chemotherapy regimens, and most of them were refractory to available agents. The response rate was 21%, and the median duration of response was 5 months. Among responding patients, 1-year survival was 65%.

Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients.
Br J Haematol. 2018 Mar;180(6):831-839.

Jurczyszyn A, Radocha J, Davila J, Fiala MA, Gozzetti A, Grząśko N, Robak P, Hus I, Waszczuk-Gajda A, Guzicka-Kazimierczak R, Atilla E, Mele G, Sawicki W, Jayabalan DS, Charliński G, Szabo AG, Hajek R, Delforge M, Kopacz A, Fantl D, Waage A, Avivi I, Rodzaj M, Leleu X, Richez V, Knopińska-Posłuszny W, Masternak A, Yee AJ, Barchnicka A, Druzd-Sitek A, Guerrero-Garcia T, Liu J, Vesole DH, Castillo JJ.

Melphalan 140 mg/m2 or 200 mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.
Haematologica. 2018 Mar;103(3):514-521.
Auner HW, Iacobelli S, Sbianchi G, Knol-Bout C, Blaise D, Russell NH, Apperley JF, Pohlreich D, Browne PV, Kobbe G, Isaksson C, Lenhoff S, Scheid C, Touzeau C, Jantunen E, Anagnostopoulos A, Yakoub-Agha I, Tanase A, Schaap N, Wiktor-Jedrzejczak W, Krejci M, Schönland SO, Morris C, Garderet L, Kröger N.
In this retrospective study, 1719 patients with multiple myeloma received melphalan 200 mg/m2 as conditioning regimen for an autologous stem cell transplant, whereas 245 received 140 mg/m2, due to anticipated high risk of toxicities. Overall survival and progression-free survival were similar in the 2 groups. Multivariable subgroup analysis showed that melphalan 200 mg/m2 was better in patients transplanted in less than partial response, whereas the opposite was true in patients with VGPR or complete response.



Giampaolo Talamo, MD